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Rep:Mod:OaB6317

2013-02-08T16:19:11Z

Ob810: /* Spectroscopy of an intermediate in the synthesis of Taxol */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimerisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2a''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''3''' and '''4''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome. Molecules '''9''' and '''10''' both contain fused rings which results in their slow interconversion, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_MM2.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:18:35Z

Ob810: /* Mini Project: Simulation of spectroscopic data for a literature molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimerisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2a''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''3''' and '''4''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome. Molecules '''9''' and '''10''' both contain fused rings which results in their slow interconversion, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_MM2.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:15:26Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimerisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2a''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''3''' and '''4''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome. Molecules '''9''' and '''10''' both contain fused rings which results in their slow interconversion, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_MM2.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:13:24Z

Ob810: /* Taxol */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimerisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2a''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''3''' and '''4''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome. Molecules '''9''' and '''10''' both contain fused rings which results in their slow interconversion, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:09:56Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimerisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2a''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''3''' and '''4''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:08:06Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimerisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2a''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:04:22Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to produce dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T16:01:29Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:59:54Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref>name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra, but this discrepancy is very small. This task highlights how important computational NMR is, and the vital role it plays in confirming the synthesis of complex molecules.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:58:20Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 800 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px | thumb | Figure 14: methylene protons in '''20a''' and '''20b''']]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the correct isomer in literature<ref>name="Lit2"></ref>. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''' to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table 14. They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table 14 and 16 for isomers '''20a''' and '''20b'''.

{| class="wikitable" border="1"
|+ Table 14: Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ Table 15: IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+Table 16: IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra of '''20a''' and '''20b'''. Additionally, no IR data is provided in literature. Therefore it is not possible to draw relevant conclusions from the computational IR spectra and it is not an adequate tool in differentiating between the two isomers.

Conclusion

Overall, the structures of '''20a''' and '''20b''' have been correctly assigned in literature <ref name="Lit2"></ref>. There is a minor disagreement in the proton NMR spectra but this discrepancy is very small. This task highlights how important computational NMR is and

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:48:31Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference reported in literature. This is summarised in Table 12.

{| class="wikitable" border="1"
|+ Table 12: Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons or methyl protons as they were assigned as multiplets in literature <ref name="Lit2"></ref>

[[File:LIT_1_2_DATA_OB810.PNG| 400 px | Thumb | Table 13: Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 300 px]]

Table 13 indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:42:42Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI|10042/23175}} {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:42:08Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref>. In this report, I will examine the 13C NMR of both atropisomers of 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure 12), leading to a mixture of atropisomers '''20a''' and '''20b''' (Figure 13).

The regiochemistry of the NOC reaction is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Figure 12: Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by removing this planar geometry. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table 11. The different C atoms have been numbered in Figure 13 and the calculated chemical shifts have been assigned to each C atom. [[File:LIT_C_OB810.PNG | 300 px | thumb | Figure 13: Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table 11 : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure 13. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:32:17Z

Ob810: /* Spectroscopy of an intermediate in the synthesis of Taxol */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure 11). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ Figure 11: NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|400 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 400 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:29:40Z

Ob810: /* Mini Project: Simulation of spectroscopic data for a literature molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussian. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:22:32Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables 7 and 8. MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods, and considers through space interactions.

{| class="wikitable" border="1"
|+ Table 7: Energies of intermediates '''1a-4a''' and '''1b-4b''' using an MM2 force field
! Energy Iteration (kcal/mol) !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates '''1b-4b''', compared to '''1a-4a''' intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table 9.

{| class="wikitable" border="1"
|+ Table 9: Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for '''1a''' and '''3a''' are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversely, a small neighboring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

Furthermore, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table 10. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ Table 10: Angle of Attack for intermediates '''1a-4a''' from MOPAC calculations
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance effects. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:16:27Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond (Figure 9). Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the stereospecificity of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Figure 9: Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different intermediates and their corresponding second oxenium intermediates and reaction routes are provided in Figure 10.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Figure 10: Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative energy. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates '''1a-4a''' and '''1b-4b''' are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:12:45Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | center | thumb | Figure 8: Electrostatic Potential of '''12'''. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:12:11Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | thumb | Figure 8: Electrostatic Potential of 12. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:11:30Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | thumb | Figure 7: Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | thumb | Figure 8: Electrostatic Potential of 12. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:09:50Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Figure 5: Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Figure 6: Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (Figure 5) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each force field method were superimposed (Figure 6). It is noted that the MM2 force field placed the endo ring lower in energy than the MOPAC force field.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table 5.

{| class="wikitable" border="1"
|+ Table 5: MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations may be noted for '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''. The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered endo face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Hence, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure 7. The C=C vibrations are summarised in Table 6.

[[File:Molecule11_IR_OB810.PNG | 400 px | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ Table 6: IR analysis of '''12'''
! Vibration !! Frequency (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency than the endo C=C stretching frequency. This can be rationalised by the reduced electron density in the exo C=C bond. The frequencies for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

[[File:Molecule11_electro_OB810.PNG | 150 px | thumb | Figure 8: Electrostatic Potential of 12. ]]The electrostatic potential of '''12''' is given in Figure 8. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge and the red colour represents areas of positive charge.

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T15:00:11Z

Ob810: /* Taxol */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure 4)[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Figure 4: Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which leads to them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid being placed at bridgeheads in a ring system. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed lack of reactivity of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:53:07Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). [[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | 200 px | thumb | Figure 3: Hydrogenation of '''2a''' ]]

{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. However, despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure )[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which will result in them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed slow interconversion of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:50:03Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 </ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure )[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which will result in them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed slow interconversion of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:48:55Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px|thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 /<ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure )[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which will result in them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed slow interconversion of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:48:26Z

Ob810: /* Hydrogenation of Cyclopentadiene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a major isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of '''2a''' and '''2b''' from MM2 Forcefield
! Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact major isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of '''2a''' and '''2b'''.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions<ref> Organic Chemistry J. Clayden, N. Greeves, S. Warren and P. Wothers Oxford University Press(2001) p916-917 /<ref> between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (Figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (Figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products '''3''' and '''4''' using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in '''4''' is 124.7°, which is again closer to an optimal bond angle of 120° for an sp2 C. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure )[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which will result in them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed slow interconversion of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:39:03Z

Ob810: /* Taxol */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have very important uses in pharmaceuticals <ref>Agnew. Chem. Int., 48: 6498-6401</ref>. Atropisomers are conformers that due to steric hinderance or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Molecules '''9''' and '''10''' (Figure )[[File:Molecules9_and10_OB810.PNG | 250 px | thumb | Atropisomers '''9''' and '''10''' ]] are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation so that the 6 membered ring adopted a chair conformation, instead of a higher energy boat or twist boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

{| class="wikitable" border="1"
|+ Table 3: MM2 Energies for '''9''' and '''10'''
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ Table 4: MMFF94 Energies for '''9''' and '''10'''
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by 4.4104 kcal/mol and 7.1696 kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome in order for their conversion to proceed. Molecules '''9''' and '''10''' both contain fused rings which will result in them interconverting relatively slowly, with respect to cyclohexane, via the corresponding boat conformation.

