The occurrence, induction, or inhibition of preferential enrichment is described for four new analogous racemic ammonium sulfonates. Racemic [2-[4-(2-hydroxy-3-phenoxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-nitrobenzenesulfonate [(±)-1a] showed preferential enrichment in EtOH, but the efficiency was modest. The deposited crystals were an α1-form or a mixture of the α1-form and a new μ-form, depending on the solvent used. The terminal p-fluorophenoxy analogue (±)-1b showed more efficient preferential enrichment in EtOH, followed by the exclusive deposition of the α1-form crystals. On the other hand, (±)-[2-[4-(2-hydroxy-3-phenoxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-toluenesulfonate [(±)-2a] failed to show preferential enrichment in any solvent to give the μ-form deposited crystals exclusively, whereas the terminal p-fluorophenoxy analogue (±)-2b showed very efficient preferential enrichment in EtOH, accompanied by the exclusive deposition of the α1-form crystals. Addition of the α1-form seed crystals of (±)-2b to the supersaturated EtOH solution of (±)-2a successfully induced the epitaxial transition to lead to the occurrence of preferential enrichment of (±)-2a, accompanied by the exclusive deposition of the α1-form crystals. From these results, it has been concluded that (i) polymorphic transition of the initially formed γ-form into the α1-form is essential for the occurrence of preferential enrichment of (±)-1 and (±)-2 and (ii) the direct transformation of the γ-form polymorph into the μ-form fails to show preferential enrichment.

A new mode of solvent-assisted solid-to-solid polymorphic transformation of the first-formed and metastable γ-form into a stable, new R 1 -form, which occurs during crystallization from individual supersaturated EtOH solutions of a series of (()-[2-[4-(2-hydroxy-3-phenoxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-halobenzenesulfonates [(()-1], has been found to cause an unusual symmetry-breaking enantiomeric resolution phenomenon called preferential enrichment. This polymorphic transition has been followed by the in situ attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) (ReactIR) measurement of the crystallization mixture and differential scanning calorimetry (DSC) analysis of the deposited crystals. The crystal structures with the R 1 -form have been solved either by X-ray crystallographic analysis of the single crystal or by the direct-space approach employing the Monte Carlo method with the subsequent Rietveld refinement from powder X-ray diffraction data of the powder sample. By comparison of the supramolecular structure characteristic of the metastable γ-form with that of the stable R 1 -form, the mechanism of this polymorphic transition has been interpreted in terms of a new type of rearrangement of weak intermolecular interactions caused by slight molecular movement inside the crystal lattice, in which intermolecular π/π and CH/π interactions as well as hydrogen bonds prominently control the crystal structure. This finding shows the flexibility in 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 α2‐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)

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