The intrinsic reaction coordinate for neutral, base promoted, and N- and O-protonated acid catalyzed hydrolyses of formamide with a single H2O, H3O+, or OH- reactant are determined in MP2(FULL)/6-31G**//4-31G calculations. Of the four pairs of reactants or protonated intermediates, N-protonated formamide is the most easily hydrolyzed, the calculated barrier for the breaking of the C-N bond being 6 kcal/mol. Nucleophilic addition to the carbonyl carbon is barrierless for the reaction with hydroxide ion, but the resulting stable intermediate must overcome a barrier of 19 kcal/mol for scission of the C-N bond. While O-protonation is energetically favored over N-protonation by 14 kcal/mol, nucleophilic addition to C in O-protonated formamide faces a barrier of 24 kcal/mol to yield a tetrahedral intermediate, one which faces a further barrier of 16 kcal/mol for the breaking of the C-N bond. The neutral reactants face a barrier of 44 kcal/mol to yield products. N-protonation pyramidalizes nitrogen and results in a lengthening and weakening of the C-N bond, the same consequences as are incurred by a rotation about the C-N bond. The protonation of N is the essential step in crossing the activation barrier in each of the reactions, being the primary step in the N-protonated reaction. The possibility of N-protonation providing a single step mechanism for the acylation of a protease enzyme in the hydrolysis of peptides is discussed. © 1992 American Chemical Society.