Elucidation of the enantiomer migration order of atenolol by theoretical calculations

Enantioselective separation of atenolol (ATL) enantiomers employing carboxymethyl-β-cyclodextrin as chiral selector has been reported in a limited number of studies. However, none of these experimental works achieved enantiomer assignment, precluding the elucidation of the enantiomeric migration order (EMO). In this sense, to elucidate for the first time the fundamental principles governing the enantioselective recognition of atenolol enantiomers, we conducted a comprehensive theoretical study of the formation mechanisms of their inclusion complexes. As main result, based on structural, electronic, and energetic properties, we were able to indicate that (-)-(S)-ATL is anticipated to exhibit a prolonged migration time compared to (+)-(R)-ATL. This differential migration behavior stems from the stronger interaction between (-)-(S)-ATL and the chiral selector, resulting in a more stable inclusion complex and consequently, enhanced retention. These findings highlight the remarkable potential of molecular modeling techniques in deepening our understanding of enantioseparation mechanisms.