Discrimination of Chiral BCPs by Möbius Cyclacene: A DFT Study.

Chiral discrimination plays a pivotal role in the development of enantiomerically pure pharmaceuticals, as stereochemistry directly influences both the pharmacological efficacy and safety profiles. In this study, a twisted nitrogen-substituted cyclacene comprising 15 fused benzene rings was employed as a host framework for the enantiomeric recognition of chiral bicyclo[1.1.1]pentane (BCP) analogues. Unlike conventional diastereomer-based chiral resolution methods, the cyclacene host enables direct enantiomeric discrimination of BCP analogues. The interaction behavior of four R/S enantiomeric pairs of BCP derivatives with the cyclacene host was systematically explored by using density functional theory (DFT) simulations. Key interaction parameters, including binding energies, hydrogen bonding, noncovalent interaction (NCI), and electron density difference (EDD) maps, were examined in detail. The results indicate that the R enantiomers exhibit stronger binding affinities and enhanced chiral selectivity relative to their S counterparts, as evidenced by a greater number of hydrogen bonds and more favorable host-guest interaction distances. Remarkably, BCP3 and BCP4 demonstrated the highest degrees of chiral discrimination, highlighting the nitrogen-substituted twisted cyclacene as a promising candidate for enantioselective separation. Collectively, these findings provide valuable theoretical insights into the rational design and development of advanced nanostructured host systems for selective chiral recognition and separation technologies. Furthermore, this study may contribute to the advancement of next-generation supramolecular materials for pharmaceutical purification, asymmetric sensing, and molecular-scale recognition systems, thereby supporting broader efforts toward safer drug development and more efficient enantiomeric separation methodologies.