Quantum-chemical predictions of pKa's of thiols in DMSO.

The deprotonation of thiols (on the S-H bond) is widely involved in organic and bio-organic reactions. With the aid of density functional theory (DFT) calculations, the present study focuses on predicting the pKa's of thiols. Efforts were first put in searching for an appropriate computational method. To achieve this goal, the accuracy of 13 different DFT functionals (i.e., B3LYP, BB1K, PBE, M06, M05, M06-2X, M06-L, M05-2X, TPSS, MPW1K, MPWB1K, MPW3LYP, TPSSLYP1W) and 6 different total electron basis sets (6-31G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p), 6-311++G(d,p), 6-311++G(2df,2p)) (with DMSO solvent and SMD solvation model) were examined. The M06-2X/6-311++G(2df,2p) (M1) method was found to give the best performance in reproducing the reported 16 pKa's of thiols, with a standard deviation (SD) of about 0.5 pKa unit. Meanwhile, the M1 method was found to be excellent in reproducing the gas phase Gibbs free energies of 17 thiols, providing extra evidence for the reliability of the M1 method in treating thiol systems. On this basis, M1 was then used to predict the pKa's of 291 thiols whose experimental pKa values remain unknown. Accordingly, the scope of pKa's of different thiols was constructed.