Rep:Mod:SXC1322a

Experiment 1C: Advanced molecular modelling and assigning the absolute configuration of an epoxide

Conformational analysis using Molecular Mechanics

The Hydrogenation of Cyclopentadiene Dimer

During the dimerization of the cyclopentadiene, both of dimer 1 and 2 can form; however, in fact, only dimer 2 forms. The dihydro derivatives 3 and 4 are initially produced by the hydrogenation of dimer 1 but only the tetrahydro one exists after the prolonged hydrogenation. By calculating the energies of the four species 1-4, we can infer that which specie is more stable.

The molecule geometries were optimised by using MMFF94s force field in Avogadro, with the structures of the species constructed in Chemdraw Pro. Therefore the energies of them can also be calculated in Avogadro.

Dimer 1

Dimer_1

Dimer 2

Dimer_2

Dimer 3

Dimer_3

Dimer 4

Dimer_4

Relative Contributions of Different Energies
	Dimer 1 (kcal/mol)	Dimer 2 (kcal/mol)	Dimer 3 (kcal/mol)	Dimer 4 (kcal/mol)
Total Bond Stretching Energy	3.54276	3.46589	3.31146	2.81369
Total Angle Bending Energy	30.76922	33.18499	31.98610	24.99990
Total Stretch-bending Energy	-2.04133	-2.08141	-2.10578	-1.63866
Total Torsional Energy	-2.73368	-2.96007	-1.51657	-0.29312
Total Out-Of-Plane Bending Energy	0.01424	0.02217	0.01286	0.00096
Total Van Der Waals Energy	12.80711	12.39890	13.63837	10.57677
Total Electrostatic Energy	13.01384	14.19724	5.11943	5.14812
Total Energy	55.37335	58.19416	50.44587	41.60766

Table.1 Result energy of dimer 1, 2, 3 and 4

From the simulation, Angle bending energy contributes the most among the total energies of these four species. Dimer 1 has lower energy than dimer 2, indicating the cyclodimerisation is under kinetic control; and similarly specie 4 is more thermodynamically stable due to the lower energy.

Atropisomerism in an Intermediate related to the Synthesis of Taxol

Taxol is a significant drug in treating ovarian cancers. Isomer 9 or 10, is an important intermediate in the synthesis of this drug, either with the carbonyl group pointing up or down, existing atropisomerism. By calculating the energies of the two isomers in the same way described above, the relative stability of them can be found out.

Isommer 9

Dimer_1

Isomer 10

Dimer_2

Relative Contributions of Different Energies
	Isomer 9 (kcal/mol)	Isomer 10 (kcal/mol)
Total Bond Stretching Energy	7.61695	8.96178
Total Angle Bending Energy	28.31531	22.96519
Total Stretch-bending Energy	-0.10252	-0.15088
Total Torsional Energy	0.50813	4.27377
Total Out-Of-Plane Bending Energy	0.97717	1.62090
Total Van Der Waals Energy	32.98055	36.81104
Total Electrostatic Energy	0.30750	0.40923
Total Energy	70.60309	74.89102

Table 2. Result energy of isomer 9 and 10

We can infer from the results that isomer 9 is more stable than isomer 10, whereas Van Der Waals energy is the largest contributor, therefore resulting two different stereochemistry of carbonyl addition of these two isomers. The lower bending energy of isomer 10 is due to the smaller bond angle, 50.3^o, comparing to 51.8^o of isomer 9. Calculated by MMFF94s force field, the olefinic strain, corresponds to the double bond twisting, lowers the difference between the HOMO and the LUMO and therefore more reactive. However, “hyperstable” olefins locate at the bridgehead and are thermodynamically more stable therefore highly unreactive. So the alkene reacts slowly.

Reference for this part

1. W. F. Maier, P. Von Rague Schleyer, J. Am. Chem. Soc., 1981, 103, 1891.DOI:10.1021/ja00398a003

Spectroscopic Simulation using Quantum Mechanics

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

By using the powerful HPC system, the ¹H and ¹³C spectra of molecules 17 and 18 are simulated. Therefore the calculated chemical shifts can be compared to the literature values.

Here, molecule 17 is choosen for the simulation.

