Rep:Mod:jb4109

Module 1

Basic Techniques of Molecular Mechanics and Semi-empirical Molecular Orbital Methods for Structural and Spectroscopic Evaluations

Hydrogenation of Cyclopentadiene Dimer

Using the MM2 force-field, the exo dimer 1 has a total energy of 31.9 kcal/mol, whereas the endo dimer 2 has a total energy of 34.0 kcal/mol. The exo dimer 1 has a lower energy, even though the endo dimer 2 is observed to be the more favoured mode of dimerisation. Hence, the cyclodimerisation of cyclopentadiene is kinetically controlled.

Hydrogenation product 3 has the following relative energy contributions: 1.25 (stretching), 19.2 (bending), 11.1 (torsional), -1.64 (non-1,4 van der Waals) and 5.80 (1,4 van der Waals). Hydrogenation product 4 has the following: 1.10 (stretching), 14.5 (bending), 12.5 (torsional), -1.07 (non-1,4 van der Waals) and 4.51 (1,4 van der Waals). For both products, there is no hydrogen bonding present. Except for torsional contribution, product 3 has higher energy contributions, and hence a higher total energy, than product 4 (35.0 kcal/mol for product 3, compared with 31.2 kcal/mol for product 4). Therefore, product 4 is more stable. If product 3 is formed, the hydrogenation of the dimer is kinetically controlled. If product 4 is formed, the hydrogenation is thermodynamically controlled.

Stereochemistry and Reactivity of Intermediate in Synthesis of Taxol

Using the MM2 force-field, isomer 9 has a total energy of 53.3 kcal/mol, while isomer 10 has a total energy of 48.2 kcal/mol. Because the latter has a lower energy, it is determined to be the more stable isomer. The alkene reacts slowly, i.e. hyperstable, because bridgehead alkenes are stabilised by strain (smaller thermodynamic driving force). In addition, the adjacent bridgehead sterically hinders any incoming electrophile (kinetic). The MMFF94 field produces greater total energy values: 76.3 kcal/mol for isomer 9 and 66.3 kcal/mol for isomer 10. Similarly, isomer 10 is shown to be the lower energy, and so the more stable isomer.

Regioselective Addition of Dichlorocarbene

Compound 12 is minimised by MM2 force-field, followed by MOPAC/PM6 method. This method discriminates between the two alkene bonds. The HOMO indicates that the alkene on the side facing the Cl atom is the more nucleophilic of the two alkenes. The following Molecular Orbitals (MOs) are mapped: HOMO-1, HOMO, LUMO, LUMO+1, LUMO+2. It can be seen here that the shape of the MOs reflect the molecular symmetry of the molecule.

The PM6 optimised geometry of 12 and its monohydrogenated product (hydrogenated on the side opposite of the Cl atom) are run on the Gaussian interface using the 6-31G basis set and their stretching vibrations calculated. For 12, v(Cl-C) = 689.48 cm^-1; v(C=C) = 1480.67 cm^-1, 1491.19 cm^-1. The monohydrogenated product has, v(Cl-C) = 673.90 cm^-1; v(C=C) = 1504.29 cm^-1. In the dialkene, the Cl-C bond is stronger, but the C=C bond weaker, than the monoalkene.

Monosaccharide Chemistry: Glycosidation

R = Me is used to minimise computational demand. Oxonium cation rings A and B, together with the ring-inverted conformer of each of them, are minimised using MM2, then MOPAC/PM6. PM6 is a more suitable method, because it takes into account Molecular Orbitals (MOs), rather than just simple atoms as in the MM2 force-field. The PM6 method also considers the possibility of formation of new chemical bonds, which the MM2 cannot do. B and its conformer B' (24.1 and 30.2 kcal/mol respectively) have a lower energy than A and its conformer A' (44.4 and 36.6 kcal/mol respectively).

Intermediates C and D with their conformers are minimised in a similar way. The stabilisation energy by neighbouring-group-participation is 11.3 kcal/mol for C and 5.5 kcal/mol for its conformer C', and 6.3 kcal/mol for the conformer D'. However, D itself is destabilised by 7.9 kcal/mol, compared to its starting compound B.