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as an alkene is found in both structures at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes. This idea of hyperstable alkenes, further supports the observed slow interconversion of '''9''' and '''10'''.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:12:13Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of '''12'''
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:11:38Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI |0042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 21;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:10:13Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

[[File:Q3_RS_OB810.PNG | 150 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 150 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]] The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity <ref>J. Org. Chem., 1991, 56 (19), pp 5553–5556</ref>. Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI | 10042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 10;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The exo C=C has a lower stretching frequency the endo C=C stretching frequency, as a result of the reduced electron density in the endo C=C bond. The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T14:01:27Z

Ob810: /* Regioselective Addition of Dichlorocarbene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

[[File:Q3_RS_OB810.PNG | 200 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 200 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]]

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; in this case the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI | 10042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised below.

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch ||818 || 35 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 10;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|}

The wavenumbers for the C=C stretches are perhaps higher than expected. In order to improve the results, the structure of '''12''' could be optimised again to ensure that a minimum structure was obtained.
The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of electrophilic attack. The blue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T13:56:27Z

Ob810: /* Regioselective Addition of Dichlorocarbene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

[[File:Q3_RS_OB810.PNG | 200 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 200 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]]

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for <jmolFile text="12">Molecule11_OB810_OB810.mol</jmolFile>
|-
| Stretch || 0.6189
|-
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The heat of formation from the MOPAC/RM1 for <jmolFile text="12">OB810_molecule11_MOPAC3.mol</jmolFile> calculation was 22.82755 kcal/mol.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 force field. The calculation was performed using a DFT method with B3LYP functional and 6-31G(d,p) basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in below.

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G(d,p) basis set and was published to D-Space: {{DOI | 10042/23272}} The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 2 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| C-Cl stretch || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 10;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol> || 818 || 35
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

File:OB810 molecule11 MOPAC 3.mol

2013-02-08T13:49:21Z

Ob810:

Rep:Mod:OaB6317

2013-02-08T13:43:51Z

Ob810: /* Regioselective Addition of Dichlorocarbene to a diene */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the optimization of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most susceptible to electrophilic attack. The optimised structures of '''12''' from each forcefield method were superimposed. It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

[[File:Q3_RS_OB810.PNG | 200 px | thumb | Regioselective Addition of Dichlorocarbene]]
[[File:Q3_overlay_OB810.PNG | 200 px | thumb | Superimposed Image of '''12''' from MM2 and MOPAC forcefield]]

{| class="wikitable" border="1"
|+ MM2 Energy Interation (kcal/mol) for '''12'''
|-
| Stretch || 0.6189
|
| Bend || 4.7376
|-
| Stretch-Bend || 0.400
|-
| Torsion || 7.6591
|-
| Nom 1,4 VDW || -1.0674
|-
| 1,4-VDW || 5.7940
|-
| Dipole-Dipole || 0.1123
|-
| Total Energy || 17.8945
|}

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

File:Molecule11 OB810 MM2.mol

2013-02-08T13:43:40Z

Ob810:

File:Q3 overlay OB810.PNG

2013-02-08T13:35:13Z

Ob810:

File:Q3 RS OB810.PNG

2013-02-08T13:31:00Z

Ob810:

Rep:Mod:OaB6317

2013-02-08T13:25:50Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations ('''1a, 2a, 3a''' and '''4a''') are lower in energy than their corresponding intermediate oxenium cations ('''1b, 2b, 3b''' and '''4b'''). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates '''1a''' and '''3a''' are lower in energy than '''2a''' and '''4a'''. This trend can be explained by considering the neighboring group effect of the acetyl group of each intermediate. Hence, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for '''4a''', the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in '''1a''' and '''3a'''. Conversley, a small neighbouring group effect is observed for '''2a''' and '''4a''', as demonstrated by the larger distance between the carbonyl O and the anomeric center.

In addition, the angle of attack of the nucleophile was also by considered. For an SN1 reaction, the optimum angle of attack of the nucleophile is 107°, which corresponds to the Burgi Dunitz angle. The MOPAC structures for intermediates '''1a-4a''' were used to determine the angle of attack of the nucleophile on the anomeric centre. The results are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| '''1a''' || 105.9
|-
| '''2a''' || 154.3
|-
| '''3a''' || 106.2
|-
| '''4a''' || 152.9
|}

'''1a''' and '''3a''' exhibit bond angles closest to the ideal Burgi Dunitz angle, highlighting again the strong neighboring group effects present.

Lastly, the '''1b''' and '''3b''' intermediates have a lower energy compared to '''2b''' and '''4b''', as demonstrated from the MM2 and MOPAC calculations. '''1b''' and '''3b''' are more stable as they can be stabilised by resonance. Thus, to conclude, the primary route of glycosidation proceeds via intermediates '''1a''' and '''1b''' or '''3a''' and '''3b''', which both afford the 1,2-trans product.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T13:09:26Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
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|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
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<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
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|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
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The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates 1a, 1b, 3a and 3b are lower in energy than 2a, 2b, 4a and 4b. This observed trend can be explained by considering the neighboring group effect of the acetyl group. In order to do this, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 1.57 || 2.33 || 1.56 || 3.35
|-
|}

Apart for 4a, the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach. Furthermore, the shorter distances observed for 1a and 3a are in agreement with them having the lowest energies from the MM2 and MOPAC calculations. Therefore, there is a greater neighboring group interaction in 1a and 3a, as demonstrated by the distance between the carbonyl O and the anomeric center. Conversley, a small neighbouring group effect is observed for 2a and 4a.
The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

When the acetyl group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the acetyl group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer.
{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T13:01:54Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates. Additionally intermediates 1a, 1b, 3a and 3b are lower in energy than 2a, 2b, 4a and 4b. This observed trend can be explained by considering the neighboring group effect of the acetyl group. In order to do this, the distances between the carbonyl oxygen atom and the anomeric center in the pyranose ring were considered and the results are presented in Table .

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || || 2.32 || 3.35
|-
|}

Apart for 4a, the MOPAC distances are shorter than the MM2 distances. The shorter MOPAC distances can be rationalised by MOPACs ability to form and break bonds due to its quantum mechanical approach.
The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

When the acetyl group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the acetyl group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer.
{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T12:45:08Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate ('''B'''). The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 400 px | thumb | Glycosidation Reaction Scheme]]

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.

