Dissecting Hydrophobic and Hydrogen-Bonding Contributions in the Rim Binding of Pyromellitic Diimides to β-Cyclodextrin

Abstract The relative contributions of hydrophobic interactions and hydrogen bonding in cyclodextrin host–guest systems remain a fundamental challenge in supramolecular chemistry. In the present study, a series of pyromellitic diimide (PMDI) derivatives bearing alkyl substituents of different sizes was employed to investigate the origin of rim-binding interactions with β-cyclodextrin (β-CD). NMR, ROESY and ICD studies established that PMDIs interact with β-CD through the narrow rim, with the alkyl substituents penetrating the cavity. The PMDI chromophore remained outside the cavity of the β-CD. In contrast, α-cyclodextrin (α-CD) complexes underwent shallow binding through their wider rim. The 13C NMR experiments revealed the presence of hydrogen-bonding interactions between PMDI carbonyl oxygens and the primary hydroxyl groups of β-CD. DFT calculations reproduced the experimentally observed binding geometries for both α- and β-CDs. NCI-RDG, NBO and QTAIM analyses confirmed the coexistence of hydrogen-bonding and weak dispersive/van der Waals contacts that are structurally consistent with hydrophobic inclusion. The computational studies also showed that β-CD complexes exhibited stronger hydrogen bonds than the corresponding α-CD complexes. Temperature-dependent ITC revealed distinct thermodynamic signatures for the two cyclodextrins. The α-CD complexes displayed small positive or near-zero heat-capacity changes and strongly entropy-driven binding, indicating shallow association dominated by solvent release and weak hydrophobic interactions. In contrast, β-CD complexes showed a systematic transition from hydrogen-bond-dominated binding for H-PMDI to cooperative weak dispersive/van der Waals interactions and hydrogen-bond stabilization for tert-butyl-substituted PMDI. The heat-capacity changes and enthalpy–entropy compensation behavior collectively demonstrated that the relative contributions of hydrophobic interactions and hydrogen bonding can be tuned through the size of the alkyl substituent and the cyclodextrin cavity.