Rep:Mod:TW1C

Tingmang Wu's 1C Report

Part 1

The Hydrogenation of Cyclopentadiene Dimer

Scheme 1:Reaction Scheme for the Dimerisation

As shown on Scheme 1,at room temperature, it could be predicted that cyclopentadiene could undergo dimerisation rapaidly giving two possible dimers which are endo and exo. In fact, only one of the dimers will be formed, which is the endo. In order to investigate the reason that endo dimer is preferred, two dimers (Molecules 1 and 2) were drawn in ChemDraw with geometries optimised by Avogadro. Energy minima were worked out using the MMF94s force field and conjugate gradients algorithm. The hydrogenation of the endo dimer afford Molecules 3 and 4. Same optimisations as described above were also applied to molecule 3 and 4. The results were summarized in table 1.

Table 1: Energy minima after optimizations

Molecules	1 (kcal/mol)	2 (kcal/mol)	3 (kcal/mol)	4 (kcal/mol)
Geometries	1 55.373744.mol	2_58.19070.mol	3_50.44579.mol	4_41.25751.mol
Total Bond Stretching Energy	3.54155	3.46890	3.30628	2.82471
Total Angle Bending Energy	30.77441	33.18922	31.97995	24.68561
Total Stretch-Bending Energy	-2.04053	-2.08234	-2.10217	-1.65772
Total Torsional Energy	-2.73115	-2.94945	-1.51294	-0.37796
Total Out-of-Plane Bending Energy	0.01486	0.02193	0.01266	0.00027
Total VAN DER WAALS Energy	12.80053	12.35804	13.64239	10.63555
Total Electrostatic Energy	13.01379	14.18440	5.11961	5.14704
Total Energy	55.37346	58.19070	50.44579	41.25751

Referring to table 1, the endo(Dimer 2) has a greater total energy than the exo(Dimer 1), which indicates that the endo is thermodynamically less stable than the exo. The greater total angle bending energy of endo reveals that its structure is more bending than that of the exo, which explains its angle measured is more deviated from ordinary sp² carbon angle(120^o ) and sp³ carbon angle(109.4^o ) compared to those of the exo. However, cyclopentadiene dimerises giving specifically the endo dimer 2 rather than the exo dimer 1, therefore, the reaction is strictly kinetically controlled that affords less thermodynamically stable endo dimer according to Hammond postulate.

In comparison, Molecule 4 is more thermodynamically stable than Molecule 3, which mainly attributes to lower total angle bending energy. By looking at the measured angle, the bending angles of Molecule 3 have larger deviation from ordinary sp² carbon angle(120^o ) and sp³ carbon angle(109.4^o ) than those of Molecule 4. Consequently, under thermodynamic control, the major product of Dimer 2 hydrogenation is Molecule 4.

Atropisomerism in an Intermediate related to the Synthesis of Taxol

Scheme 2:Molecules 9 and 10

Referring to Paquette , Molecule 9 and 10 are two key intermediates in synthesis of Taxol. These two molecules are antropisomers, which only differ in orientation of the carbonyl group, and they can be converted onto each other.

In order to investigate which antropisomer is more stable, two molecules were drawn in ChemDraw with geometries optimised by Avogadro. Energy minima were worked out using the MMF94s force field and conjugate gradients algorithm. It was reported that alkene reacted abnormally slowly during subsequent functionalisation, hence suggested by Maier et al, hydrogenated products of Molecule 9 and 10 (Molecule 9* and 10*) were drawn and optimized with methods shown above. The results were summarized as Table 2.

Table 1: Energy minima of Molecule 9 and 10 and their hydrogenated products 9* and 10*

Molecules	9 (kcal/mol)	10 (kcal/mol)	9* (kcal/mol)	10* (kcal/mol)
Geometries	No.9_67.72289_kcal.mol	No.10_61.03681_kcal.mol	No.9H.mol	No.10H.mol
Total Bond Stretching Energy	7.15853	7.13838	7.42181	6.49398
Total Angle Bending Energy	23.08453	22.41210	28.19522	21.46097
Total Stretch-Bending Energy	-0.29174	-0.24364	0.15451	0.21131
Total Torsional Energy	3.45643	-1.90152	8.53543	12.52149
Total Out-of-Plane Bending Energy	0.98053	0.67824	0.28534	0.18833
Total VAN DER WAALS Energy	33.10543	32.12839	34.10091	32.30608
Total Electrostatic Energy	0.22844	0.82482	0.00000	0.00000
Total Energy	67.72216	61.03678	78.69321	73.18217

According to the Table 2, the Molecule 10 has a lower total energy than Molecule 9, hence Molecule 10 is more stable. The relative stability mainly attributes to the total torsional energy, which means that Molecule 9 has more torsional strain, possibly due to the clash between between methyl group and carbonyl group.

