Enantioselective recognition of metaclazepam enantiomers by cyclodextrins studied using capillary electrophoresis, NMR spectroscopy and molecular modeling

In the present study, an attempt was made to explain enantioselective noncovalent interactions of metaclazepam (MCZ) enantiomers with three native cyclodextrins (CDs) with different cavity size by combined use of capillary electrophoresis (CE), nuclear magnetic resonance (NMR) spectroscopy and quantum-mechanics (QM) calculations. With CE, it was observed that the medium size β-CD binds the enantiomers of MCZ most strongly although with very low enantioselectivity. The affinity of the MCZ enantiomers was lowest towards α-CD. Both α- and β-CDs bind (R)-MCZ more tightly than (S)-MCZ, while the opposite is the case with γ-CD. ROESY experiments in NMR spectroscopy provided an explanation of the affinity strength of MCZ enantiomers towards the studied CDs based on the extent of insertion of the guest molecule into the cavity of CDs. QM calculations indicated the importance of intermolecular hydrogen bonding in selector-selectand interactions, as well as supported experimentally observed enantiomer affinity pattern towards CDs under this study. On the other hand, binding energy values calculated using QM did not always correlate with the binding strengths experimentally observed in CE. In addition, binding energy differences calculated based on QM are at least one order of magnitude higher when compared to the binding energy differences calculated based on the selectivity of enantioseparations in CE. Thus, QM tools need further development (refinement) in order to properly describe fine noncovalent interactions between CDs and their guests.