Molecule 17

Dimer_1

Relative Contributions of Different Energies
	Isomer 17 (kcal/mol)
Total Bond Stretching Energy	15.57460
Total Angle Bending Energy	32.40643
Total Stretch-bending Energy	0.01688
Total Torsional Energy	11.58311
Total Out-Of-Plane Bending Energy	1.23413
Total Van Der Waals Energy	51.21533
Total Electrostatic Energy	-7.56874
Total Energy	104.46173

Table 3. Result energy of molecule 9 and 10

Calculated Energies
	Energy
Zero-point correction	0.467966 (Hartree/Particle)
Thermal correction to Energy	0.489479
Thermal correction to Enthalpy	0.490423
Thermal correction to Gibbs Free Energy	0.420577
Sum of electronic and zero-point Energies	-1651.412064 kcal/mol
Sum of electronic and thermal Energies	-1651.390551 kcal/mol
Sum of electronic and thermal Enthalpies	-1651.389607 kcal/mol
Sum of electronic and thermal Free Energies	-1651.459453 kcal/mol

Table 4. Calculated values for energies

Figure 1 to 4 are the calculated ¹H and ¹³C NMR data and spectra for molecule 17.

And figure 5 diplays the literature values of ¹H NMR for molecule 17.

*Figure 1. Simulated ¹H NMR data for molecule 17*

*Figure 3. Simulated ¹³C NMR data for molecule 17*

¹³C NMR (75 MHz, C6D6) ppm 211.49, 148.72, 120.90, 74.61, 60.53, 51.30, 50.94, 45.53, 43.28, 40.82, 38.73, 36.78, 35.47, 30.84.30.00, 25.56, 25.35, 22.21, 21.39

Literature ¹³C NMR data for molecule 17

It is noted that these simulated NMR spectra, with a reasonable range of error, are fairly similar to those in the literature.

Reference for this part

1. Spectroscopic data: L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, J. Am. Chem. Soc.,, 1990, 112, 277-283.DOI:10.1021/ja00157a043

Analysis of the properties of the synthesised alkene epoxides

The two catalytic systems

The two catalysts, the shi asymmetric Fructose catalyst and the Jacobsen asymmetric catalyst, are used to catalyse asymmetric expodation of alkenes.

The Shi asymmetric Fructose catalyst

The Jacobsen asymmetric catalyst

These two molecules' structures are also simulated in Avogadro.

The Shi catalyst

Dimer_1

The Jacobsen asymmetric catalyst

Dimer_2

The crystal structures of the two catalysts above

Molecule 21 and 23 are the pre-catalysts in the synthesis process of the Shi catalyst and the Jacobsen catalyst respectively.

Pre-catalyst 21

Chloro-(N,N'-bis(3,5-di-t-butyl-salicylidene)cyclohexane-1,2-diamine)-manganese

The two catalysts were searched in the Cambridge crystal database(CCDC) by using the Conquest program. The C-O bond lengths in the molecules were then obtained using the Mercury program.

Figure 6. The C=O bond lengths of the anomeric centres

As shown in Figure. 6, the C-O bond lengths of the two anomeric centres can be investigated by using Mercury, which are 146, 140.6, 143 and 144.2 pm respectively, all different from the normal C=O bond length(143 pm). This shortening of bonds is due to the elongation of the bonds in the molecule. The lone pair on the oxygen donates its electron to the C-O bond results in the strengthening of that bond and the weakening of the neighbour C-O bond.

1,2:4,5-Di-O-isopropylidene-b-D-erythro-hexo-2,3-diulo-2,6-pyranose

Pre-catalyst 23

Epoxidation of alkene 1 and 2

The calculated NMR properties of the epoxidation products

The NMR of the epoxidation products are calculated by using the same method as the molecule 17 and 18. The optimised structures are as follows

1,2-dihydronaphthalene epoxidation product

Dimer_1

Styrene epoxidation product

Dimer_2

Figure 7 to 14 are the computed NMR spectra and data for epoxide 1 and 2.

*Figure 11. Calculated ¹H NMR data for epoxide 1*

*Figure 12. Calucated ¹³C NMR data for epoxide 1*

*Figure 13. Calculated ¹H NMR data for epoxide 2*

*Figure 14. Calucated ¹³C NMR data for epoxide 2*

Assigning the absolute configuration of the epoxides

Using the checkpoint documents produced before, .gjf documents can be generated in Gaussview. By entering different codes in the NotePad++ program, the .gjf documents can be used for different calculations (e.g. ECD, VCD, optical rotary power) in the HPC system. The result spectra can be then obtained by viewing output .log documents in Gaussview and the values obtained simply in Notepad.

The reported literatures for optical rotations

1.The optical rotation at a specified wavelength of light (the optical rotatory power, or ORP)

OPR, the optical rotatory power, measures the optical rotation at a defined wavelength of light.

