Free Energy of a Solvent Molecule: Conventional Ideal Gas Approximation versus Experimental Thermodynamics Data

Incorporating solvent molecules into computational models is often essential for obtaining reliable results, yet the common approach for computing their free energies relies on the ideal gas approximation that is hardly accurate for a solvent. Here we extract accurate free energy contributions for several solvents from experimental thermodynamics data, compare them to values obtained with conventional computational approaches, and benchmark them on a set of solvent-ligand exchange reactions with accurately measured enthalpies and entropies. While the conventional approaches usually provide free energy contributions <1 kcal/mol from the experimental ones, in some cases they deviate by ∼2 kcal/mol. In such cases, the experimental free energy contributions provide 1-2 kcal/mol more accurate results for solvent-ligand exchange reactions, showing that experimentally derived pieces of energy can be combined with computed ones to yield improved results. Thus, we recommend the use of experimental solvent free energy contributions to model processes involving coming or leaving of solvent molecules when they act as reagents or active participants as in highly polar transition states or intermediates.