Rep:Mod:XJB36170329

Conformational Analysis using Molecular Mechanics

The Hydrogenation of Cyclopentadiene Dimer

A cyclopentadiene dimer forms due to the cyclodimerisation between two cyclopentadiene. Only one endo dimer 2 is specially produced out of two expected dimers (endo 2 and exo 1). The cyclopentadiene dimer is further treated with short-time hydrogenation to give one of the dihydro derivatives 3 or 4 which after a prolonged hydrogenation the final tetrahydro derivative forms.

With the knowledge of favour towards the endo dimer, we can then evaluate the relative stabilities of two dimers in form of energy in order to decide whether the reaction is under thermodyamic or kinetic control. In similar way, 3/4 can be compared thus deciding the less strained one in a thermodynamic sense.

Figure 1. The dimerisation and hydrogenation products 1-4

Procedure The ChemBio3D suite enables drawing of molecules in better 2D view and then automatically generated the 3D geometries which allows further analysis in Avogadro but it is not excellent for directly optimizing due to longer time and sometimes crashing of structures. Avogadro on the other hand as a 3D molecular modelling program, allows us here optimize the geometry using MMFF94s force field (suitable for most organic molecules) and analyze the relative contributions of energy in terms of total bond stretching energy, total angle bending energy, total stretch-bending energy, total torsitional energy, total van der Waals energy and total electrostatic energy.

Results

Dimer 1

Dimer_1

Dimer 2

Dimer_2

Dimer 3

Dimer_3

Dimer 4

Dimer_4

Table 1. Relative Contributions of Minimized Energy

Property	Dimer 1 (kcal/mol)	Dimer 2 (kcal/mol)	Dimer 3 (kcal/mol)	Dimer 4(kcal/mol)
Total Bond Stretching Energy	3.54276	3.46959	3.30835	2.82268
Total Angle Bending Energy	30.77267	33.15574	30.86465	24.68612
Total Stretch-bending Energy	-0.8361	-2.07990	-1.92667	-1.65686
Total Out-of-plane Bending Energy	0.014904	0.20184	0.012340	0.00019
Total Torsional energy	-2.72949	-2.97281	0.05894	-0.37702
Total VAN DER WAALS Energy	12.80021	12.39890	13.28121	10.63528
Total Electrostatic energy	13.01369	14.21518	5.12099	5.14703
Total energy	55.37348	58.20978	50.72283	41.25751

Discussion From the table we can see that the exo dimer 1 has lower energy than the actual preferred endo dimer 2 thus decideing the fact that the dimerisation is under kinetics control. It can be seen clearly from the table that the major energy difference exists in angle-bending energy between dimer 1 and 2. The greater angle bending energy for 2 indicates the more bending structure of it because of the positions of hydrogen. Similarly the dihydro derivative 4 with lower energy indicates the relative high stability thermodynamically. The main contribution of higher energy in 3 comes from the total bending energy and the total VAN DER WAALS energy.

Atropisomerism in an Intermediate related to the Synthesis of Taxol

Atropisomers are stereoisomers due to restricted rotation about single bonds where the high steric demand involves. In the synthesis of an important ovarian cancer drug - Taxol, the carbonyl group can point either up or down in the key intermediate as 9 or 10. Our job is to assess the stabilities of the two atropisomers thus to decide the stereochemistry of the intermediate.

Figure 2. Atropisomers in an intermediate in the synthesis of Taxol

Procedure As above

Results

9

9

10

Dimer_2

Table 2. Relative Contributions of Minimized Energuy

Property	Intermediate 9 (kcal/mol)	Intermediate 10 (kcal/mol)
Total Bond Stretching energy	7.66002	7.66332
Total Angle Bending energy	28.28087	19.27628
Total Stretch-bending energy	-0.08421	-0.14576
Total Out-of-plane bending energy	0.85227	0.83234
Total Torsional energy	0.27595	2.73232
Total VAN DER WAALS energy	33.13805	35.26373
Total Electrostatic energy	0.30098	-0.26399
Total energy	70.54402	66.17233

Discussion

Figure 3. Four possible transition states

As the result, the atropisomer 9 is less stable than atropisomer 10 in terms of product energy in thermodynamic control. The formation is investigated to be made specificly through the endo-chair transition state (see four possible transition states in figure 3) with complete stereoinduction to produce stereochemically homogeneous bridgehead olefinic ketones. The subsequent fuctionalisation of alkene reacts very slowly, mainly because of the olefinic strain which can be calculated by force field programs. There is large strain existed in bridgehead olefins due to the twisting around double bond which decreases the HOMO-LUMO difference thus these kinds of alkenes should be highly thermodynamically stable and unreactive.

