Theoretical modeling of pKa's of thiol compounds in aqueous solution

Thiol compounds have been shown to be important in many fields such as protein chemistry and carbohydrate chemistry. Their pKa's in aqueous solution are important for understanding the properties and reactivities of thiols in complex biochemical systems. To elucidate the structure–activity relationships and substituent effects on pKa's of thiols, pKa's of 58 thiols were calculated using different DFT methods with two types of solvation models including PCM-Bondi and SMDsSAS. It was found that the M06-2X method with the SMDsSAS model can give the optimal precision with the smallest RMSE value of 0.77 pK unit. Based on this model, the pKa's of thiols (R-SH in which R = alkyl, cycloalkyl, aryl, heterocyclyl and fluorinated hydrocarbyl) were systematically investigated. The substituent effects as well as the structure–activity relationships behind these data were also examined. Significant substituent effects were found in heterocyclyl, alkynyl and fluorinated hydrocarbyl thiols with a wide pKa range of over 10.0 pK units. In addition, analyses including the natural bond orbital (NBO) and the energies of frontier orbitals were performed in order to further understand the substituent effects on pKa's. Good linear relationships between the pKa's with substituent constants σp+ and natural charges on S atoms were observed in different types of thiols.