Gas-phase acidity of sulfonamides: implications for reactivity and prodrug design

A computational study at the density functional theory level was performed on bioactive and model sulfonamides with the aim of determining the factors affecting the acidity of the sulfonamido group. The effects of introducing different substituents at either the para-aryl or the N¹-sulfonamide positions were independently analyzed. A linear correlation was found between sulfonamide acidity and the Hammett constants or charge of the SO₂ group of substituents at the para-aryl position. Most N¹-substituents were taken from bacteriostatic sulfonamide structures and presented a more complex behavior, possibly due to a conjugation of steric and electronic factors. In the latter situation, sulfonamide acidity and the charge of the SO₂ group were not linearly correlated. Interestingly, the acidity of the sulfonamido group was found to be correlated with the reactivity of sulfa drugs towards acylating agents. The implications for the design of suitable sulfonamide prodrugs are discussed.