[[File:Reaction_Routes_OB810.PNG | 400 px | thumb | Different reaction routes for glycosidation]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T12:42:34Z

Ob810: /* Monosaccharide chemistry and the mechanism of glycosidation */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. When an acetyl group is placed on the C atom adjacent to the anomeric center, a high degree of stereoselectivity is observed. The orientation of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second oxenium intermediate. The nucleophile can either attack from the top or bottom face, forming the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

There are two configuration possibilities for the acetyl group (axial or equatorial) on the pyranose ring. Additionally, there are two conformational orientations for the carbonyl oxygen on the acetyl group; either on the top or bottom face of the oxenium cation. These four different orientations and their corresponding second oxenium intermediates are provided below.
[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 force field was applied to each intermediate to determine its relative enrgies. A MOPAC/PM6 force field was then applied to each intermediate. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and . MM2 and MOPAC are two different types of force field. An MM2 force field considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods.

{| class="wikitable" border="1"
|+ Energies of 8 intermediates using an MM2 force field
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for eight intermediates using a MOPAC/PM6 force field
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T12:01:22Z

Ob810: /* Spectroscopy of an intermediate in the synthesis of Taxol */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Figure ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted. The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

{| class="wikitable" border="1"
|+ NMR data for '''18'''
|-
| [[File:Taxol_NMR_OB810.svg|300 px | thumb | Predicted 13C NMR of '''18''']] || [[File:13C_NMR_TAXOL_OB810.PNG|300px| thumb| Tabulated chemical shifts for 13C NMR for both calculated and experimental]] ||[[File:Taxol_NMR_GRAPH_OB810.PNG| 300 px | thumb |Deviation from calculated and experimental 13C chemical shifts for '''18''']]
|-
|}

Overall, there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachment (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed. However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:52:48Z

Ob810: /* Mini Project: Simulation of spectroscopic data for a literature molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determining the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. These difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of a Taxol derivative ('''18''') and 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20''') were determined. The results obtained were compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR of '''18''' was predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G(d.p) basis set and a CPCM solvation field in benzene. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were used: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound <ref name="TaxolNMR">J. Am. Chem. Soc., 1990, 112 (1), pp 277–283</ref> (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that overall there is good agreement for the calculated and experimental chemical shifts. However, the predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:43:12Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determing the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of ... and .... were determined and compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR and 1H NMR of '''18''' were predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G basis set and a CPCM solvation field in benzene were used. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were evoked: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that there is good agreement for the calculated and experimental chemical shifts, apart for the carbon that is attached to the dithiane group. The predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20a'''
! Wavenumber (cm-1) !! Intensity
|-
| 1823|| 666
|-
| 1480 || 297
|-
| 1385 || 123
|-
| 1392 || 122
|-
| 1428 || 108
|-
|}

{| class="wikitable" border="1"
|+ IR Analysis for '''20b'''
!Wavenumber (cm-1) !! Intensity
|-
| 1822 || 668
|-
| 1478 || 304
|-
| 1383 || 139
|-
| 1392 || 119
|-
| 1871 || 108
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:33:40Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
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|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
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</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
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<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
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|-
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The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determing the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of ... and .... were determined and compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR and 1H NMR of '''18''' were predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G basis set and a CPCM solvation field in benzene were used. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were evoked: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that there is good agreement for the calculated and experimental chemical shifts, apart for the carbon that is attached to the dithiane group. The predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}}. {{DOI|10042/23174}} The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI|10042/23176}} The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI|10042/23195}}. {{DOI|10042/23194}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI|10042/23178}}. {{DOI|10042/23179}}. The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra. Additionally, no IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:27:38Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determing the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of ... and .... were determined and compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR and 1H NMR of '''18''' were predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G basis set and a CPCM solvation field in benzene were used. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were evoked: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that there is good agreement for the calculated and experimental chemical shifts, apart for the carbon that is attached to the dithiane group. The predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}} {{DOI | 10042/23174}}. The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}}. {{DOI | 10042/23176}} . The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI | 10042/23194}}. {{DOI|10042/23195}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref name="Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref name="Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI| 10042/23178}}. {{DOI| 10042/23179}} The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref name="Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra.
No IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:25:47Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determing the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of ... and .... were determined and compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR and 1H NMR of '''18''' were predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G basis set and a CPCM solvation field in benzene were used. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were evoked: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that there is good agreement for the calculated and experimental chemical shifts, apart for the carbon that is attached to the dithiane group. The predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}} {{DOI | 10042/23174}}. The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}} {{DOI | 10042/23176}} . The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature <ref name="Lit2"></ref> differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature <ref name="Lit2"></ref>. Unfortunately, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI | 10042/23194}} {{DOI|10042/23195}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

Table indicated that the chemical shifts for the protons on the -CH2 group have been incorrectly assigned to the wrong isomer in literature. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature <ref =name"Lit2"></ref> as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature <ref =name"Lit2"></ref> as 0.27 ppm. This is a somewhat small discrepancy, but nonetheless the correct assignment may prove useful for future studies.

Frequency Analysis

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI| 10042/23178}} {{DOI| 10042/23179}} The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for '''20a''' and '''20b''' are provided below.

''Low frequencies for '''20a'''''
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

''Low frequencies for '''20b'''''
<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in Table . They are very similar, which is in agreement with their observed ratio of 2.6:1 in literature<ref =name"Lit2"></ref>. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar and are provided below. The most intense stretching frequencies are given in Table .

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra.
No IR data is provided in literature.

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:18:30Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determing the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of ... and .... were determined and compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR and 1H NMR of '''18''' were predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G basis set and a CPCM solvation field in benzene were used. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were evoked: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that there is good agreement for the calculated and experimental chemical shifts, apart for the carbon that is attached to the dithiane group. The predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 </ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}} {{DOI | 10042/23174}}. The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}} {{DOI | 10042/23176}} . The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature. Unfortunatlye, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI | 10042/23194}} {{DOI|10042/23195}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

From Table it is clear that the chemical shifts for the protons on the -CH2 group have been assigned to the wrong isomer. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature as 0.27 ppm. This is a somewhat small discrepency in the reported literature, but the nonetheless the correct assignment may prove useful for future studies.

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI| 10042/23178}} {{DOI| 10042/23179}} The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for 20a and 20b are provided below.
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in table . They are very similar, which is in agreement of their observed ratio of 2.04:1 ref. No IR data is provided in literature. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar. The most intense stretching frequencies are given. There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra.

