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.