Uzoh, OG; (2015) Modelling molecular flexibility for crystal structure prediction. Doctoral thesis , UCL (University College London).

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Abstract

In the crystal packing of molecules wherein a single bond links aromatic groups, a change in the torsion angle can optimise close packing of the molecule. The improved intermolecular interactions, Uinter, outweigh the conformational energy penalty, ΔEintra, to give a more stable lattice energy, Elatt = Uinter + ΔEintra. This thesis uses this lattice energy model hierarchically in a new Crystal Structure Prediction (CSP) algorithm, CrystalPredictor version 1.6, which varies the low-barrier torsion angles at the start of generating hypothetical crystal structures. The crystal structure of 1-benzyl-1H-tetrazole was successfully predicted in an informal ‘blind test’ when given the chemical diagram and the number of molecules in the asymmetric unit cell. Then, the concept of whether specific molecular fragments favour polymorphism (i.e. polymorphophore) was investigated by analysing the crystal energy landscapes of the monomorphic fenamic acid and the polymorphic derivative tolfenamic acid. The CSP results show that the polymorphophore promotes but does not guarantee polymorphism and that the substituents on the polymorphophore fragment decide the relative energies of the crystal structures. Molecular Dynamics (MD) cannot use this lattice energy model because many ab initio calculations of ΔEintra on a single molecule are expensive. However, the examination of the physical origin of the torsional barrier in fenamates aided the derivation of an analytical model fo ΔEintra. This thesis develops codes for fitting analytical intramolecular force fields to ab initio conformational profiles of fenamates. An intramolecular exp-6 atom-atom term (for the non-bonded repulsion-dispersion contributions) plus a cosine term (that represents the changes to the Molecular Orbitals) accurately model the ab initio conformational energy surfaces of fenamic and tolfenamic acids. This thesis provides a first step in extending ΔEintra data generated from CSP studies to help MD on condensed phases of pharmaceutical-like organic molecules.

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