Accurate acid dissociation constant (pK_a) calculation for the sulfachloropyridazine and similar molecules

Accurate calculation of the acid dissociation constant (pK_a) has fundamental importance for the description of molecular systems with pharmacological activities. The search for a more appropriate procedure for its determination is always welcome and has aroused increasing interest from the scientific community. In this sense, this work presents a computational study involving the combination of ten DFT functionals (M062X, M06L, B3LYP, BLYP, PBEPBE, BP86, LC-BLYP, SPBE, CAM-B3LYP, LC-PBEPBE) and HF method, eight basis set functions (6-311G, 6-311 + G, 6-311G(d,p), 6-311 + G(d,p), 6-311+ +G(d,p), 6-311(2d,2p), 6-311+ +G(2d,2p), and aug-cc-pVDZ), and three solvation models (SMD, PCM, and CPCM) for an accurate sulfachloropyridazine (SCR) pK_a determination. It was found that the smallest deviation (0.02 unit of pK_a) between the current study and experimental result was achieved with the BLYP/6-311 + G(d,p)/PCM combination. Therefore, this combination was extended to calculate the pK_a of six SCR similar molecules selected through the eletroshape similarity method. For all these molecules, the difference between the obtained results and experimental data ranged between 0.14 and 0.69 units of pK_a. This feature suggests that the obtained combination can determine pK_a with experimental precision for complexes that are formed by sulfonamide functional group (SO₂NHR). Graphical Abstract A computational study involving the combination of different levels of theory, basis sets and solvation models for an accurate sulfanamide pK_a determination.