We present an ab initio study of the pK(a) of a series of twisted amides in aqueous solution. The shift of the pK(a) with respect to the known value for trimethylamine (TMA) is used in the evaluation. Calculations were made with density functional theory using the B3PW91 functional. Aqueous solvent effect is introduced by use of the polarizable continuum model. The protocol is tested on a series of tertiary amines and twisted amides, and a good agreement with the available experimental data is found. Finally, mechanistic implications of the change in basicity of the nitrogen as a function of the twist of the amide bond for the activation of C-N bond hydrolysis are discussed.