Complexation of (RS)-benzhexol with β-cyclodextrin: structure elucidation of diastereomeric complexes by use of quantitative 1H-1H ROESY and computational methods

Abstract

The structural aspects of the complexation of (R)- and (S)-benzhexol with β-cyclodextrin (β-CD) were explored using quantitative rotating-frame overhauser effect spectroscopy (ROESY) analysis and molecular mechanics (MM) and molecular dynamics (MD) simulations. Several modes of penetration of phenyl ring, studied by MM2 minimizations, confirmed preference for wide side entry. MD simulations were performed through wider side only and interproton distances between phenyl ring of benzhexol (BEN) and β-CD cavity obtained from lowest energy structures were used to calculate relative ROESY peak intensities. The structures for which calculated intensities were found in better agreement with experimental were then fine-tuned to obtain proposed structures. The results show that highly symmetrical cyclodextrin should be used for computational studies and kept static throughout the simulation. The energy should not be taken as the only criterion for final selection but a comparison of calculated ROESY intensity ratios with experimental ratios is better. The results also imply that ROESY peak intensity ratios can be used for quantitative purposes even with higher mixing time.