Cyclodextrin–adamantanecarboxylate inclusion complexes: A model system for the hydrophobic effect

Abstract

Abstract Thermodynamic studies of the binding of adamantanecarboxylate to cyclodextrins have been made as a function of temperature and added organic cosolvent (methanol) using flow microcalorimetry. The negative heat capacity change associated with the adamantanecar‐boxylate/β‐cyclodextrin interaction and the fact that the interaction is weakened by the addition of methanol implicate the binding process as being a hydrophobically driven one. The negative enthalpy change (Δ H 0 = −5.5 kcal/mol) and near‐zero entropy change (Δ S 0 = 1.5 cal/mol deg) are quite different from the values normally expected for a hydrophobic bond, indicating that other bonding forces are important in addition to the hydrophobic effect. The relative contribution of the hydrophobic effect and other bonding forces (most likely van der Waals forces) to the overall binding was judged from an analysis of the dependence of the thermodynamics of the association process on the surface tension of the water–methanol mixtures following a model for “solvophobic” bonding described by Sinanoglu [ Molecular Associations in Biology (1968) Academic Press, New York, pp. 427–445]. From this analysis, adamantane–carboxylate/cyclodextrin complex formation is found to be driven to the extent of −1.9 kcal/mol by the hydrophobic effect. Furthermore, the hydrophobic driving force is found to be characterized by a positive Δ S 0 of 10 cal/mol deg. The remaining free energy of binding (and the Δ H 0 of binding of ∼−6 kcal/mol) is then due to the intrinsic (surface‐tension‐independent) van der Waals interaction between the ligand and cyclodextrin cavity.