Module 1

Modelling Using Molecular Mechanics

The Hydrogenation of Cyclopentadiene Dimer

Cyclopentadiene dimerises into the two dimers, shown right, using the molecular mechanics technique the dimers are optimised to their minimum energy in ChemBio3D. It is known that the endo product is preferred and the major product from the dimerisation but is this controlled kinetically or thermodynamically?

Comparison of the MM2 optimised dimers are tabulated below. The endo dimer can be hydrogenated initially producing a dihydro derivative, the two possible derivatives shown right, MM2 calculations also allows inspection of these molecules and which one if the thermodynmaically stable derivative.

Comparison of MM2 Calculations of the Endo/Exo dimer and the Hydrogenation Derivatives
Property	Exo	Endo	Dihydro 3	Dihydro 4
Stretch	1.2850	1.2507	1.2352	1.0972
Bend	20.5783	20.8476	18.9388	14.5237
Stretch-bend	-0.8382	-0.8358	-0.7609	-0.5497
Torsion	7.6559	9.5109	12.1235	12.4968
1,4 VDW	4.2346	4.3195	5.7288	4.5132
Dipole/Dipole	0.3775	0.4476	0.1631	0.1406
Total energy	31.8765 kcal/mol	33.9975 kcal/mol	35.9266 kcal/mol	31.1520 kcal/mol

The above table shows that the Exo dimer is actually the thermodynamic product meaning that the dimerisation is under kinetic control if endo is the major product, comparing the two dimers it is clear that the endo is favored because of its increased dipole/dipole interactions as well as a lesser bend. Dihydro 4 is the most thermodynamically stabled and if reaction is not kinetically controlled will be the major product, less stretch-bend and bend contribute to its stabilization however it does have more torsion strain than dihyrdo 3.

Endo Dimer

Exo Dimer

Hydrogenation product 3

Hydrogenation product 4

Atropisomerism in an Intermediate Related to the Synthesis of Taxol

A key intermediate for the anti-cancer drug Taxol is shown on the right in its two atropisomers in the total synthesis of the drug the carbonyl is shown either up or down in which is apparently isomerises to the alternative carbonyl isomer, the most stable. Using ChemBio3D the most stable atropisomer can be found.

Comparison of MM2/MMFF94 Calculations of the Atropisomers (1) and (2)
Property	MM2(1)	MMFF94(1)	MM2(2)	MMFF94(2)
Stretch	2.4652		2.6381
Bend	12.3805		12.5604
Stretch-bend	0.2131		0.4253
Torsion	16.2292		19.1193
1,4 VDW	12.4518		12.8595
Dipole/Dipole	-1.5851		-1.7018
Total energy	40.1481 kcal/mol	60.0679 kcal/mol	44.2887 kcal/mol	63.2835 kcal/mol

Atropisomer(1) is shown to be the most stable in both the MM2 and MMFF94 calculations, however MMFF94 shows them at a higher energy and closer in value than the MM2 method.

Atropisomer 1

Atropisomer 2

Modelling Using Semi-empirical Molecular Orbital Theory

Regioselective Addition of Dichlorocarbene to a Diene

The above experiments have been of a classical, mechanical treatment of the molecule here a quantum mechanical method is used with the MOPAC calculation method. The diene molecule shown right is put under investigation probing its electrostatic potential, molecular orbitals and the vibrational frequency using Gaussian and also comparing the MOPAC method to the classical MM2.

A comparison of the MM2 and MOPAC calculation can be seen below in the .mol file, the structures look very similar but different straining in the center of the molecule and at the chloride atom, the results of the calculation are summarised below giving differing energies.

------------ Mopac Interface ------------
Model: georgedoucy_cl_diene.mol

Mopac Job: AUX  RM1 CHARGE=0 EF GNORM=0.100 SHIFT=80
Finished @ RMS Gradient = 0.08068 (< 0.10000)   Heat of Formation = 22.82754 Kcal/Mol
-----------------------------------------

------------MM2 Minimization------------
Warning: Some parameters are guessed (Quality = 1).
  Iteration  150: Minimization terminated normally because the gradient norm is less than the minimum gradient norm
  Stretch:                0.6185
  Bend:                   4.7328
  Stretch-Bend:           0.0397
  Torsion:                7.6627
  Non-1,4 VDW:           -1.0645
  1,4 VDW:                5.7928
  Dipole/Dipole:          0.1124
Total Energy:            17.8945 kcal/mol
Calculation completed
------------------------------------

Georgedoucy cl diene comparision.mol

Diene Gaussian Frequency Calculation