On the other hand, by comparing Molecule 9 and 10 to their hydrogenated products 9* and 10* respectively, it could be obtained that both of the hydrogenated products have higher total energies, mainly attributes to increase in total angle bending energies or total torsional energies. By invoking the concept of a "hyperstable alkene", the alkenes are stabilized when the double bonds are at the bridgehead location, hence are more thermodynamically stable than other isomers, In other words, they are remarkably inert. The bridgehead alkene gives the hyperstability which decreases the energy from trans-annular interactions of its hydrogenated product, which is a saturated alkane. Again, the total energy of the alkenes are low, therefore hydrogenation are unfavourable.

Spectroscopic Simulation using Quantum Mechanics

Scheme 3 Molecules 17 and 18

Molecule 17 (Scheme 3) were drawn and optimized by Avogadro with energy minimized. The geometry at the denisty functional level was calculated using Gaussian. 13C and 1H NMR spectra were simulated under B3LYP theory and 6-31G(d,p) basis, with chloroform as the solvent (Figure 1 and 2) (DOI:10042/27494 ). The chemical shifts of two spectra were summarized in Table 3 and 4.

Figure 1 Predicted ¹³C NMR of molecule 17

Table 3: 13C NMR shifts for Molecule 17

Shift (ppm)	Degeneracy	Atoms
216.3934000000	1.0000	5
150.6715000000	1.0000	8
118.6185000000	1.0000	9
90.7563000000	1.0000	12
58.7623000000	1.0000	7
55.8272000000	1.0000	11
54.6872000000	1.0000	3
51.2235000000	1.0000	21
48.7909000000	1.0000	13
47.9213000000	1.0000	4
45.8486000000	1.0000	19
44.5531000000	1.0000	18
39.5022000000	1.0000	14
32.4960000000	1.0000	2
30.6104000000	1.0000	10
27.3032000000	1.0000	1
26.7638000000	1.0000	22
25.2232000000	1.0000	15
19.8853000000	1.0000	20
19.5205000000	1.0000	23

Figure 2 Predicted ¹H NMR of molecule 17

Table 4: 1H NMR shifts for Molecule 17

Shift (ppm)	Degeneracy	Atoms
5.3625000000	1.0000	31
3.2847000000	1.0000	44
3.0881000000	3.0000	43,42,41
2.8848000000	1.0000	24
2.7547000000	1.0000	32
2.6387500000	2.0000	34,30
2.4369000000	2.0000	29,52
2.3573000000	1.0000	27
2.1986250000	4.0000	35,25,33,28
1.9938000000	1.0000	36
1.8915000000	1.0000	39
1.7219000000	1.0000	38
1.5645666667	3.0000	40,26,49
1.2564500000	2.0000	45,37
1.1486000000	1.0000	46
0.8984000000	2.0000	50,51
0.8264500000	2.0000	48,53
0.7628000000	1.0000	47

Comparing to the literature value , the predicted ¹H NMR spectrum gives higher shifts, especially for the alkene proton 31. It could be concluded that the simulated proton NMR spectrum did not perfectly match with the experimental spectrum.

A bar chart was plotted to compare the difference of shifts between predicted and experimental ¹³C spectra by Excel.(Figure 3)

Figure 3 Chemical shifts difference between predicted and experimental ¹³C NMR spectra of molecule 17

Referring to Figure 6, it can be seen that the predicted spectrum generally matches with the experimental spectrum, but most of the shifts are slightly higher in ppm. The difference between shifts may be attributed to the use of different solvents. Also, spin-coupling errors of carbon coupling to other heavy atoms like sulphur should not be ignored. For carbon-sulphur bonds, the shifts are supposed to be corrected by -3 ppm which is approximately same as the correction of carbon-chloride bonds,due to nearly equal in molecular weight.

