Module 1 - Structure and Spectroscopy

Introduction

Molecular Mechanics and Semi Empirical Molecular Orbital methods will be used to computationally determine investigate a series of reactions, by theoretically determining their structures and/or spectra.

Modelling using Molecular Mechanics

The Hydrogenation of Cyclopentadiene Dimer

Formation of the Dimer

Planar cyclopentadiene (1) readily dimerises, at room temperature. This reaction produces a single isomer, the endo isomer compound 2, but a second exo dimer, compound 3 could also theoretically be formed:

After geometry optimisation using MM2, the exo dimer of the cyclopentadiene dimer had a calculated energy of 31.881 kcal/mol. However the endo dimer had an higher calculated energy of 34.004 kcal/mol. The higher calculated energy shows that the intramolecular interactions in the exo dimer are more favourable than those present in the endo dimer, suggesting that the exo dimer is more thermodynamically stable.

But as noted the thermodynamically stable exo isomer is not produced. This would suggest that the reaction proceeds irreversibly, with the geometry of reaction being kinetically controlled.

Hydrogenation of the Dimer

Hydrogenation of the endo dimer can produce one of two products, as shown. Compound 5 has a calculated energy of 34.9660 kcal/mol, while compound 5 has a calculated energy of 29.2551 kcal/mol. Thus compound 5 is significantly more thermodynamically stable.

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A breakdown of the energy terms used in the MM2 calculation provides more information on how energy differences arise between the two structures:

Table of Energies for **Compounds 4** and 5
Energy Term	Energy / kcalmol^-1
Energy Term	Isomer 4	Isomer 5
Stretch	1.2794	1.1245
Bend	19.0909	13.0210
Stretch-Bend	-0.8432	-0.5648
Torsion	11.1365	12.4238
Non-1,4 VDW	-1.6454	-1.3323
1,4 VDW	5.7864	4.4420
Dipole/Dipole	0.1622	0.1409
Total	34.9660	29.2551

The stretching, stretch-bend and hydrogen bonding energy terms in the calculated energies all vary by much less than 1 kcal/mol, suggesting these interactions are similar in both products. The major discrepancies in energy arise from the bending, torsion and Van der Waals energy terms, with compound 5 having Van der Waal interactions 1.0313 kcal/mol less than compound 4 and bending energy 6.0699 kcal/mol less but torsional interactions 1.0313 kcal/mol greater.

The increased Van der Waal forces in compound 4 are likely to arise as the newly added hydrogens must interact with the adjacent hydrogens in the unbridged C₅ ring. Comparatively adding extra hydrogens to the bridged system, as in compound 5 will lead to less interactions as the adjacent substituents are held in a constrained geometry out of line with the added hydrogens.

The difference in the bending will arise due to the difference in the nature of the ring systems. compound 4, with the double bond in the bridged ring system, will not have its bending energies greatly distorted by the presence of the double bond, as bending in this ring is already restricted by the bridge. However placing a double bond in the unbridged ring, as in compound 5, will significantly reduce the ability of the ring to bend, lowering the bending energies.

Due to it being more thermodynamically stable overall, in equilibriating conditions it is likely that a majority of compound 5 will form.

Stereochemistry of Nucleophilic Additions to a Pyridinium Ring

Example 1

When a Grignard reagent such as MeMgI is added to the pyridinium reactant C, high regio- and stereospecificity is shown for the formation of product D. It is thought that this may be due to coordination between the Grignard reagent and the carbonyl. ^[1]

In order to probe this stereospecificity, the possible positions of the carbonyl group with respect to the aromatic ring were determined. A series of distortions were performed on the 7 and 5 atom ring systems was performed to explore possible conformers of this molecule. These conformers are displayed in the table below alow with the energy after MM2 optimisation and dihedral angles between the carbonyl groups and the aromatic rings. The conformer seen to display the lowest energy is conformer A.

Conformer	Energy / kcal mol^-1	Carbonyl - Aryl Dihedral
	43.1315	11.7 °
	44.8107	22.1 °
	44.4065	23.4 °
	44.6311	13.3 °

In all cases it is observed that the dihedral angle between the carbonyl and the ring system is a small positive angle, i.e. it is tilted slightly above the aryl ring.

This may account for the stereospecificity as if the Grignard reagent coordinates with the carbonyl, then the carbonyl will effectively hold the Grignard reagent in place, ensuring that it attacks the top face of the aromatic group resulting in the expected stereochemistry.

Example 2

Compound 8 is analogous to compound 6, and thus displays very similar chemistry. Again the focus is on nucleophillic addition to an aromatic ring, but this time with NH₂Ph.

Again, the carbonyl group is expected to play a key role in the "anchoring step" of the addition ^[2], and so again the orientation of the carbonyl group will be looked at for major conformers.

Conformer	Energy / kcal mol^-1	Carbonyl - Aryl Dihedral
	69.1295	20.4 °
	66.3691	20.7 °
	88.1663	25.0 °
	85.6956	26.1 °

Stereochemistry and Reactivity of an intermediate in the Synthesis of Taxol

Structure 10 and structure 11 are two possible isomers of a key intermediate of the synthesis of Taxol. Different only in the rotation of the C=O double bond around a single bond, this is an example of atropisomerism and isomerism will take place even at room temperature. Structure10 and structure 11 were both geometry optimised using both the MM2 and MMFF94 force fields to analyse the stability of each structure.

