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

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journal contribution
posted on 12.11.2019, 16:39 by Koichi Kodama, Kozue Kawasaki, Meng Yi, Kaguya Tsukamoto, Hiroaki Shitara, Takuji Hirose
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 technique has been successfully applied to the preparation of both pure enantiomers of m-Cl-MA.