Rep:Mod:benton2

Module 1 - Intro

In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature. Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for. MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here. Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

Week 1

Hydrogenation of the Cyclopentadiene Dimer

The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% (at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers)

Molecule	Exo	Endo
	Optimised	Optimised
Optimisation	MM2 E minimisation	MM2 E minimisation
Total E (kcal/mol)	33.9975	31.8764

The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control. Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

Molecule	Different hydrogenation sites
	Optimised	Optimised
Optimisation	MM2 E minimisation	MM2 E minimisation
Stretch	1.2489	1.1303
Bend	19.1608	13.10259
Torsion	11.0730	12.4118
VDW	5.7962	4.4398
Dipole-Dipole	0.1622	0.1410
Total E (kcal/mol)	34.9643	29.2475

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol^-1 more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

Atropisomerism in an Intermediate related to the synthesis of Taxol

In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette a key intermediate is either "Precursor 9" or "Precursor 10".

Molecule	Precursor 10	Precursor 9
	Optimised	Optimised
Optimisation	MM2 E minimisation	MM2 E minimisation
Stretch	2.4687	2.7846
Bend	10.5555	16.5411
Torsion	17.4240	18.2518
VDW	13.1930	13.1096
Dipole-Dipole	-1.8818	-1.7248
Total E (kcal/mol)	39.1215	47.8395

Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.

Comparison of MMFF94 and MM2 minimisations
Molecule	Precursor 9	Precursor 10
MM2 minimised Energy (kJmol<-1)	39.1215	47.8395
MMFF94 minimised Energy (kcalmol<-1)	58.7513	70.5377

Regioselective Addition of Dichlorocarbene to a diene

The addition of a dichlorocarbene to 9-chloromethanonaphthalene occurs in a surprisingly stereospcific manor. Why this happens can be predicted using computational techniques.

Molecule A, 9-chloromethanonaphthalene, was initially optimised using a molecular mechanics (MM2) calculation

Molecule A

It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

Comparison of two optimisation calculations
Overlay of two optimised molecules	MM2 optimised molecule	MOPAC Optimised Molecule
The MM2 optimised molecule is coloured yellow for clarity	Molecule A	Molecule A
Distances between corresponding atoms on the overlaid molecules (Å)	C(34)-C(9)	0.5247
	C(26)-C(1)	0.5246
	H(47)-H(22)	0.8526
	H(38)-H(13)	0.8524
	Cl(37)-Cl(12)	0.0689

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

MOs

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)

Homo-1	Homo
	Orbital
Lumo	Lumo+1	Lumo+2
Electrostatic diagram.

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile. Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule. The electrostatic diagram at the bottom displays how there is more negative charge on the endo alkene, which again is favourable to electrophillic attack.

Glycosidation

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107. Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2. As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states. The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area. The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

Mechanisms

Initial molecule	Conformation		1	2	3	4
	MM2 minimisation	Molecule	Optimised	Optimised	Optimised	Optimised
		Total Energy Kcalmol-1	11.5430	46.2672	35.5277	29.5144
	MOPAC minimisation	Molecule	Optimised	Optimised	Optimised	Optimised
		Heat of formation Kcalmol-1	-90.51343	-70.57703	-72.56010	-85.04737
Intermediate	Conformation		chemdraw	chemdraw	chemdraw	chemdraw
	MM2 minimisation	Molecule	Optimised	Optimised	Optimised	Optimised
		Total Energy Kcalmol-1	28.4913	43.2706	41.0918	31.8763
	MOPAC minimisation	Molecule	Optimised	Optimised	Optimised	Optimised
		Heat of formation Kcalmol-1	-91.66112	-66.72331	-84.44899	-88.08089

Comparison of coumpational results to a molecule from literature.

Taxol intermediate

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal^-1

Optimised

This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature. The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10 possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.

Atom number	Calculated ppm value	Lit. ppm value
1	27.5886	25.66
2	31.6721	28.79
3	52.6851	48.5
4	146.8944	144.63
5	51.4817	46.8
6	20.6456	18.71
7	27.0826	23.86
8	125.7193	125.33
9	50.5885	45.76
10	218.6545	218.79
11	Oxygen
12	54.1882	52.52
13	30.8219	28.29
14	63.85	56.19
15	29.5406	26.88
16	89.99	72.88
17	48.9728	39.8
18	24.6905	20.96
19	41.3115	32.66
21	44.3139	35.85
22	45.5337	38.81

Literature Molecule

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

Molecule A	Syn	Anti
	Optimised	Optimised

|} Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the ¹³C nmr.

Difference in measured and calculated chemical shift values in ppm, for each carbon atom

Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.

Comparison of correct and incorrect assignment for the two conformers

Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm^-1 in the syn form of the molecule and the CH bend region between 1000-1500cm^-1 is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

Comparison of the two computed IR spectra

Zoom showing main differences between spectra

As can be seen above, the differences, while there, are slight and insufficient to draw conclusions from.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

Despite the inconclusive IR I believe the correct assignments have been made in this case due to the close correlation between the predicted and measured ¹³C and H nmr; this highlights the importance of computational chemistry, it can easily help corroborate results.