Solvent-Induced Chirality Switching in the Enantioseparation of Halogen-Substituted Mandelic Acids: Structural Effects on Molecular Packing

Abstract

The solvent effect on the enantioseparation of halogen-substituted mandelic acid derivatives via diastereomeric salt formation has been investigated. The diastereomeric salts of para-halogen-substituted mandelic acid derivatives (p-X-MA) were obtained with high efficiency. In addition, both diastereomeric salts of p-F-MA were successfully obtained by controlling the concentration of the acetone solution. Efficient solvent-induced chirality switching was generally observed for meta-halogen-substituted mandelic acid derivatives (m-X-MA). Water, aprotic solvents, and short-chain alcohols such as i-PrOH gave the (S)-salt, whereas the (R)-salt is preferentially formed from long-chain alcohols such as n-BuOH and s-BuOH. Crystallographic analysis of the salts showed that the inclusion of the alcohol solvent in the diastereomeric salts changed the hydrogen-bonding network and molecular packing. The molecular packing was dependent on the size of the halogen substituents and the solvent used. Finally, this techniqu...