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

==References==

<references></references>

Rep:Mod:OaB6317

2013-02-08T11:17:56Z

Ob810: /* Literature Molecule */

===Hydrogenation of Cyclopentadiene===

The dimerisation of cyclcopentadiene ('''1''') to product dicyclopentadiene ('''2''') proceeds via a Diels Alder, 4πs +2πs, cycloaddition reaction (Figure 1). One molecule of '''1''' acts as the dienophile, and another as the diene. The stereochemistry of the reactants are maintained in the products and depending on the orientation of the dienophile, two different stereoisiomers can be formed; the endo-isomer ('''2a''') or the exo-isomer ('''2b'''). In '''2a''' the substituents on the dienophile are pointing towards the diene. Whereas, in '''2b''' the substituents are pointing away from the diene.

[[File:OB810_reaction_scheme.PNG | 200 px | center |thumb | Figure 1: Dimerisation of cyclopentadiene]]

The dimerisation of cyclopentadiene leads to the formation of a single isomer, '''2a''', indicating that the reaction must proceed under thermodynamic or kinetic control. The former is a reversible reaction and leads to the formation of the most stable product. The latter is an irreversible reaction and proceeds via the lowest energy pathway. Such reactions are performed rapidly at low temperature. In order to determine if the dimerisation of cyclopentadiene proceeds under thermodynamic or kinetic control, the relative energies and geometries of isomers '''2a''' and '''2b''' were examined.An MM2 forcefield was applied and the resulting energies are presented in Table 1.

{| class="wikitable" border="1"
|+ Table 1: Energies of 2a and 2b from MM2 Forcefield
| Molecule !! Image !! Minisimed Structure !! Energy kcal/mol !!
|-
| Endo Isomer ('''2a''') || [[File:OB810_ENDO.PNG | 150 px]] ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_ENDO.mol</uploadedFileContents>
</jmolApplet>
</jmol> || 33.9775
|-
| Exo Isomer (''''''2b) || [[File:OB810_EXO.PNG| 150 px]] || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 11;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>OB810_EXO.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|| 31.8765
|-
|}

From Table 1, it is noted that isomers '''2a''' and '''2b''' differ in energy by 2.1025 kcal/mol. Thus '''2b''' is the more stable isomer with a lower energy. However, experimentally it is found that '''2a''' is in fact the single isomer that is formed. Therefore, the dimierisation of cyclopentadiene proceeds under kinetic control. If the reaction was controlled thermodynaically, isomer '''2b'''would be the major isomer observed. The preference for the formation of '''2''' can be explained by considering the transitions states of 2 and 3.

Isomer '''2a''' is favoured due to the presence of secondary orbital interactions between the HOMO of the diene and the LUMO of the dienophile in the endo transition state (figure 2). These interactions do not lead to the formation of new bonds, but stabilise the transition state with respect to the the transition state of the exo isomer. Secondary orbital interactions are not possible in the exo transition state due to the orientation of the dienophile.

[[File:Transition_States_OB810_2.PNG | 200 px | center | thumb| Figure 2: Transition States for exo and endo addition]]

Hydrogenation of '''2a''' (figure 3) initially gives one of the dihydro derivatives '''3''' or '''4'''. Complete hydrogenation of both C=C bonds to give the tetrahydro derivative '''5''' is only observed after prolonged reaction time. The relative energies of '''4''' and '''5''' were examined. An MM2 forcefield was applied to both molecules. The results are summarised in Table 2.

[[File:Hydrogenation_Scheme_OB810.PNG | center | thumb | Figure 3: Hydrogenation of '''2a''' ]]
{| class="wikitable" border="1"
|+ Table 2: Energies of hydrogenation products of 2b using an MM2 forcefield
! Energy Term (kcal/mol) !! <jmolFile text="3">Molecule3_OB810.mol</jmolFile> !! <jmolFile text="4">Molecule4_OB810.mol</jmolFile> || Energy Difference (kcal/mol
|-
| Stretch || 1.2774 || 1.1293 || -0.0156
|-
| Bend || 19.8597 || 13.0149 || 6.8448
|-
| Stretch-Bend || -0.8344 || -0.5646 || -0.2698
|-
| Torsion || 10.8118 || 12.4125 || -1.6007
|-
|Non-1,4 VDW || -1.2242 || -1.4262 || -2.6504
|-
| 1,4-VDW || 5.6327 || 4.4406 || 1.1921
|-
| Dipole-Dipole || 0.1621 || 0.1410 || 0.0211
|-
| Total Energy || 35.6850 || 29.2475 || 6.4376
|}

Table 2 reveals that '''4''' is lower in energy than '''3''' by 6.4375 kcal/mol and is thus the more stable isomer. Therefore the hydrogenation of '''2a''' proceeds with the hydrogenation of C=C in the six membered ring, followed by the double bond in the five membered ring. This observation can be explained by considering the bending and torsional energy terms for '''3''' and '''4'''. Isomer '''3''' displays a larger bending term than '''4'''. This indicates that one or more of the bond angles in '''3''' must deviate significantly from optimal bond angles. In '''3''', the H(1)-C(2)-C(3) bond angle at the C=C is 127°, which is significantly different from an optimal bond angle of 120.0° for a sp2 C. The corresponding H(1)-C(2)-C(3) bond angle in '''4''' is 110.8°, which is closer to an optimal bond angle of 109.5° for a sp3 C. Additionally, the C=C bond angle in 4 is 124.7°, which is again closer to an optimal bond angle of 120°. On the other hand, '''4'''has a larger torsion term than '''3'''. This can be explained by considering the dihedral angles. In '''4''', the dihedral angle between H(4)-C(6)-C(7)-H(8) is. Whereas, for '''3''' a dihedral bond angle of is recorded. Despite processing a higher torsional energy term, '''4''' exhibits a lower stretching and bending energy terms. Thus rendering it more thermodynamically stable.

===Taxol===

Atropisomers have important uses in pharmaceuticals. ref chem review one. Atropisomers are conformers that due to steric or electronic reasons, interconvert slowly (half like > 1000s) and they may be isolated. Ref agnew chem 2005 117 5518. Molecules '''9''' and '''10''' (Figure ) are atropisomers and are key intermediates in the total synthesis of Taxol. Taxol is a chemotherapy drug which is used to treat patients with lung, ovarian and breast cancer. '''9''' and '''10''' differ in their orientation of the carbonyl group. In '''9''', the carbonyl points up relative to the ring and in '''10''' the carbonyl group points down relative to the ring. On standing, '''9''' and '''10''' isomerise between each other, leading to the accumulation of the more thermodynamic stable atropisomer. The relative energies of '''9''' and '''10''' were determined using an MM2 forcefield (Table 3). The minimum structures of '''9''' and '''10''' were improved by adjusting the conformation of the 6 membered ring so as it adopted a chair conformation, instead of a boat. The structures of '''9''' and '''10''' were also minimized using an MMFF94 forcefield (Table 4).