Literature Values for Optical Properties of Epoxides 1 and 2 (solvent = CHCl₃)
	Epoxide 3 (R)	Epoxide 3 (S)	Epoxide 4 (R)	Epoxide 4 (S)
Structure
Concentration (g/100ml)	0.5	1.02	0.81	0.91
Enantiometric Excess (%)ee	-	99	-	-
Optical Rotation Power	-21.9^o	32.1^o	-129^o	-38.8^o
Wavelength (nm)	589	589	589	589
Temperature	25^oC	25^oC	20^oC	25^oC

Table 5. Literature optical properties for epoxides

The calculated chiroptical properties of the product

Calculated Values for Optical Properties of Epoxides 1 and 2 (solvent = CHCl₃, wavelength = 589 nm)
	Epoxide 3 (R)	Epoxide 3 (S)	Epoxide 4 (R)	Epoxide 4 (S)
Structure
Optical Rotation Power	-30.18^o	28.36^o	-103.31^o	-23.46^o

Table 6. Calculated optical properties for epoxides

2. The electronic circular dichroism (ECD)

ECD, the electronic circular dichroism, is effective in recording with polarised light but not very helpful epoxides due to the lack of appropriate chromophore.

Figure 15. Simulated ECD for epoxide 1

Figure 16. Simulated ECD for epoxide 2

3. The vibrational circular dichroism (VCD)

VCD, the vibrational circular dichroism, is not available in our department but very helpful.

Figure 17. Simulated ECD for epoxide 1

Figure 18. Simulated ECD for epoxide 2

Using the (calculated) properties of transition state for the reaction (β-methyl styrene)

For checking the enantiommeric assignments, the relative free energy of the transition state obtained by computer simulation and the calculated optical rotations of the epoxide were compared.

The working on calculating the value of energy constant k are shown below.

Calculated Values for k
	(R,R)	(S,S)
Free energy, G of TS1	-1343.02297	-1343.017942
Free energy, G of TS2	-1343.019233	-1343.015603
Free energy, G of TS3	-1343.029272	-1343.023766
Free energy, G of TS4	-1343.032443	-1343.024742
Average Free Energy, G	-1343.02598	-1343.020513
Difference in Free Energy, G (in Hartree)	-0.00546625
Difference in Free Energy, G (KJ/mol)	-14351.6373
Value of k calculated	326.917

Table 7. Calculation for constant k

From the calculations above in Table 7. , the free energy constant k = 326.917, indicating that the enantiomers with R,R stereochemistry is much more preferable over S,S enantiomers. And the value of the free energy is relatively large therefore the enantiomers are very stable.

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

Hydrogen bonds,electrostatic attractions and dispersion-like close approach of pair of electrons, are all included in NCl, the non-covalent interactions. These analysis was done by using Gaussview.

Figure 19. NCL analysis of R,R series for Shi expodation of β-methyl styrene

As Figure 19. displays above, attractive interactions are indicated by the different colours, therefore helpful for identifying regions of reacting system that reaction of substrate and catalyst may take place.

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

QTAIM, the electronic topology, Focus on the weaker interactions defined by a NCl analysis and the electron density in the covalent area of species, is complementary to the NCl analysis.

Figure 20. QTAIM analysis of R,R series for Shi expodation of β-methyl styrene

Figure 20. above is the QTAIM analysis of R,R series for Shi expodation of β-methyl styrene. This was done in Avogadro program on a mac.

Suggesting new candidates for investigations

Through searching on Reaxys, a molecule with optical rotary power > -500 can be found out. Therefore (-)-lochnericine is chosen for discussion.

Literature Values for Optical Properties of (-)-lochnericine
Structure
Solvent	CHCl₃
Optical Rotation Power	-528^o
Wavelength (nm)	589
Temperature	15^oC

Table 8. Literature Optical Properties of (-)-lochnericine

Reference for this part

1. S. Pedragosa-Moreau , A. Archelas , R. Furstoss J. Org. Chem., 1993, 58 (20), pp 5533–5536 DOI:10.1021/jo00072a044

2. Journal of Molecular Catalysis B: Enzymatic, 2010 , vol. 67, # 3-4 p. 236 - 241 DOI:10.1016/j.molcatb.2010.08.012

3. Tetrahedron, 1996 , vol. 52, # 13 p. 4593 - 4606 DOI:10.1016/0040-4020(96)00135-4

4. Patent: US6348608 B1, 2002

5. Moza,B.K.; Trojanek,J. Collection of Czechoslovak Chemical Communications, 1963 , vol. 28, p. 1419 - 1426 DOI:10.1135/cccc19631419