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

Abstract

Thiol compounds have been shown to be important in many fields such as protein chemistry and carbohydrate chemistry. Their pK_a'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 pK_a's of thiols, pK_a's of 58 thiols were calculated using different DFT methods with two types of solvation models including PCM-Bondi and SMD_sSAS. It was found that the M06-2X method with the SMD_sSAS model can give the optimal precision with the smallest RMSE value of 0.77 pK unit. Based on this model, the pK_a'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 pK_a 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 pK_a's. Good linear relationships between the pK_a's with substituent constants σ_p⁺ and natural charges on S atoms were observed in different types of thiols.