Defining the pH* Scale in Methanol: Determination of Accurate Values for the Solvation Free Energies of CH3OH2+ and CH3O- in Methanol.

A correction factor for the autoprotolysis constant of methanol is proposed in the present work to obtain thermodynamic data for the standard solvation free energies of CH3OH2+ and CH3O- ions in methanol and pKa*. Using this corrected constant, KMOH*, along with known values for the standard solvation free energy of proton ΔGsol*(H+) and of the methanol molecule ΔGsol*(CH3OH), in its own liquid, in three different thermodynamic cycles, we obtain ΔGsol*(CH3OH2+) = -91.41 ± 2.76 kcal mol-1, ΔGsol*(CH3O-) = -88.36 ± 2.10 kcal mol-1, and pKa*(methanol) = 22.67 ± 2.97. To validate our approach, we applied the same thermodynamic cycles for water in its own liquid, resulting in experimental values of ΔGsol*(H3O+) = -110.20 ± 1.91 kcal mol-1, ΔGsol*(OH-) = -104.60 ± 0.25 kcal mol-1, and pKa(water) = 15.73 ± 1.42. Employing quantum mechanics calculations combined with Monte Carlo simulation, we calculated the standard deprotonation free energy and the pKa values of water and methanol in their respective liquids. These calculations were performed using an explicit model of the solvent, with Free Energy Perturbation theory in Monte Carlo simulation (FEP-MC), three different pure implicit solvation models (HF-PCM, the Conductor-like Polarizable Continuum Model (C-PCM), the solvation model based on density (SMD)), and a hybrid model (cluster-SMD). Excellent agreement with experimental data was achieved using FEP-MC, HF-PCM, and cluster-SMD. Methanol is the simplest alcohol, and its pKa* value is a critical parameter in chemical and biological systems. Hence, its understanding, along with its pH* scale, enables better control and utilization of methanol in diverse applications, ranging from pharmaceuticals to industrial processes.