Study On The Resolution And Chiral Discrimination Of Two Halogenated Mandelic Acids By Diastereomeric Salt Formation

Optically active a-phenethylamine((S)-(-)-PEA)and N-benzylphenethylamine((R)-(+)-BPA)were used as resolving agents to resolve 4-Bromomandelic acid(4-BrMA)and 4-Fluoromandelic acid(4-FMA)by diastereomeric salt formation,the resolution effects were compared with 4-chloromandelic acid(4-ClMA).The results are as follows:Firstly,the resolution of 4-FMA by(S)-(-)-PEA and(R)-(+)-BPA were studied.The optimal resolution conditions were screened by orthogonal experiments.To understand the difference of thermodynamic properties between less and more soluble salts,melting point and melting enthalpy of the diastereomeric salts(S)-(+)-FMA*(S)-(-)-PEA,(S)-(+)-FMA'(R)-(+)-PEA,(S)-(-)-FMA·(R)-(+)-BPA and(R)-(+)-FMA·(R)-(+)-BPA were analyzed by DSC and 1H-NMR.Crystal structure of less soluble salts(S)-(+)-FMA-(S)-(-)-PEA and more soluble salts(S)-(+)-FMA-(R)-(+)-PEA were determined by X-ray diffraction.The texting results show that the hydrogen bonding,Van der Waals interaction,halogen bond in less soluble salts are stronger than those in more soluble salt.Secondly,the resolution of 4-BrMA by(S)-(-)-PEA and(R)-(+)-BPA were studied.The optimal resolution conditions were determined by orthogonal experiments.The thermodynamic properties of diastereomeric salts(S)-(+)-BrMA·(S)-(-)-PEA?(S)-(+)-BrMA·(R)-(+)-PEA,(R)-(-)-BrMA-(R)-(+)-BPA and(S)-(+)-BrMA-(R)-(+)-BPA were determined by DSC and 1H-NMR.The crystal structure of less soluble salt(S)-(+)-BrMA·(S)-(-)-PEA,(R)-(-)-BrMA-(R)-(+)-BPA and more soluble salts(S)-(+)-BrMA·(R)-(+)-BPA were determined by X-ray diffraction.Through analyzing hydrogen bonds,CH/?,Van der Waals interaction,halogen bonds and other interactions in less and more soluble salts,The structure of less soluble salts are more compact than that in more soluble salt,Br...Br and Br...? type halogen bonds were also found in less and more soluble salts.Finally,the resolution efficiency of two halogenated mandelic acids(4-FMA,4-BrMA)under optimal conditions were compared with the resolution efficiency which was carried out from literature of 4-ClMA by same resolving agents(S)-(-)-PEA and(R)-(+)-BPA.Through the comparison of the melting point,heat of fusion and the role of halogen effects as well as the single crystal structure of the diastereomeric salts.The thermodynamic basis and chiral recognition mechanism on the resolution of halogen-substituted mandelic acid by PEA and BPA were recognized.