Spectroscopic Simulation using Quantum Mechanics

A practice molecule: Spectroscopy of an intermediate relayed to the synthesis of Taxol

The two derivatives of 9 and 10 are molecules 17 and 18 which are shown below. These two are the products of a tandem [3.3] sigmatropic shift-methylation sequence. 17 is completely transformed into its more thermodynamically favored conformational isomer 18 after being heated in tetrahydrofuran for several days. Their spectroscopic information has already been analysed in literature reports, our aim is to simulate the ¹H and ¹³C spectra for these two to verify the validity of the assignment of literature spectra.

Figure 4. Derivatives 17 and 18

Procedure The ChemBio3D suite again can be used to draw molecule 17 and then it is analysed using Avogadro to minimize the energy by optimizing the structure. The position of atoms can be manually altered in order to correct the orientations. The NMR of such molecule can be generated using Avogadro by setting correct theory, basis, solvation model, frequency, etc. The following involves submitting to the HPC system, which is a powerful system for Gaussian calculations and generates corresponding DOI reference. After loading into GaussView with setting the appropriate nucleus and TMS reference value, NMR can be generated. Thermodynamic values can also be given by downloading the log file.

Results

Molecule 17

17

Table 3. Relative Contributions of Minimized Energy

Property	Derivative 17 (kcal/mol)
Total Bond Stretching energy	15.49150
Total Angle Bending energy	32.54348
Total Stretch-bending energy	0.01666
Total Out -of-plane Bending energy	1.21223
Total Torsional energy	11.28734
Total VAN DER WAALS	51.63773
Total Electrostatic energy	-7.54637
Total energy	104.46170

Figure 5. ¹H NMR for molecule 17 DOI:10042/25758

Figure 6. ¹³C NMR for molecule 17

Table 4: ¹H NMR data for molecule 17

Shift (ppm)	Degeneracy	Atoms
5.6498472601	1.0000	24
3.4113292364	1.0000	40
2.7909488173	1.0000	37
2.7408334888	1.0000	39
2.6666433829	1.0000	38
2.6046646468	1.0000	36
2.5150020227	3.0000	51,33,29
2.1612673897	1.0000	27
2.0948517863	1.0000	53
2.0158715258	1.0000	25
1.9638852643	1.0000	30
1.8573933012	2.0000	34,24
1.7418806801	1.0000	26
1.6094444118	3.0000	40,41,42
1.2557013030	3.0000	43,44,45
1.0898032240	3.0000	37,38,39

Table 5: ¹³C NMR data for molecule 17

Shift (ppm)	Degeneracy	Atoms
217.0103164970	1.0000	5
144.9261459465	1.0000	20
126.3502941015	1.0000	1
89.3987609555	1.0000	8
59.8871687192	1.0000	3
54.7843515100	1.0000	4
54.4024622649	1.0000	17
52.3356913042	1.0000	21
49.1626548825	1.0000	9
45.3849147228	1.0000	16
43.7459305267	1.0000	22
40.0753748699	1.0000	13
37.3677794227	1.0000	12
33.9422863194	1.0000	2
29.8859157277	1.0000	10
28.2114918679	1.0000	18
27.9950561772	1.0000	7
26.5464667301	1.0000	22
23.0725425500	1.0000	19
21.7038311635	1.0000	6

Table 6. Thermodynamic Quantities

Property	Hartree (=2625.5KJ/mol)
Zero-point correction	0.467587
Thermal correction to Energy	0.489290
Thermal correction to Enthalpy	0.419799
Thermal correction to Gibbs Free Energy	13.28734
Sum of electronic and zero-point Energies	-1651.419969	E0 = Eelec + ZPE
Sum of electronic and thermal Energies	-1651.398267	E = E0 + Erot + Etrans
Sum of electronic and thermal Enthalpies	-1651.397323	H = E + RT
Sum of electronic and thermal Free Energies	-1651.467758	G = H - TS

Table 7: Literature values of NMR data for molecule 17

1H NMR shift (ppm)	Atom number	13C NMR shift (ppm)
5.21	1	221.49
3.00-2.70	6	148.72
2.70-2.35	4	120.90
2.20-1.70	6	74.61
1.58	1	60.53
1.50-1.20	3	51.30
1.10	3	50.94
1.07	3	45.53
1.03	3	43.28
		40.82
		38.73
		36.78
		35.47
		30.84
		30.00
		25.56
		25.35
		22.21
		21.39
		19.89

Discussion The comparison of the computational NMR and the literature assigned NMR is fairly good but there is a general larger chemical shift in both the hydrogen and carbon NMR. Different chemical shift can be caused by different solvents, different conformations, chemical shift corrections etc.

