Resolution of β-blockers on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid: Unusual temperature effect

A chiral stationary phase (CSP) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid has been successfully employed in the liquid chromatographic resolution of eleven β-blockers containing a secondary amino functional group. As the result of an effort to find out the optimal mobile phase condition, the mixture of trifluoroacetic acid-triethylamine-ethanol-acetonitrile with the ratio of 0.1/0.5/20/80 (v/v/v/v) was concluded to be the best mobile phase condition, the separation (α) and the resolution factors (RS) for the resolution of 11 β-blockers being in the range of 1.13-1.85 and 1.36-5.79, respectively. Surprisingly, in contrast to the resolution of other racemic compounds containing a primary amino functional group, the separation factors (α) for the resolution of β-blockers were observed to improve as the column temperature increased and these unusual chromatographic behaviors were rationalized as the entropically controlled enantioselectivity.