Entropy contributions in pKa computation: Application to alkanolamines and piperazines

The pKa values of 17 amines, alkanolamines, and piperazines have been computed using quantum chemistry techniques and the IEFPCM continuum solvation model. Several techniques were tested, including B3LYP and MP2 levels of electronic structure theory, the addition of an explicit water molecule inside the continuum cavity, and special scaling of cavity radii for ions. Entropy corrections for multiple conformers, often neglected in pKa studies, are discussed and utilized. The use of explicit water inside the cavities reduced the pKa rms error by 34%. As noted several years ago, ringed compounds do seem to be pathological cases for continuum solvation models, and the use of a second fitting parameter for these compounds dramatically lowered the overall rms error a further 42-45%, to below 0.9. Our best procedure reduces the errors found in a previous technique for similar compounds by 62%.