Molecular modelling of structural changes which affect chromatographic selectivity in chiral separations

Abstract A molecular mechanics program, MM2, was utilized to model two chromatographic systems. It was first used to locate the most stable conformers of homologs of two derivatized silica stationary phases, N-tert -butyloxycarbonyl- d -valine- N ′-n-butylamide and N-tert -butyloxycarbonyl- d -alanine- N ′-n-butylamide, and also of the enantiomers of 2,2,2-trifluoroanthrylethanol (TFAE). The most stable (R) and (S) conformers of TFAE were then docked with those of the amino-acid derivatives. The calculations correctly predicted the elution order as well as the relative resolving powers of the two bonded phases. Replacing the n-butyl “spacer” chain with a methyl, ethyl, or n-propyl group confirmed the importance of chain length. Calculations involving the n-propyl spacer correctly predicted the elution order of enantiomers of TFAE on both phases as well as the relative enantiomeric resolving power of the two stationary phases. Similar calculations involving either ethyl or methyl spacers on the alanine derivative did not make correct predictions, thereby confirming the important influence of the spacer on fractionation of enantiomers.