Chiral resolution by crystallization of host-guest supramolecular complexes

Abstract

The crystallization behaviour and the physical characterization of supramolecular complexes formed between permethylated-α-cyclodextrin (TMα-CD) and the enantiomers of phenylethanol (PE) are investigated. According to crystal structure analyses, complexes containing the pure guest enantiomers are almost isomorphous, indicating that the host presents a poor ability to distinguish PE enantiomers at a molecular level. Nevertheless, crystallizations from racemic PE in water induce an efficient chiral discrimination and allow the enantio-separation of the guests despite the existence of a solid solution revealed by XRPD and coupled TG-DSC analyses. The enantiodifferentiation is explained by solubility differences between the two diastereomeric complexes in the studied temperature range. Moreover, it is shown that the diastereomeric complex TMα-CD/(S)-PE crystallizes in two distinct phases: a monohydrate and an anhydrous form, with a transition temperature close to 37°C. The insertion of a water molecule in the crystals grown below 37°C does not involve any other change of the crystal packing nor of the molecular conformation, but leads to different crystal growth mechanisms inducing different morphologies and distinct thermal behaviours.