Analysis of the properties of the synthesised alkene epoxides

The asymmetric synthesis can prepare chiral compounds in an enantiomerically pure form which is very important in drug synthesis. The synthetic progress of alkene epoxidation involves two chiral catalysts, the Shi and the Jacobsen catalyst.

Figure 7. The Shi Fructose catalyst 21 and the Jacobsen catalyst 23

The crystal structures of the two catalysts above

Procedure The Conquest program is used to either sketch or enter the chemical formula to search the Cambridge crystal database (CCDC) for the pre-catalysts 21 and 23. The subsequent results can be analysed in Mercury where possible angle, distance, tortion, etc. can be measured conveniently.

Result

Shi Catalyst

9

Jacobsen Catalyst

9

The Shi catalyst is a ketone catalyst derived from fructose which is introduced by Yian Shi and coworkers at Colorado State University.

Figure 8. The measured C-O bond distances in the Shi catalyst

Discussion The bond lengths of the Shi catalyst are shown in above figure 8, the two anomeric centres has one C-O bond shorter and one longer than the normal bond length (the sum of covalent radii) which is about 143 pm. They are, reading from the graph, 146.0, 140.6, 143.0, 144.2 pm respectively. The inductive withdrawing effect of the carbonyl bond shorten the C-O bond where the donation of electrons from oxygen to the C-O anti-bonding orbital enlongate the bond length.

Jacobsen’s catalyst is a transition metal oxidation catalyst with a valent metal center and nitrogen and oxygen dononation to the center. The ligand binds to the center metal with four bonds which makes it tetradentate. To examine the catalyst from a side view, we can see that the molecule is almost planar (dihedral angle between aromatic rings about 170^o). In this way the axial chlorine and the ortho-position t-butyl groups can be clearly examined that the steric effect is more pronounced .

The calculated NMR properties of your products

Styrene and β-methyl styrene, two alkenes are chosen out of four. Their epoxidation products are monitored by their NMRs using GaussView to check the integrity of them.

Figure 9. The epoxidation of two alkenes

Results

Epoxide 1

1

Epoxide 2

2

Figure 10. ¹H NMR for epoxide 1 DOI:10042/25754

Figure 11. ¹³C NMR for epoxide 1

Table 8: ¹H NMR data for epoxide 1

Shift (ppm)	Degeneracy	Atoms
134.7139527718	1.0000	4
124.8117539229	1.0000	8
124.0891234461	1.0000	6
123.6824374418	2.0000	5,7
119.0114744421	1.0000	9
54.9822658473	1.0000	2
54.8505447181	1.0000	1

Table 9: ¹C NMR data for epoxide 1

Shift (ppm)	Degeneracy	Atoms
134.7139527718	1.0000	16,14,13,15
6.6067003260	1.0000	17
3.1841266572	1.0000	10
2.6461845145	2.0000	11
2.1223716068	1.0000	12

Figure 12. ¹H NMR for epoxide 2 DOI:10042/25757

Figure 13. ¹³C NMR for epoxide 2

Table 10: ¹H NMR data for epoxide 2

Shift (ppm)	Degeneracy	Atoms
6.8520619791	4.0000	19,17,16,18
6.6183560179	1.0000	20
2.9610261158	1.0000	11
2.3973330383	1.0000	12
1.2135656278	1.0000	14
1.1203497361	1.0000	13
0.2985045672	1.0000	15

Table 11: ¹C NMR data for epoxide 2

Shift (ppm)	Degeneracy	Atoms
134.5769728051	1.0000	5
124.7553016300	1.0000	9
124.0049015147	1.0000	7
123.5456535466	1.0000	6
123.4401128953	1.0000	8
119.2291872352	1.0000	10
63.1815663967	1.0000	2
61.3649395888	1.0000	1
20.8578387954	1.0000	4

Assigning the absolute configuration of the product

The ketone Shi catalyst is a very effective catalyst for the epoxidation of trans and trisubstituted olefins. The main reason for the enantioselectivity is steric effect. As the figure below showing the proposed transition states of the epoxidation, spiro A is supposed to be the major transition state whereas spiro B is the minor one due to the steric repulsion between the dimethyl ketal group and the substituent on the reacting alkene.

Figure 14. transiton states for epoxidation by Shi catalyst

Procedure The assignment of the absolute configuration of the two epoxides can be done in three different ways. The first one involves searching in the Reaxys which is a powerful tool to find rotation values of enantiomers in literature. The second method involves computation of chiroptical properties which are the optical rotation at a specified wavelength of light thus comparing with that in the literature. The third methodology is to compute the electronic circular dichroism (ECD) and the vibrational circular dichroism (VCD).

