Theoretical Study on Acidities of (S)-Proline Amide Derivatives in DMSO and Its Implications for Organocatalysis

The acidities (pKa values) of proline amide derivatives are of great importance for understanding the catalytic activity of proline-based organocatalysts. The development of new catalysts could also benefit from the systematic study of the pKa values of these compounds. However, only a few pKa values of the proline-based organocatalysts are currently available due to the difficulty in experimentally measurements. In this work, we set out to study the pKa values of various proline amide derivatives with theoretical calculations. Different theoretical methods were evaluated and the combined method, B3PW91/6-311++G(3df,2p)//B3LYP/6-31+G(d)//HF//CPCM/UA0, was found to be the best one in reproducing the pKa values of structurally unrelated amides and amide derivatives in DMSO. The MAD and RMSE of the newly developed theoretical model equal to 0.98 and 1.3 pK units, respectively. The method also enabled the systematically study on various structural effects on pKa values of proline amide derivatives, such as th...