Enantioseparation of three constitutional isomeric 2-(methylphenyl)propanoic acids by countercurrent chromatography

Abstract

2-(3-Methylphenyl)propanic acid and 2-(4-methylphenyl)propanoic acid were successfully enantioseparated by countercurrent chromatography using hydroxypropyl-β-cyclodextrin (HP-β-CD) as a chiral selector. 2-(2-Methylphenyl)propanoic acid was also studied to compare the enantioseparation ability of three isomeric 2-(methylphenyl)propanoic acids. Totally 20 mg of 2-(3-methylphenyl)propanic acid and 20mg of 2-(4-methylphenyl)propanic acid were enantioseparated individually by countercurrent chromatography. Recovery for the (±)-2-(3-methylphenyl)propanic acid enantiomer was in the range of 85%-90% with 98.0%-98.8% purity and recovery for the (±)-2-(4-methylphenyl)propanic acid enantiomer was in the range of 80%-83% with 97.0%-98.0% purity. The enantioseparation factor in countercurrent chromatography for 2-(4-methylphenyl)propanic acid and 2-(3-methylphenyl)propanic acid were 1.31 and 1.26, and the peak resolution in HPLC reached 2.2 and 1.4. However, no enantioseparation could be found for 2-(2-methylphenyl)propanic acid. In addition, the inclusion complexes were investigated by UV spectrophotometer. The inclusion formation constant of inclusion complex between 2-(4-methylphenyl)propanic acid, 2-(3-methylphenyl)propanic acid, 2-(2-methylphenyl)propanic acid and HP-β-CD were determined as 121.73 mol/L, 78.12 mol/L and 53.18 mol/L, respectively. The present results showed that enantiorecognition was greatly affected by substituted positions of methyl group on the benzene ring. Combined with our previous results, the steric hindrance had a significant effect on inclusion interaction between HP-β-CD and racemic 2-(substitutedphenyl)propanoic acids. No enantiorecognition could be achieved for 2-(substitutedphenyl)propanoic acids with ortho-substituent group on benzene, while the influence of meta- and para- group on enantiorecognition varies with different substituent groups on benzene ring.