Case Study on the Effects of Molecular Structure on the Mode of Polymorphic Transition Inducing Preferential Enrichment

A series of (±)‐ N ‐{2‐[4‐(2‐hydroxy‐3‐ethoxypropoxy)phenylcarbamoyl]ethyl}‐ N ‐methylpyrrolidinium p ‐halobenzenesulfonates [(±)‐ 1a – c ] were found to cause an unusual symmetry‐breaking enantiomeric resolution phenomenon called preferential enrichment, whereas the N ‐methylpiperidinium analogues (±)‐ N ‐{2‐[4‐(2‐hydroxy‐3‐ethoxypropoxy)phenylcarbamoyl]ethyl}‐ N ‐methylpiperidinium p ‐halobenzenesulfonates [(±)‐ 2a – c ] failed to show this phenomenon. By X‐ray crystallographic and ATR‐FTIR spectroscopic studies, (±)‐ 1a – c were found to undergo the desired solvent‐assisted solid‐to‐solid polymorphic transition of the first‐formed and metastable γ‐form into the stable δ‐form, which could induce preferential enrichment. In contrast, (±)‐ 2a – c were subject to the undesired solvent‐mediated polymorphic transition of the γ‐form into the α 2 ‐form, and similarly, (±)‐ 1d and (±)‐ 2d bearing a p ‐toluenesulfonate ion also showed the undesired solvent‐mediated polymorphic transition of the γ‐form into the β‐form; in these cases, preferential enrichment was not observed. Accordingly, the structure of the cyclic ammonium group as well as the basicity of the p ‐substituted benzenesulfonate ion largely affected the mode of the polymorphic transition. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)