Solvation Free Energies of Ion Dissociations in Dichloromethane: En Route to Accurate Computations

Calculating
accurate free energies for solution-phase reactions
is notoriously difficult. In our previous joint experimental and computational
studies, we observed a striking failure of quantum mechanical calculations
with popular implicit solvent models to even qualitatively reproduce
the experimental trends of dissociation free energies of numerous
proton-bound pyridine dimers in organic solvents [Pollice, R. . J. Am. Chem. Soc. 2017, 139(37), 13126–13140]; [Pollice, R. . Angew. Chem., Int. Ed. 2019, 58(40), 14281–14288]. In this article, we expand the computational
study of the dissociation of proton-bound pyridine dimers in the gas
phase and in dichloromethane (DCM). In an effort to determine the
prerequisites for reproducing the experimental trends and magnitudes
of the dissociation free energies (ΔGdiss) in solvent, we investigated the impact of accounting for the ensemble
free energy, umbrella sampling, thermodynamic integration, and explicit
solvation using semiempirical quantum mechanics and molecular mechanics.
We estimated the effect of conformational free energy contributions
with semiempirical quantum mechanics (SE). Molecular dynamics (MD)
with explicit solvation and classical molecular mechanics (MM) was
used as a method to treat not only the solute but also the solvent
configurational entropy. We found that explicit solvation with MM
is indeed capable of reproducing ΔGdiss in DCM for our test system within an acceptable error margin. We
analyze and discuss the results and limitations of our approach for
calculating the solvation free energy.