Computing pK(a) Values in Different Solvents by Electrostatic Transformation

摘要

We introduce a method that requires only moderate computational effort to compute pK(a) values of small molecules in different solvents with an average accuracy of better than 0.7 pH units. With a known pK(a) value in one solvent, the electrostatic transform method computes the pK(a) value in any other solvent if the proton solvation energy is known in both considered solvents. To apply the electrostatic transform method to a molecule, the electrostatic solvation energies of the protonated and deprotonated molecular species are computed in the two considered solvents using a dielectric continuum to describe the solvent. This is demonstrated for 30 molecules belonging to 10 different molecular families by considering 77 measured pK(a) values in 4 different solvents: water, acetonitrile, dimethyl sulfoxide, and methanol. The electrostatic transform method can be applied to any other solvent if the proton solvation energy is known. It is exclusively based on physicochemical principles, not using any empirical fetch factors or explicit solvent molecules, to obtain agreement with measured pK(a) values and is therefore ready to be generalized to other solute molecules and solvents. From the computed pK(a) values, we obtained relative proton solvation energies, which agree very well with the proton solvation energies computed recently by ab initio methods, and used these energies in the present study.