Binding of Hydrophobic Guests in a Coordination Cage Cavity is Driven by Liberation of “High‐Energy” Water

The cavity of an M(8)L(12) cubic coordination cage can accommodate a cluster of ten water molecules in which the average number of hydrogen bonds per water molecule is 0.5 H‐bonds less than it would be in the bulk solution. The presence of these “hydrogen‐bond frustrated” or “high‐energy” water molecules in the cavity results in the hydrophobic effect associated with guest binding being predominantly enthalpy‐based, as these water molecules can improve their hydrogen‐bonding environment on release. This contrasts with the classical form of the hydrophobic effect in which the favourable entropy change associated with release of ordered molecules from hydrophobic surfaces dominates. For several guests Van't Hoff plots showed that the free energy of binding in water is primarily enthalpy driven. For five homologous pairs of guests related by the presence or absence of a CH(2) group, the incremental changes to ΔH and TΔS for guest binding—that is, ΔΔH and TΔΔS, the difference in contributions arising from the CH(2) group—are consistently 5(±1) kJ mol(−1) for ΔΔH and 0(±1) kJ mol(−1) for TΔΔS. This systematic dominance of ΔH in the binding of hydrophobic guests is consistent with the view that guest binding is dominated by release of “high energy” water molecules into a more favourable solvation environment, as has been demonstrated recently for some members of the cucurbituril family.