Part 2: Analysis of the properties of the synthesised alkene epoxides

Scheme 4. 21 Jacobsen and 24 Shi's catalyst

the Jacobsen and shi's Catalyst

Jacobsen and shi's catalysts (Scheme 4) were used to promote asymmetric epoxidation of alkenes. The Conquest was used to search for the crystal structure of these catalysts in Cambridge Crystal Database (CCDC). Also, Mercury program was introduced to analyze those crystal structures. Two crystal structures were shown as following .

Crystal structure of Shi and Jacobsen catalyst

21Jacobsen catalyst	23Shi's catalyst
Jacobsen structure	Shi's structure

The presence of anomeric centres (carbon centres connecting to two oxygen) in Shi's catalyst should be noted. At each anomeric centre, one of the C-O bond is shorter than the average C-O bond length (142 pm),whilst the other one is longer.(see Figure 4). This is due to the lone pair electrons donation from one of the oxygen to the C-O σ ^* orbital, which shortens the carbon oxygen bond between the oxygen that has donated the lone pair electrons and the carbon, lengthening the other carbon oxygen bond whose electron density in the σ ^* anti-bonding orbital increases.

As for Jacobsen catalyst, four distances between two closely distributed hydrogen atoms on two tertiary butyl groups were measured as shown on Crystal structure of Shi and Jacobsen catalyst. All the values of those interaction were compared to the van der Waals distance for hydrogen (2.40 Å), . It could be found the interactions between all four pairs of hydrogen atoms are attractive. Therefore, during alkene epoxidation, these interactions prevents alkene from approaching to the manganese centre from tertiary butyl side, ensuring that alkenes could be stereoselectively epoxidized.

The Calculated NMR Properties of the Epoxides

Scheme 5. Epoxidations of trans-stilbene and 1,2-dihydronaphthalene

Two alkenes (trans-stilbene and 1,2-dihydronaphthalene) were chosen to be epoxidized, each giving two alkene oxides enantiomers (see Scheme 5). Each products were optimized by Avogadro with energy minimized (Optimized Alkene Oxides). The geometries of R,R-trans-stilbene oxide and R,S-dihydronaphthalene oxide at the denisty functional level were calculated using Gaussian. 13C and 1H NMR spectra were simulated under B3LYP theory and 6-31G(d,p) basis, with chloroform as the solvent(Figure 4 to 7) (DOI:10042/27496 and DOI:10042/27497 ). The chemical shifts of four spectra were summarized in Table 5 to 8.

Optimized Alkene Oxides

R,R-trans-stilbene oxide	S,S-trans-stilbene oxide	R,S-Dihydronaphthalene oxide	S,R-Dihydronaphthalene oxide
R,R-Stilbene_Oxide.mol	S,S-Stilbene_Oxide.mol	R,S-Dihydronaphthalene_oxide.mol	S,R-Dihydronaphthalene_oxide.mol

Figure 4 Predicted ¹³C NMR of trans-stilbene oxide

Table 5: 13C NMR shifts of trans-stilbene oxide

Shift (ppm)	Degeneracy	Atoms
134.0871000000	2.0000	5,9
124.2190000000	2.0000	3,13
123.5175000000	2.0000	1,11
123.2128500000	2.0000	12,2
123.0773500000	2.0000	10,6
118.2643500000	2.0000	14,4
66.4246500000	2.0000	7,8

Figure 5 Predicted ¹H NMR of trans-stilbene oxide

Table 6: 1H NMR shifts of trans-stilbene oxide

Shift (ppm)	Degeneracy	Atoms
7.5704000000	2.0000	18,26
7.4791750000	8.0000	20,23,16,24,17,25,19,27
3.5380500000	2.0000	21,22

Figure 6 Predicted ¹³C NMR of dihydronapthalene oxide

Table 7: 13C NMR shifts of dihydronapthalene oxide oxide

Shift (ppm)	Degeneracy	Atoms
135.3878000000	1.0000	4
130.3706000000	1.0000	5
126.6665000000	1.0000	6
123.7911000000	1.0000	2
123.5334000000	1.0000	3
121.7442000000	1.0000	1
52.8212000000	1.0000	10
52.1925000000	1.0000	7
30.1803000000	1.0000	8
29.0635000000	1.0000	9

