The Molecular Basis of Enantiomeric Discrimination: Predictive Optimisation of Chiral HPLC Final Report

1 Summary This proposal was for a combined computer simulation and experimental study to develop new tools for designing and optimising chiral HPLC. Of particular interest was to show that it is now feasible to perform realistic molecular simulations of HPLC, and that such simulations can aid in the design and optimisation of HPLC columns. In particular, it was proposed to carry out a combined simulation / experimental investigation into a possible correlation between circular dichroism spectra on mixed solutions and chiral HPLC columns based on the same components to determine whether such a correlation could be relied upon to optimise the conditions for chiral HPLC. The major findings of this project have been: (i) to show that molecular simulation can be used to good effect in understanding the interactions that drive chiral discrimination in an HPLC column; (ii) to develop a new method of calculating ∆∆G values (and hence selectivities) for chiral HPLC based on atomistic simulations and using explicit solvent; this method provides a good balance between accuracy and ease of implementation; (iii) to show that the correlation between circular dichroism spectra and HPLC resolving power is also found with cellulose stationary phases, and to verify from simulations that there is a common molecular mechanism to underpin this linkage; (iv) to show that chiral discrimination in flexible molecules (i.e. compounds that can exist in a number of different conformations under operating conditions) must be understood in terms of an ensemble of different dimer geometries, and involves a subtle balance of discriminations in favour of both enantiomers; (v) to verify that solvent structure can have a major effect on chiral discrimination; in particular, tetrahydrofuran shows both important packing effects arising from its cyclic shape and hydrogen-bond formation, and the balance of these two effects can determine which of the favourable analytestationary phase geometries is found most often under the specified operating conditions.