Theoretical Prediction of pKa in Methanol: Testing SM8 and SMD Models for Carboxylic Acids, Phenols, and Amines

Methanol is a widely used solvent for chemical reactions and has solvation properties similar to those of water. However, the performance of continuum solvation models in this solvent has not been tested yet. In this report, we have investigated the performance of the SM8 and SMD models for pK(a) prediction of 26 carboxylic acids, 24 phenols, and 23 amines in methanol. The gas phase contribution was included at the X3LYP/TZVPP+diff//X3LYP/DZV+P(d) level. Using the proton exchange reaction with acetic acid, phenol, and ammonia as reference species leads to RMS error in the range of 1.4 to 3.6 pK(a) units. This finding suggests that the performance of the continuum models for methanol is similar to that found for aqueous solvent. Application of simple empirical correction through a linear equation leads to accurate pK(a) prediction, with uncertainty less than 0.8 units with the SM8 method. Testing with the less expensive PBE1PBE/6-311+G** method results in a slight improvement in the results.