where n rot is the number of rotatable bonds. Gas phase PM3 calculations were complemented with the prototypical solvents used in EAS chemistry, chloroform (dielectric = 4.8) and N,N-dimethylformamide (DMF, dielectric = 37.0). Structures where protons have transferred and/or other bonds were broken are removed from the analysis. Gas phase, chloroform, and DMF were evaluated using PM3 and the COSMO solvation model in MOPAC. PM3/COSMO was chosen because it gave the best results in a previous study of amine pK a values. It is important to include solvent as gas phase calculations failed for fourteen cases versus three and four cases for chloroform and DMF, respectively. Predictions with chloroform as a solvent resulted in nine or ten incorrect predictions using PM6 and PM7 or AM1 and PM6-DH+, respectively. In summary, PM3/COSMO/chloroform gave the most correct predictions and further work was limited to this method henceforth referred to as RegioSQM.