Results

Table 12 Literature Values for Optical Properties of Epoxides 1 and 2

	Epoxide 1(R,R)	Epoxide 1(S,S)	Epoxide 2(R,R)	Epoxide 2(S,S)
Concentration (g/100ml)	1	1	0.56	1
Enantiometric Excess (%)ee	99	99.8	89	91
Solvent	Chloroform	Chloroform	Chloroform	Chloroform
Optical Rotation Power	-19.5o	25.1o	-205.2o	343.6o
Wavelength (nm)	589	589	589	589
Temperature	22oC	25.1oC	20oC	24oC

Table 13 Computed Values for Optical Properties of Epoxides 1 and 2

	Epoxide 1(R,R)	Epoxide 1(S,S)	Epoxide 2(R,R)	Epoxide 2(S,S)
Optical rotation at 589nm	-29.17o	15.23o	-321.21o	238.21o

Discussion The two enationmers are generated again to predict the optical rotation of an asymmetric molecule using the Cambridge variation on the B3LYP density functional method. The wavelength of the incident light is at 589nm and reading [ALPHA](5890.0A) gives the estimated optical rotation for the built enantiomer. These values can be compared to the literature values.

The properties of the data which we concern should be both the sign of the angle and the order of magnitude. Both of the signs are correct and the magnitude though not completely numerically accurate, gives a generally good results compared to the literature values. The experimental data shall be compared further after the synthesis lab.

Results

Figure 15. The electronic circular dichroism (ECD) of epoxide 1

Figure 16. The electronic circular dichroism (ECD) of epoxide 2

Figure 17. The electronic circular dichroism (ECD) of epoxide 1

Figure 18. The electronic circular dichroism (ECD) of epoxide 2

Discussion Both of the ECD and the VCD can be computed nowadays but they are not currently available in the complementary synthesis lab. The ECD is derived from the UV/Vis spectrum recorded with polarised light, which is in fact not useful for those epoxides because no appropriate chromophore exists but it is an useful way to practice in order to apply this technique in future analysis. VCD is an excellent technique instead derived from IR but also not available in the department. Those enantiomers should be in mirror image of each other in those spetra so only one of them is computed.

Results The relative computed free energies of the transition states can also be used to check the enantiomeric assignment. The eight Shi catalyst epoxidation for β-methyl syrene transition states are chosen to be computed using the log file. The total free energy for each system is given and after converting unit from Hartree to KJ/mol (1 Hartree = 2625.5 KJ). the difference in free energies can be calculated to get the corresponding k value (G = RT - lnk). The results are given in the below table.

Table 14. Free energies of transition states and calculation of k value

	RR	SS
Free energy of TS1	-1343.02297	-1343.017942
Free energy of TS2	-1343.019233	-1343.015603
Free energy of TS3	-1343.029272	-1343.023766
Free energy of TS4	-1343.032443	-1343.024742
Average G	-1343.02598	-1343.020513
Difference in G (in Hartree)	-0.00546625
Difference in G (KJ/mol)	-14351.6373
Value of k	326.917

Discussion

In general, free energies of RR transition states are larger (-ve) than that of SS thus more energetically stable. The value of constant k reveals the excess RR enantiomer compared to SS.

Investigating the non-covalent interactions (NCI) in the active-site of the reaction transition state

Figure 19. NCI surface for β-methyl styrene (R,R) transition state

Non-covalent interactions (NCI) involves analysis of the properties of electron density. The colors indicates the interaction where blue = attractive, green = mildly attractive, yellow = mildly repulsive and red = strongly repulsive. Such interactions enables identification and characterisation of both stablization (hydrogen bonding in blue and dispersion in green) and destablization (steric repulsion in red).

Investigating the Electronic topology (QTAIM) in the active-site of the reaction transition state

Figure 20. Electronic topology for β-methyl styrene (R,R) transition state

The QTAIM is a complementary technique to the NCI. The NCI deals with weak interactions where the QTAIM focuses on much stronger bonding interations in the covalent regions of molecule.

Suggesting new candidates for investigations

The above techniques can be applied to numerous of molecules. Reaxys is used here again for another epoxide with optical rotary power >500 or <-500. By selecting one of the qualified epoxides, the below synthesis route can be also given by Reaxys where 1 is the reacting alkene and 2 and 3 are S and R enatiomers respectively. The alkene is shown available for lab use thus providing an alternative way to do the comparison of computational and experimental.

Figure 21. Synthesis route for new candidate

Table 15: Optical rotary power for the new candidate

	R	S
Concentration	0.03	N/A
Solvent	ethanol	N/A
ORP	853.9 deg	50 deg
Wavelength	324nm	589nm
Temperature	25o	N/A