Understanding enantiodifferentiation through molecular simulations

Michael Alan Peterson, Purdue University

Abstract

Enantiomer separation is of significance in many areas of the chemical sciences. The primary method of optical isomer isolation is chiral chromatography using chiral stationary phases based on oligo- and polymeric sugars. Because surprisingly little is understood about how these phases differentiate between two mirror image isomers, the goal of this dissertation was to develop atomistic molecular simulation methods to explain enantioselective binding in chiral chromatography. Using molecular modeling it is shown how the chiral stationary phase permethyl-$\beta$-cyclodextrin discriminates between optical isomers, including where on the stationary phase the analyte molecules tend to bind. A data reduction method called moment analysis was developed so that the structural and dynamical features of the cellulose triacetate crystallite used in chiral chromatography could be understood. Analysis of the molecular simulations of the various cyclodextrin/chiral analyte complexes show that Monte Carlo simulations, which do not allow any type of induced-fit processes, are poor models for predicting experimental retention orders. In contrast, long dynamical simulations allowing induced-fit structural changes are able to produce differential average energies in accord with experiment. The dynamical simulations also show the most probable binding sites for the alcohol and acetate analytes studied to be on the interior of the cyclodextrin, although many excursions into and out of the cyclodextrin cavity are observed. The forces holding the complexes together are found to be primarily the short range van der Waals interactions between the analyte and the cyclodextrin. The differentiating forces are a combination of the van der Waals forces and the longer-range electrostatic forces. The simulations on the cellulose triacetate structures reveal that the surface strands are overall quite rigid with no propensity to unravel. The strands do, however, tend to rotate about their long axis, exposing the acetate groups, creating small cavities in the surface. The acetate groups rotate freely, allowing them to bind many analyte molecules in a wide range of orientations.

Degree

Ph.D.

Subject Area

Chemistry|Organic chemistry|Analytical chemistry

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