Thermodynamic study of N-trifluoroacetyl-O-alkyl nipecotic acid ester enantiomers on diluted permethylated β-cyclodextrin stationary phase

Thermodynamic studies were performed on 12 pairs of N-trifluoroacetyl-O-alkyl nipecotic acid ester enantiomers on diluted permethylated β-cyclodextrin stationary phase (CP Chirasil-Dex CB). The influence of ester alkyl group structure on interaction with permethylated β-cyclodextrin (Me-CD) and enantioselectivity was studied. The types of alkyl groups studied included n-alkyl (C1–C5) and groups containing branching at differing locations relative to the chiral center of the molecule. The results show that for a given molecular weight, the n-alkyl esters have stronger interactions with Me-CD than esters containing branched alkyl groups. However, although having weaker interactions with Me-CD, esters containing α-branched alkyl groups exhibit higher enantioselectivity than the corresponding n-alkyl or β-branched isobutyl esters. From the retention data, thermodynamic parameters were estimated using the retention increment method and enthalpy–entropy compensation plots (ln R′ versus ΔH) were constructed. The results suggest that ester enantiomers with branching at the α-carbon of the ester alkyl group have additional and/or different types of enantioselective interactions with Me-CD than the C1–C5 n-alkyl esters or β-branched isobutyl ester. In order to obtain a qualitative sense of the interaction with Me-CD, structures of the diastereomeric complexes formed between Me-CD and some of the ester enantiomers were modeled using simulated annealing molecular dynamics.