Figure 7 Predicted ¹H NMR of dihydronapthalene oxide

Table 8: 13C NMR shifts of dihydronapthalene oxide oxide

Shift (ppm)	Degeneracy	Atoms
7.6151000000	1.0000	15
7.3894000000	2.0000	13,12
7.2515000000	1.0000	14
3.5596000000	1.0000	16
3.4831000000	1.0000	21
2.9466000000	1.0000	17
2.2673000000	1.0000	18
2.2090000000	1.0000	19
1.8734000000	1.0000	20

The Assignment of the Absolute Configurations for products

Alkenen epoxidation is stereospecfic with respect to alkenes that would not alter the trans/cis configuration of the alkene. It proceeds via a concerted syn-addition mechanism, therefore the trans-stilbene gives R,R- or S,S-trans-stilbene oxides whereas 1,2-dihydronapthalene (a cis- alkene) gives 1R,2S- or 1S,2R-dihydronapthalene oxide as shown on Scheme 5. Consequently, the stereochemistry of final products after epoxidation should be characterized using analytical techniques.

Optical rotatory power

The optical rotatory power is one of the measurements that distinguish the absolute configurations of the enantiomes. Initially, literature values of optial rotatory powers of four epoxides were searched from Reaxys (Table 9). Computational analyses were carried out to predict the optical rotatory powers of four optimized epoxides in chloroform at 589 nm and 365 nm using Gaussian with CAM-B3LYP method, 6-311++g(2df,p) basis. The outcomes were summarized in Table 10.

Table 9: Literature Values for Optical Properties of dihydronaphthalene oxides and trans-stilbene oxides

Epoxides	R,S-dihydronaphthalene oxides	S,R-dihydronaphthalene oxides	S，S-trans-stilbene oxides	R,R-trans-stilbene oxides
Concentration (g/100ml)	0.81	0.21	0.56	0.73
Enantiometric Excess (%)	99	99	89	97
Solvent	CHCl3	CHCl3	CHCl3	CHCl3
Optical Rotation	129o	-39o	-205.2o	334.6o
Wavelength (nm)	589	589	589	589
Temperature	20oC	25oC	20oC	25oC

Table 10: Computed Values for Optical and Thermodynamic Properties of dihydronaphthalene oxides and trans-stilbene oxides

epoxides	R,R-trans-stilbene oxides DOI:10042/27501	S,S-trans-stilbene oxidesDOI:10042/27523	R,S-dihydronaphthalene oxides DOI:10042/27499	S,R-dihydronaphthalene oxides DOI:10042/27524
αd at 589 nm	102.87o	-24.18o	177.43o	-52.74o

The predicted values calculated by the method mentioned above agrees with the literature values found with some extend of deviation tolerated. The sign of all predicted values perfectly match with the literature values. Therefore, the method introduced is reliable in calculating the optical rotatory power of those two epoxides.

VCD and ECD

Apart from optical rotatory power, the absolute configuration could be assigned by vibrational circular dichroism (VCD) and the electronic circular dichroism (ECD). VCD spectra of R,R- and S,S-trans-stilbene oxides were plotted to assign the configuration (Figure 8 and 9). As for ECD, due to lacking of chromophore in epoxides, it fails to assign the configuration by using UV/Vis spectrum.

Figure 9:VCD spectrum of R,R-trans-stilbene oxide

Figure 8:VCD spectrum of S,S-trans-stilbene oxide

The VCD spectra of R,R-trans-stilbene oxide and S,S-trans-stilbene oxide are nearly mirror images to each other since their vibrational environments are completely opposite to each other. This technique is definitely applicable in assigning the configurations for enantiomers.

Using the (calculated) properties of transition state for the reaction

The enantiomeric excess of four product mixtures(two epoxidation promoted by each catalyst) could be calculated using free energy difference between two diastereomeric transition states (ΔG). The ratio of concentrations of the two species (K) for each product mixture could be converted from the each ΔG according to the equation "ΔG=-RTlnK". Knowing the values of K, each enantiomeric excess was calculated (Table 11 to 14).

