Why heptakis(2,3-di-O-acetyl)-β-cyclodextrin can separate terbutaline enantiomers better than β-cyclodextrin: nonbonding and hydrophobic interactions

The chiral separation of terbutaline (TB) using β-cyclodextrins (β-CD) and its derivatives has aroused intensive interest. Herein, the enantioseparation mechanisms of β-CD and heptakis(2,3-di-O-acetyl)-β-CD (HAD-β-CD) towards TB are investigated by a molecular dynamics/quantum mechanics/continuum solvent model (MD/QM/CSM) approach based on the experimental data. One of the two experimentally predicted binding modes of HAD-β-CD/TB is confirmed by our approach and ascribed to the R-complex. R-TB is compactly included by HAD-β- CD: the aromatic ring is within the CD cavity, while the alkyl moiety is also included and almost parallel to the secondary rim of the CD. As indicated by the computed binding affinity, this tight binding mode of R-complex enhances the host–guest hydrophobic interaction and renders the R-complex significantly more stable than the S-complex. In contrast, the binding modes of R- and S-TB with β-CD are similar due to the poor flexibility of the host, which jeopardizes its ability to differentiate R- and S-TB.