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

• Published in: European Journal of Organic Chemistry Vol. 2008; no. 20; pp. 3496 - 3505
• Main Authors: Horiguchi, Masahiro, Yabunaka, Shinsuke, Iwama, Sekai, Shimano, Eiji, Lepp, Zsolt, Takahashi, Hiroki, Tsue, Hirohito, Tamura, Rui
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.07.2008; WILEY‐VCH Verlag; Wiley
• Subjects: Chemistry; Chemistry, Organic; Chiral resolution; Chirality; Physical Sciences; Polymorphism; Science & Technology; Symmetry breaking; CRYSTALLIZATION; symmetry breaking; chirality; MECHANISM; CRYSTAL-STRUCTURE; chiral resolution; ENANTIOMERIC RESOLUTION PHENOMENON; polymorphism; SEED CRYSTALS; HYDROGEN-BONDS
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200800228

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) A series of new compounds (±)‐1 and (±)‐2 were prepared, and their preferentialenrichment experiment was performed. As a result, (±)‐1a–c showed preferentialenrichment, whereas (±)‐1d and (±)‐2a–d failed to show this phenomenon. These experimental results and each mode of polymorphic transition occurring during crystallization are reported.