Comparison of Computed Energies for **Structure 10** and **Structure 11**
Atropisomer	MM2 minimised	MMFF94 minimised
Structure 10	48.8845 kcal/mol	70.5467 kcal/mol
Structure 11	44.3146kcal/mol	60.5584 kcal/mol

Modelling using Semi-empirical Molecular Orbital Theory

Regioselective Addition of Dichlorocarbene

Upon the addition of dichlorocarbene, alkenes react to form dichlorocyclopropanes^[3]. Compound 12, upon reaction with dichlorocarbene will show regioselectivity, with the endo double bond being selectively attacked ^[4].

After performing an initial MM2 geometry optimisation, the MOPAC/PM6 method was used to generate an approximate of the molecular orbitals of interest.

Molecular Orbital	Image	Comment
HOMO -1
HOMO
LUMO
LUMO +1
LUMO +2

Key Vibrational Modes
Compound	Vibration	Frequency / cm^-1
Diene	C-Cl Stretch	770.89
	exo C=C Stretch	1737.07
	endo C=C Stretch	1757.36
exo hydrogenated	C-Cl Stretch	779.93
exo hydrogenated	endo C=C Stretch	1753.76

Mini Project

Crassalactones, a series of compounds initially extracted from the leaves and twigs of Polyalthia Crassa, have been found to show cytotoxic effects on a range of mammalian cancer cells ^[5]

A synthetic route to one of these compounds, (+)-Crassalactone D (compound 17) has since been devised that shows high stereospecificity. In the Total Synthesis of (+)-Crassalactone D ^[6] a key step involves the oxidation of the furan group in compound 14, and the subsequent intramolecular reaction with a hydroxy group to form two lactols, product 15 and product16, both of which contain a spiroketal centre, in a 10:1 ratio respectively.

The NMR calculations and results for product 15 can be found at DOI:10042/to-7448 , while product 16 can be found at DOI:10042/to-7475 .

List of calculated ¹³C NMR signals for **product 15**
Chemical Shift / ppm computed	Chemical Shift / ppm literature	Carbon Atom
134.35	135.5	11
133.278	134.2	6
132.529	131.2	7
125.237	128.7	13, 15
124.054	128.3	14
122.753	126.8	12
121.743	126.8	16
114.503	116.7	2
102.369	101.2	8
82.8121	84.9	5
75.7145	74.2	4
49.1892	44.1	3

Most of the chemical shifts calculated lie within 5ppm of the literature values. Two of the carbons that deviate from this most are carbons 3 and 4. As they are adjacent, it is likely that this discrepancy has arisen as the model used for calculation had a slightly incorrect conformation of the central five membered ring.

The splitting of the peaks and deviation from the literature value for 12 and 16 is easily explained by the concept of averaging. The single bond between carbons 5 and 11 will freely spin at room temperature, causing carbons 12 and 16 to form an average signal. At points in the rotation, the shielding may change eg. as it passes close to the hydroxy group leading to significant deshielding. In the computed model, each carbon was investigated interacting with its surrounding in a stationary molecule, leading to difference in the environment of carbons 12 and 16.

List of calculated ¹³C NMR signals for **product 16**
Chemical Shift / ppm	Carbon Atom
135.971	11
132.764	8
131.842	9
124.646	15
124.646	16
124.438	13
123.795	14
123.261	12
117.117	2
103.028	7
87.1726	5
75.2999	4
46.9157	3

References

↑ A. G. Shultz, L. Flood and J. P. Springer, J. Org. Chemistry, 1986, 51, 838. DOI:10.1021/jo00356a016
↑ S. Leleu, C. Papamicael, F. Marsais, G. Dupas, V. Levacher. Tetrahedron: Asymmetry, 2004, 15, 3919-3928. DOI:10.1016/j.tetasy.2004.11.004
↑ W. von E. Doering and A. K. Hoffmann., J. Am. Chem. Soc., 1954., 76., 6162–6165., DOI:10.1021/ja01652a087
↑ B. Halton, R. Boese and H. S. Rzepa., J. Chem. Soc., Perkin Trans 2, 1992, 447. DOI:10.1039/P29920000447
↑ P. Tuchinda, B. Munyoo, M. Pohmakotr, P. Thinapong, S. Sophasan, T. Santisuk, and V. Reutrakul., J. Nat. Prod.., 2006., 69., 1728-1733., {DOI|10.1021/np060323u}}
↑ Z. Yang, P. Tang, J. F. Gauuan, B. F. Molino., J. Org. Chem.., 2009., 74., 9546-9549., DOI:10.1021/jo902055b

[jo00356a016-1] A. G. Shultz, L. Flood and J. P. Springer, J. Org. Chemistry, 1986, 51, 838. DOI:10.1021/jo00356a016

[j.tetasy.2004.11.004-2] S. Leleu, C. Papamicael, F. Marsais, G. Dupas, V. Levacher. Tetrahedron: Asymmetry, 2004, 15, 3919-3928. DOI:10.1016/j.tetasy.2004.11.004

[chlorocarbene-3] W. von E. Doering and A. K. Hoffmann., J. Am. Chem. Soc., 1954., 76., 6162–6165., DOI:10.1021/ja01652a087

[P29920000447-4] B. Halton, R. Boese and H. S. Rzepa., J. Chem. Soc., Perkin Trans 2, 1992, 447. DOI:10.1039/P29920000447

[polyalthia-5] P. Tuchinda, B. Munyoo, M. Pohmakotr, P. Thinapong, S. Sophasan, T. Santisuk, and V. Reutrakul., J. Nat. Prod.., 2006., 69., 1728-1733., {DOI|10.1021/np060323u}}

[crassalactone-6] Z. Yang, P. Tang, J. F. Gauuan, B. F. Molino., J. Org. Chem.., 2009., 74., 9546-9549., DOI:10.1021/jo902055b

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