[[File:Molecules9_and10_OB810.PNG | 200 px | thumb | Atropisomers '''9''' and '''10''' ]]
The energies obtained from the MM2 and MMFF94 calculations indicate that isomer '''10''' adopts the most stable conformation by kcal/mol and kcal/mol. This implies that over time all of isomer '''9''' will covert to isomer '''10'''. However, this process is slow, indicating that there is a high energy barrier that must be overcome for their conversion to proceed. As shown in calculations above, both molecules '''9''' and '''10''' adopt a chair conformation. Closer examination of their structures reveals that they are mirror images of each other. Hence, you would expect them to interconvert relatively easily with reference to cyclohexane, via the corresponding boat conformation. However, molecules '''9''' and '''10''' both contain fused rings, resulting in the slow process of ring flipping, due to the high energy barrier.

{| class="wikitable" border="1"
|+ MM2
! Energy Iteration (kcal/mol) !! <jmolFile text="Isomer 9">molecule9_MM2_OB810.mol</jmolFile> !!<jmolFile text="Isomer 10">molecule10_MM2_OB810.mol</jmolFile>
|-
| Stretch|| 2.7074 || 2.61892.l
|-
| Bend ||14.7207 || 11.3402
|-
| Stretch-Bend || 0.2791 || 0.3430
|-
| Torsion || 19.1515 || 19.6778
|-
| Non 1,4 VDW || -1.7365 || -2.1700
|-
| 1,4 VDW || 13.7288 || 12.8752
|-
| Dipole/Dipole || -1.7570 || -2.0021
|-
| Total Energy || 47.0934 || 42.6830
|-
|}

{| class="wikitable" border="1"
|+ MMFF94
! !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile> !! <jmolFile text="Isomer 9">molecule9_MMFF94_OB810.mol</jmolFile>
|-60.
| Final Energy (kcal/mol) || 67.7335 || 60.5639
|-
|}

repear <ref name="one"> insert ref </ref>

Both isomers '''9''' and '''10''' show a lack of reactivity. This is unexpected as the location of the alkene in both structures is found at a bridgehead. Hence, it would be expected for such bridgehead alkenes to be highly reactive, and possible reactions would lead to the relief of strain around the alkene bond. Likewise, Bredt’s rule predict that alkenes avoid bridgeheads. Olefinic Strain <ref>J. Am. Chem. Soc., 1986, 108 (14), pp 3951–3960</ref>(OS) can explain the observed unreactivity of '''9''' and '''10'''. OS is the measure of strain around an alkene, compared to its parent hydrocarbon. Bridgehead alkenes have poorer π overlap and consequently a lowering of the HOMO-LUMO energy gap. Most alkenes process a positive OS but bridgehead alkenes have a negative OS, indicating that they are more stable than their parent hydrocarbons. Such alkenes are called ‘hyperstable stable alkenes.

===Regioselective Addition of Dichlorocarbene to a diene===

MOPAC

{| class="wikitable" border="1"
|+ caption
! !! Image !!
|-
| from MM2 calculation || [[File:Molecule11_OB810_MM2_2.mol]]
|-
| || cell
|}

odel: Untitled-1

Mopac Job: AUX RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08145 (< 0.10000) Heat of Formation = 22.82783 Kcal/Mol

MM2
retch: 0.6195
Bend: 4.7371
Stretch-Bend: 0.0399
Torsion: 7.6590
Non-1,4 VDW: -1.0672
1,4 VDW: 5.7938
Dipole/Dipole: 0.1123
Total Energy: 17.8945 kcal/mol
Calculation completed
------------------------------------

superimposed
Iteration 15: Minimization terminated normally because the error is less than the minimum error
Calculation completed
but in J-Mol
1 Cl(37)-Cl(12) 0.0699
1 C(33)-C(8) 0.1171
1 C(27)-C(2) 0.0908

====Regioselective Addition of Dichlorocarbene====

The addition of dichlorocarbene with 9-chloromethanonaphthalene ('''12''') (figure ) exhibits remarkable π selectivity and orbital controlled reactivity (refhttp://pubs.acs.org/doi/abs/10.1021%2Fjo00019a015). Dichlorocarbene adds to the endo face of the ring and the regioselectivity of the reaction may be explained by considering the energies of the two alkenes present in '''12'''. The geometry of '''12''' was optimised by using an MM2 force field method. A MOPAC/RM1 method was then applied to represent the oppimsation of the valence-electron molecular wavefunction. The valence-electron molecular wavefunction provides information about which site is the most suspceptibal to electrophilic attack. The optimised structures of '''12''' from each forcefield method were overlaid (figure ), It is noted that the MM2 forcefield placed the endo ring lower in energy than the MOPAC forcefield.

The molecular orbitals (MOs) of '''12''' were determined using the optimised structure from the MOPAC/RM1 forcefield. The calculation was performed using a DFT method with B3LYP functional and 6-31G basis set. The file can be found here. A selection of MOs in HOMO-LUMO region and their corresponding energies are provided in Table .

{| class="wikitable" border="1"
|+ MOs of diene
| MO || HOMO-1 || HOMO || LUMO || LUMO+1 || LUMO +2
|-
! Energy || -9.442 || -8.682 || 4.509 || 5.308 || 5.775
|-
| Image || [[File:Molecule11_HOMO1_OB810.PNG | 200 px]] || [[File:Molecule11_HOMO_OB810.PNG| 200 px]] || [[File:Molecule11_LUMO_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO1_OB810.PNG | 200 px]] || [[File:Molecule11_LUMO2_OB810.PNG | 200 px]]
|-
|}

The following observations are noted from the MOs of '''12'''. Firstly, the HOMO may be used to distinguish between the two alkene bonds in '''12'''; The endo alkene bond to Cl is more nucleophilic than the exo. Therefore, electrophilic attack proceeds on the more hindered face. Secondly, the MOPAC minimisation produced a conformation in which the distance between the the two alkene bonds and the central bridgehead carbon are of different distances. The length between the exo alkene and C brdigehead is 2.91677 Å. Whereas, the length between the endo alkene and C bridgehead is 3.08774 Å. The exo-C length is shorter due to an antiperiplanar stabilisation interaction of the exo π(HOMO-1) orbital and the Cl-C σ* (LUMO+1) orbital. This results in the stabilisation of C=C bond, which becomes less alkene like in properties (more electrophilic), and the destabilisation of Cl-C σ* orbital. Overall, the total energy of the molecule is lowered. Thus the electrophilic dichlorocarbene adds to the more nucleophilic C=C; the endo alkene. Thus, the endo π bond is lower in energy and more nucleophilic than the exo π bond.

The regioselectivity is further explained by considering the stretching frequencies of the C=C bonds. The IR spectrum of '''12''' was calculated using a B3LYP method and 6-31G basis set and was published to D-Space: The predicted IR spectrum of '''12''' was produced and is provided in Figure . The C=C vibrations are summarised in Table .

