THE STRENGTH OF THE H-BOND: DEFINITIONS AND THERMODYNAMICS

This chapter analyzes thermodynamic parameters (ΔG°, ΔH°, ΔS°, and ΔC_p°) of the H-bond association equilibrium in gas-phase, crystalline solids, and non-polar and aqueous solvents. The key feature is the extrathermodynamic enthalpy-entropy compensation relationship, ΔH° = βS°, induced by the loss of degrees of freedom during H-bond formation and inducing a considerable reduction of the association constants (e.g., ΔG° ≅ 2/3 Δ/H° in gas-phase and ≅ 1/3 Δ/H° in non-polar solvents). H-bonds in aqueous solutions are mostly studied through drug-receptor binding thermodynamic data. A distinction is made between hydrophobic binding to cytoplasmic and hydrophilic binding to membrane receptors, respectively characterized by negative or nearly zero ΔC_p° values. The unifying aspect of all drug-receptor phenomena remains enthalpy-entropy compensation. This is interpreted in terms of solvent reorganization by the Grunwald and Steel (1995) theoretical model showing that solvent effects do not significantly affect the intrinsic ΔG° of the H-bonds which directly connect the drug to the receptor binding site.