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

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.