[[File:Molecule11_IR_OB810.PNG | 400 px | center | Thumb | Predicted IR spectrum of '''11''']]

{| class="wikitable" border="1"
|+ caption
! Vibration !! Wavenumber (cm-1) !! Intensity !! Image
|-
| exo C=C stretch|| 1784 || 2.0884 ||<jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 57;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
| endo C=C stretch || 1800 || 1.89295 || <jmol>
<jmolApplet>
<title>Vibration</title><color>white</color><size>200</size>
<script>frame 58;vectors 4;vectors scale 5.0;color vectors blue;vibration 10;</script><uploadedFileContents>Molecule11_OB810_FREQ.log</uploadedFileContents>
</jmolApplet>
</jmol>
|-
|}

The electrostatic potential of '''12''' is given in Figure. It shows that there is more of a negative charge on the endo alkene, compared to the exo alkene. And hence, illustrates the observed selectivity of elecrophilic attack. The ablue colour represent areas of negative charge. The red colour represents areas of positive charge.

[[File:Molecule11_electro_OB810.PNG | 200 px | center | thumb | Electrostatic Potential of 12. ]]

===Monosaccharide chemistry and the mechanism of glycosidation===

Glycosidation involves the loss of a leaving group at the anomeric center and the subsequent attack of the nucleophile to form the new glycosidc bond. Glycosidation is an SN1 reaction and proceeds via the formation of an oxenium ion. The stereochemistry of the C-OAc bond controls the stereochemistry of the new C-Nuc bond. This is due to the neighboring group effects of the acetyl group to form the second intermediate B. The nucleophile can either attack from the top or bottom face, to form the β-anomer or α-anomer respectfully. The aim here, is the examine the diastereospecifcally of this reaction.

[[File:Glycosidation_Scheme_ob810_2.PNG | 300 px]]

[[File:Reaction_Routes_OB810.PNG | 300 px]]

An MM2 forcefield considers only force constants. Whereas, a MOPAC/PM6 forcefield can make or break bonds in a structure, using quantum mechanical methods. The results for MM2 and MOPAC calculations for intermediates 1a-4a and 1b-4b are provided in Tables and .
{| class="wikitable" border="1"
|+ Energies of four conformations of oxonium cations
! Energy Iteration !! <jmolFile text="1a">MM2_1AA_OB810.mol</jmolFile> !!<jmolFile text="1b">MM2_TS1b_OB810.mol</jmolFile> !! <jmolFile text="2a">MM2_2a_OB810.mol</jmolFile> !! <jmolFile text="2b">MM2_TS2b_OB810.mol</jmolFile> !! <jmolFile text="3a">MM2_3AA_OB810.mol</jmolFile> !! <jmolFile text="3b">MM2_TS3b_OB810.mol</jmolFile> !!<jmolFile text="4a">MM2_4a_OB810.mol</jmolFile> !! <jmolFile text="4b">MM2_TS4b_OB810.mol</jmolFile>
|-
| Stretch || 2.5067 ||2.8805 || 2.409 ||2.7817 || 2.3591 || 1.8452 || 2.3916 || 1.8703
|-
| Bend ||10.8928 || 17.8047 || 11.3294 || 17.0506 || 9.9735 || 14.8299|| 8.8079 || 15.4973
|-
| Bend-Stretch || 0.9555 || 0.8841 || 0.9857 || 0.7749 || 0.9371 || 0.7393 || 0.8963 || 0.7111
|-
| Torsion || 2.4253 || 9.0966 || 1.4014 || 6.9748 || 1.2199 || 8.1941 ||0.8963 || 6.3485
|-
| Non 1,4 VDW || -0.0545 || -1.6201 || -1.8979 || -2.4974 ||-0.4989 || -2.6704 || -3.6719 || -4.2537
|-
| 1,4 vdw || 18.7789 || 19.6393 || 18.1688 || 19.0862 || 18.7930 || 17.4410 || 18.3025 || 17.2970
|-
| Charge Dipole || -17.3380 ||-3.7418|| -1.8366 || 5.6037 || -19.7797|| -11.5715 || 7.3526 || 5.9363
|-
| Dipoe-dipole || 7.7363 || -0.5904 || 5.7424 || 0.5255 || 7.4013 || -1.5408 || 4.7076 || 0.6121
|-
| Total Energy || 25.9028 || 44.3529 || 36.3009 || 50.3301 || 20.4054 || 27.2669 || 39.4196 || 44.0190
|}

{| class="wikitable" border="1"
|+ Energies for four conformations of oxonium cations from MOPAC/PM6 forcefield
! !! 1a || 2a || 3a || 4a || 1b || 2b || 3b || 4b
|-
|Heat of Formation kcal/mol || -87.87950 || -86.48559 || -90.51300 || -77.31197 || -67.91653 || -58.78601 || -91.64201 || -80.95964
|}

Table 12 demonstrates that the initial oxenium cations (1a, 2a, 3a and 4a) are lower in energy than their corresponding intermediate oxenium cations (1b, 2b, 3b and 4b). This difference in energy can be attributed to the strained conformations of intermediates 1b-2b, compared to 1a-4a intermediates.

When the OAc group is positioned in the equatorial position (1a and 2a), the nucelophile attacks from the top face, forming the α anomer. Conversely, when the OAc group is axial (3a and 4a), the nucleophile attacks from the bottom face, forming the β anomer. This neighboring group effect of the -OAc group can be examined by considering the distances between the carbonyl oxygen atom and the anomeric center in the glucose ring. This distances for intermediates 1a-4a are summarised in Table . It should be noted that distances calculated from the MM2 method will be longer than those from MOPAC, as MM2 cannot create new bonds. Therefore, only distances will be considered from the MOPAC calculations.

{| class="wikitable" border="1"
|+ Distance (Å) between the carbonyl O of the acetyl group and the anomeric C for MM2 and MOPAC/PM6 optimised structures
! Forcefield|| 1a || 2a || 3a || 4a
|-
! MM2 || 2.88 || 3.01||2.56 ||2.93
|-
!MOPAC || 2.33 || 1.60 || 2.32 || 3.35
|-
|}

The angle of attack of the nucleophile must also by considered. The optimum angle of attack of nucleophile for an SN1 reaction is 109.7°; the Burgi Dunitz angle. The angle of attack for intermediates 1a-4a from the MOPAC optimisation are provided in Table. The MOPAC calculations were used as it can form/break bonds.

{| class="wikitable" border="1"
|+ caption
! Intermediate !! Angle of Attack (°)
|-
| 1a || 105.9
|-
| 2a || 104.3
|-
| 3a || 106.2
|-
| 4a || 152.9
|}

Conformers 1a and 3a exhibit bond angles closest to the ideal Burgi Dunitz angle. They are more likely for form. Enforces the effect of neighbouring group effect. stabilise intermediate.

