Application of a generalised enthalpy–entropy relationship to binding co-operativity and weak associations in solution

Abstract

Enthalpy–entropy compensations are a consequence of weak associations where the binding enthalpy is much lower than typical covalent bond strengths. The general form of an enthalpy–entropy curve is presented based upon theoretical considerations and justified on the basis of experimental data for associations in the gas phase and for monatomic sublimation. The intrinsic curvature of the enthalpy vs. entropy plot provides the basis for a description of co-operativity and binding phenomena in solution. In the case of cooperativity, we divide the mutual aiding of two interactions into two distinct parts, one of which is entropic in origin and related to the classical chelate enhancement of binding of Jencks; the other is an enthalpic benefit due to improved electrostatic bonding. Since the experimental Gibbs energy for all weak associations in solution is a consequence of competing solute–solvent, solvent–solvent and solute–solute interactions, the summation of these interactions can be usefully described by a vector analysis using the enthalpy–entropy curve. We illustrate the utility of this approach by presenting a qualitative description of the various contributions to binding in the following examples: (i) one-point associations in non-polar solvents, (ii) entropy-driven association of two large discs involving the release of multiple solvent molecules and (iii) enthalpy driven associations involving metal chelation by polyamines. By considering the curvature of the enthalpy–entropy plot for a given interaction, in combination with the possibility of making or breaking multiple interactions on one template, net enthalpies and entropies of association in solution can be explored in an approximate manner.