Table 1: Values of bond lengths (A) and angles (deg) from MM2 and MOPAC/PM6

Intermediate C	a	b	c	X	Y
MM2	1.401	1.406	1.220	115.6	112.0
MOPAC/PM6	1.337	1.598	1.295	109.9	114.3
Intermediate D	a	b	c	X	Y
MM2	1.400	1.404	1.219	115.4	111.4
MOPAC/PM6	1.367	1.528	1.328	109.9	113.2

The more stable route is preferred in glycosidation. The β-anomer is formed by glycosidation via oxonium cation A' and intermediate C', whereas the α-anomer is formed via cation B and intermediate D'.

Structure-based Mini Project using DFT-based Molecular Orbital Methods

Stereoselective Dissolving Metal Reductions

The ketone is reduced to the alcohol by Li/NH₃. We can tell that the reaction has worked if the intensity of the blue Li/NH₃ solution decreases. We can tell which stereoisomer has formed by X-ray crystallography, whereby we can straightaway use visual recognition to deduce the spatial arrangement of the atoms within the molecule. The chirality of the product means that we can also distinguish it from its enantiomer by measuring its optical rotation using a polarimeter. A positive or negative angle of rotation will show if the product has dextrorotatory or levorotatory property.

The ketone reactant and alcohol product are optimised using MM2 force-field, after which it is refined using the DFT = mpw1pw91 method with 6-31G basis set, run on Gaussian. The ¹³C NMR spectra are then calculated by the GIAO method, and ³J_H-H coupling constants are also determined. In general, the predicted data match the reported structural assignment.

Table 2: ¹³NMR chemical shifts (ppm) of ketone [DOI:10042/to-12764 ] and alcohol [DOI:10042/to-12765 ]

C	Ketone δ (cal.)	Ketone δ (lit.)	Alcohol δ (cal.)	Alcohol δ (lit.)
1	38.97	38.20	30.60	26.05
2	207.73	213.25	74.25	76.86
3	47.85	45.66	42.33	43.22
4	45.57	45.24	41.23	38.88
5	33.24	33.99	33.52	33.78
6	43.21	41.74	41.46	39.19
7	31.91	27.54	30.88	30.92
8	41.60	38.32	41.71	39.93
9	26.04	23.02	26.04	23.08
10	38.39	36.32	39.06	37.10
11	23.34	22.71	24.14	22.82
12	13.70	11.18	15.38	14.87
13	146.98	146.28	147.37	147.11
14	109.70	111.06	109.32	110.67
15	18.62	16.10	18.75	16.68

Table 3: ³J_H-H coupling values (Hz) of ketone and alcohol

Ketone δ (ppm)	J (cal.)	J (lit.)
1.95	12.9	14.0
1.38	12.3	13.2
1.00	6.5	6.5
Alcohol δ (ppm)	J (cal.)	J (lit.)
2.51	13.0	14.6
2.32	12.9	14.6
2.18	11.2	13.0
1.96	11.2	13.5
1.68	11.4	13.6
1.48	12.3	14.2
1.41	11.2	13.5
1.34	9.8	13.0
1.05	6.5	6.6

In a fused bicyclic system such as the decalin considered here, the Me and H at the C1 and C6 positions are axial. The axial Me group sterically hinders the approach of t-BuOH in the last step. Because of that, t-BuOH approaches from the side opposite to the axial Me group, causing the OH group in the final product to be on the same side as the axial Me group. The other Me group, that is adjacent to the OH group, is equatorial and so does not render any steric hindrance to the incoming t-BuOH. Therefore, the stereoisomer of the alcohol product as shown here is so obtained. According to the MM2 force-field, the alcohol shown above has a lower energy (27.3 kcal/mol), and is therefore more stable, than its enantiomer (27.7 kcal/mol). This also helps to explain the selectivity.

The optical rotation of the alcohol product is calculated to be [α] = 2.3, but the value reported in literature is [α]²⁰_D = -11.6.