==Mini Project: Simulation of spectroscopic data for a literature molecule==

Introduction

The structural assignment of new complexes such as natural products still presents a significant challenge. NMR spectroscopy is one of the most powerful tools for determing the structures of complex molecules as it provides information on the chemical environment and the connectivity of the molecule. However, it is not uncommon for structures to be incorrectly assigned or spectra incorrectly interpreted. The difficulties encountered in assigning the spectrum of such challenging molecules has lead to the prediction of NMR chemical shifts by modern computational methods. In this report, the 13C NMR of ... and .... were determined and compared to experimental results to deduce if the correct molecules had been synthesised and if the NMR assignment was correct.

===Spectroscopy of an intermediate in the synthesis of Taxol===

Molecule '''18''' is a derivative of molecule '''10''' and a key intermediate in the synthesis of Taxol. The 13C NMR and 1H NMR of '''18''' were predicted using computational software and the results were compared to literature values to determine if the 13C NMR spectrum had been correctly assigned and interpreted.

The structure of '''18''' was minimised using an MM2 forcefield. The output file for the MM2 minimisation of '''10''' was used as the starting point of the calculation, due to the structure similarities between the two compounds. The results for the MM2 minimisation of 18 can be found here. <jmolFile text="here">Taxol_part2_MM2_OB810.mol</jmolFile> The energy was determined to be 65.1649 kcal/mol. The structure of '''18''' was further minimised using a DFT method, B3LYP functional,6-31G basis set and a CPCM solvation field in benzene were used. The optimisation file was published to D-Space: {{DOI|/10042/23070}} The NMR spectrum was calculated using Gaussion. The following key words were evoked: mpw1pw91/6-31G(d,p)NMR SCRF=(CPCM,solvent=benzene) where the basis set was 6-31G(d,p). The NMR calculation was published to D-Space: {{DOI|10042/23071}} and the predicted 13C NMR spectrum was viewed in Gaussview. The calculated 13C chemical shifts were compared to the experimental values obtained for the pure compound (Table ). The difference in chemical shift between the calculated and experimental chemical shifts were plotted (Figure ). The average deviation in chemical shift was determined to be 1.91 ppm,the standard deviation was calculated to be 2.62 ppm and the maximum deviation observed was 10.04 ppm.

[[File:Taxol_NMR_OB810.svg|600 px | center | Predicted 13C NMR of '''18''']]

[[File:Taxol_NMR_GRAPH_OB810.PNG| 450 px | Deviation from calculated and experimental 13C chemical shifts for '''18''']]

[[File:13C_NMR_TAXOL_OB810.PNG|400px| Tabulated chemical shifts for 13C NMR for both calculated and experimental]]

From Figure , it is observed that there is good agreement for the calculated and experimental chemical shifts, apart for the carbon that is attached to the dithiane group. The predicted 13C chemical shift for site of sulphur attachement (C-6) was approximately 10 ppm too high. This observed deviation is due to Spin-Orbit (SO) coupling, which increases due to heavy atom effect. reference needed However, there is good agreement for the other carbon atoms present in '''18''', thus indicating that the correct isomer has been identified in literature and the spectrum has been assigned accordingly.

Lit values http://pubs.acs.org/doi/abs/10.1021/ja00157a043

===Literature Molecule===

The synthesis of spiro isoxazolines can be achieved using nitrile oxide cycloaddition (NOC) reactions on exocyclic methylene groups <ref name="Lit">Australian Journal of Chemistry., 2009, 63(3) 445–451</ref> (Figure ). In this report, I will examine the 13C NMR of both atropisomers 6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-ene-7,9-dione ('''20'''). '''20''' is readily synthesised from the NOC reaction of 3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazolidine-2,4-dione ('''19''') <ref name="Lit2">J. Org. Chem., 2011, 76 (16), pp 6946–6950</ref> (Figure ), leading to a mixture of atropisomers '''20a''' and '''20b'''.

The regiochemistry of the cycloaddition is controlled by steric effects and the oxygen of the nitrile has a greater dendency to add to the disubstituted end of the dipolarophile, regardless of the polarity of the dipolarophile <ref>Org. Biomol. Chem., 2012,10, 4759-4766 /ref>. Additionally, NOC reactions displays high levels of facial selectivity <ref name ="Lit"></ref>, which is determined by atropisomerism along the N-aryl bond. Thus NOC reactions can be successfully applied to give the desired isomer.

[[File:LIT_reactionscheme_OB810.PNG | 300 px | thumb | Reaction Scheme for formation of '''20a''' and '''20b''']]

Structure Minimisation of '''20a''' and '''20b'''

The structure of <jmolFile text="2Oa">MM2_Lit1_OB810.mol</jmolFile> and <jmolFile text="20b">MM2_Lit2_OB810.mol</jmolFile> were minimised using an MM2 forcefield. The energies was determined to be 38.5920 and 45.2149 kcal/mol. The structures were further minimised using a DFT method, B3LYP functional and 6-31G(d,p) basis set. The optimisation files were published to D-Space: {{DOI |10042/23173}} {{DOI | 10042/23174}}. The DFT calculations forced the phenyl ring and 5 membered ring containing the N=C bond to be co planar in both '''20a''' and '''20b'''. Further optimisations of '''20a''' and '''20b''' were attempted by making these two rings no longer planar. However, they didn't lead to a lowering in energy of either '''20a''' or '''20b'''. Therefore, the optimised structures from the first DFT calculations were used for subsequent calculations.

13C NMR Analysis

The NMR chemical shifts for '''20a''' and '''20b''' were calculated with GIAO options, using the Mpw1pw91/6-31G(d,p) DFT method and a chloroform solvent method. The NMR calculations were published to D-Space: {{DOI| 10042/23175}} {{DOI | 10042/23176}} . The predicted 13C NMR spectra and chemical shifts are given in Table. The different C atoms have been numbered in Figure and the calculated chemical shifts have been assigned to each C atom (Table ). [[File:LIT_C_OB810.PNG | 300 px | thumb | Different Carbon environments in '''20a''' and '''20b''']]

{| class="wikitable" border="1"
|+Table : Calculated 13C NMR spectra and chemical shifts for '''20a''' and '''20b'''
! Isomer '''20a''' !! Isomer '''20b'''
|-
| [[File:Lit1_13C_NMR_OB810.svg| 350 px | thumb | Predicted 13C NMR of '''20a''']] || [[File:LIT2_13C_NMR_OB810.svg | 350 px | thumb | Predicted 13C NMR of '''20b''']]

|-
| [[File:Lit1_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20a''']] || [[File:Lit2_13C_NMR_DATA_OB810_2.PNG | 400 px | thumb | Comparison of calculated and experimental 13C chemical shifts for '''20B''']]
|-
| [[File:Lit1_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20a''']]||[[File:Lit2_NMR_CHART_OB810.PNG | 350 px | thumb | A bar chart to show the deviations in calculated and experimental 13C chemical shift for '''20b''']]
|-
|}

For isomer '''20a''', the average deviation was 1.34 ppm, the maximum deviation observed was 4.66 ppm and the standard deviation was 1.55ppm. For isomer '''20b''', the average deviation was 1.06 ppm, the maximum deviation was 3.38 ppm and the standard deviation was 1.04 ppm. Overall, the predicted 13C NMR data are in relatively good agreement with the experimental<ref name="Lit2"></ref> data, suggesting that the structures of '''20a''' and '''20b''' have been correctly assigned.