Table 11: Analysis for Computed Thermodynamic Properties of trans-stilbene oxides promoted by Shi's catalyst

Transition State	R,R-trans-stilbene oxide	S,S-trans-stilbene oxide
Free Energies of 1 (Hartrees)	-1535.14760552	-1535.14668122
Free Energies of 2(Hartrees)	-1535.14902029	-1535.14601044
Free Energies of 3(Hartrees)	-1535.16270178	-1535.15629511
Free Energies of 4(Hartrees)	-1535.16270154	-1535.15243112
Average ΔG(Hartrees)	-1535.1555072825	-1535.1503544725
Free Energy Difference (RR-SS)(Hartrees)	-0.00515281000002688
K	235.7
Relative Population (%)	99.5	0.5
Enantiomeric Excess (%)	99.0

Table 12: Analysis for Computed Thermodynamic Properties of trans-stilbene oxides promoted by Jacobsen catalyst

Transition State	R,R-trans-stilbene oxide	S,S-trans-stilbene oxide
Free Energies of 1 (Hartrees)	-3575.66547138	-3575.66429705
Free Energy Difference (RR-SS) (Hartrees)	-0.00117432999968514
K	3.5
Relative Population (%)	77.8	22.2
Enantiomeric Excess (%)	55.6

Table 13: Analysis for Computed Thermodynamic Properties of dihydronaphthalene oxides promoted by Shi's catalyst

Transition State	R,S-dihydronaphthalene oxide	S,R-dihydronaphthalene oxide
Free Energies of 1 (Hartrees)	-1381.54381947	-1381.55280118
Free Energies of 2 (Hartrees)	-1381.5472601	-1381.53607543
Free Energies of 3 (Hartrees)	-1381.556204	-1381.54761301
Free Energies of 4 (Hartrees)	-1381.54990117	-1381.55813219
Average ΔG (Hartrees)	-1381.549296185	-1381.5486554525
Free Energy Difference (RR-SS) (Hartrees)	-0.000640732500414742
K	1.9
Relative Population (%)	65.5	34.5
Enantiomeric Excess (%)	31.0

Table 14: Analysis for Computed Thermodynamic Properties of dihydronaphthalene oxides promoted by Jacobsen catalyst

Transition State	R,S-dihydronaphthalene oxide	S,R-dihydronaphthalene oxide
Free Energies of 1 (Hartrees)	-3422.06853796	-3422.06054777
Free Energies of 2 (Hartrees)	-3422.05830133	-3422.05965215
Average ΔG (Hartrees)	-3422.063419645	-3422.06009996
Free Energy Difference (RR-SS) (Hartrees)	-0.00331968499995128
K	33.8
Relative Population (%)	97.1	2.9
Enantiomeric Excess (%)	94.2

As can be seen on Table 11 to 14, R,R transition states and R,S transition states are predominant for both Shi's catalyst and Jacobsen catalyst promoted epoxidations due to having lower free energy comparing to S,S and S,R transition states respectively. Therefore, the R,R-trans-stilbene oxide and R,S-dihydronaphthalene oxide are supposed to be the major products in trans-stilbene and 1,2-dihydronaphthalene epoxidation promoted by both Shi's and Jacobsen catalyst.

NCI Analysis for the Transition State

The non-covalent interactions for R,R- transition state of Shi's catalyst promoted epoxidation of trans-stilbene was analyzed by Gaussview(Figure 10).

Orbital

Figure 10. The non-covalent interactions for R,R- transition state of Shi's catalyst promoted epoxidation of trans-stilbene

Referring to the figure shown above, the green region indicates attractive interaction that active catalyst binds to the substrate via the oxygen atoms. The substrate should have oriented itself to maximize the attractive interaction before binding to minimize the energy of the transition state. This transition state is stabilized by the attractive interactions which therefore determine the stereoselectivity of the epoxidation.

QTAIM analysis for transition state of R,R-trans-stilbene oxide promoted by Shi's catalyst

Figure 11:QTAIM for transition state of R,R-trans-stilbene oxide promoted by Shi's catalyst

The QTAIM analysis was conducted to calculate the orientation of R,R-trans-stilbene oxide in respect to Shi's catalyst. All the non-covalent bond critical points from weak interaction associated with weak interaction between oxygen and hydrogen were assigned (Figure 11).

Suggesting new candidates for investigations

An epoxide called cis R-(+)-pulegone oxide were found to have a optical rotatory power of 853.9^o in ethanol at 324 nm . Considering its high optical rotatory power (far more than 300^o)and simple structure, this molecule is suggested to be a new candidates for investigations.

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