However, it should be highlighted that there is an absence of peaks in the experimental <ref name="Lit2"></ref> data. The absence of some signals is most probably due to the rapid rotations that that C atoms undergo. This results in them experiencing the same chemical environments and ultimately leading to one signal in the 13C NMR spectrum. No signal was observed for the quaternary carbons C-13 and C-15 in the spectra for '''20a''' and '''20b''' respectfully. This is most likely due to the low abundance of 13C, which often results in signals for quaternary carbons not being observed. Furthermore, no signal was observed around 124 ppm in either spectra of '''20a''' for '''20b'''. This peak corresponds to the C-7 in Figure. Additionally, no peak for C-11 was observed in the spectrum for '''20b''' either.

In order to use the NMR data to differentiate between '''20a''' and '''20b''', a common C environment for the isomers should be compared. The chemical shift difference should be large enough ( approximately 5 ppm) so that the difference can be attributed to the different chemical environmental experienced by the C atoms, and not due to an error range. Thus C-12 and C-16 of '''20a''' were compared with C-16 and C-12 of '''20b'''. The difference in chemical shift of these two environments were determined and compared to the difference in chemical shifts reported in literature. This is summarised in Table .

{| class="wikitable" border="1"
|+ Comparison of 13C chemical shift between isomers '''20a''' and '''20b'''
|-
| [[File:13C_Compare_OB810.PNG | 400 px | thumb | Comparison of Chemical Shift between '''20a''' and '''20b''' for both calculated and experimental results]]
|}

C-16 of '''20a''' and C-12 of '''20b''', differ by 3.13 ppm. The corresponding peaks in literature differ by 2.90 ppm. Likewise, C-12 of '''20a''' and C-16 of '''20b''' differ by 1.10 ppm. The corresponding peaks in literature differ by 0.9 ppm. Hence, it can be concluded that the difference in chemical shift of C-12 and C-16 from the calculated results and that from literature, are the same and the peaks have been correctly assigned. Nevertheless, the chemical shifts of C-16 and C-12 are not diagnostic of the two isomers, as their corresponding chemical shifts do not differ by a significant amount. Consequently, they do not allow either isomer to be assigned with absolute confidence. Ideally, the difference in chemical shift between C-13 and C-15 of '''20a''' and '''20b''' would also be compared to literature. However, this data was not provided in literature.

Additionally, it might be expected for C-4 to show a difference in chemical shifts between the two isomers, as a result of the orientation of the N-aryl ring. Computational data shows that they differ by 1.47 ppm, which is in direct correlation to a difference of 1.60 ppm reported in literature. Unfortunatlye, the chemical shift difference falls within the error range and consequently cannot be used as to distinguish between the two isomers.

nJHH coupling constants

The nJH-H coupling constants for '''20a''' and '''20b''' were calculated. The following key words were used; NMR(mixed,spinspin) and a 6-31G(d,p) basis set was used. The results were published to D-Space; {{DOI | 10042/23194}} {{DOI|10042/23195}}. The coupling constants and chemical shifts for the -CH2 group for each isomer were compared to literature values. The coupling constants and chemical shifts weren't compared for the aromatic protons as they were assigned as multiplets in literature. Likewise, the methyl protons weren't compared either.

[[File:LIT_1_2_DATA_OB810.PNG| Thumb | Table Comparison of 1H coupling constants for '''20a''' and '''20b''']]

[[File:Lit_protons_OB810.PNG | 200 px]]

From Table it is clear that the chemical shifts for the protons on the -CH2 group have been assigned to the wrong isomer. This can be deduced by considering the difference in chemical shift between H1 and H2 and H1' and H2'. The difference between H1 and H2 is 0.23 ppm, but it is reported in literature as 0.71 ppm. Similarly, the difference between H1' and H2' is 0.66 ppm but is reported in literature as 0.27 ppm. This is a somewhat small discrepency in the reported literature, but the nonetheless the correct assignment may prove useful for future studies.

A frequency analysis was performed on '''20a''' and '''20b''', to determine that a minimum structure had been obtained and not a transition state. The frequency files were published to D-Space: {{DOI| 10042/23178}} {{DOI| 10042/23179}} The low frequencies for both isomers fall within plus/minus 15, thus confirming that the structures have been successfully minimised. The low frequencies for 20a and 20b are provided below.
<PRE> Low frequencies --- -4.7179 -0.0005 -0.0001 0.0004 2.0524 2.7908
Low frequencies --- 16.8959 24.5781 34.5851
</PRE>

<pre> Low frequencies --- -7.4897 -4.6924 -0.0009 -0.0006 -0.0002 2.7869
Low frequencies --- 18.2270 25.8063 34.1661
</pre>

The energies of '''20a''' and '''20b''' are provided in table . They are very similar, which is in agreement of their observed ratio of 2.04:1 ref. No IR data is provided in literature. Equally, the IR spectrum of '''20a''' and '''20b''' are significantly similar. The most intense stretching frequencies are given. There is insufficient data to draw relevant conclusions regarding the IR spectra. And it is not a adequate tool in differentiating between the two isomers. Therefore it is not possible to draw relevant conclusions from the computational IR spectra.

{| class="wikitable" border="1"
|+ Energies of 20a and 20b from OPT FREQ analysis
! Isomer !! Energy (a.u.) !! Energy(kcal/mol) !! IR spectrum
|-
| <jmolFile text="Isomer 20a">Lit_1_opt_freq_OB810.log</jmolFile>|| -1163.52927755 || -730114.6217 || [[File:Lit1_IR_OB810.PNG | 250 px | thumb | Predicted IR spectrum of '''20a''']]
|-
| <jmolFile text="Isomer 20b">Lit2_opt_freq_OB810.log</jmolFile> || -1163.53066864 || -730115.4946 || [[File:Lit2_IR_OB810.PNG| 250 px | thumb | Predicted IR spectrum of '''20b''']]
|}

==References==

<references></references>