Acyl group vs nitrogen protonation of carboxylic and non-carboxylic amides in the gas phase and water

The site of protonation of carboxylic and non-carboxylic amides (whether the amido nitrogen or an atom in the acyl group, generally oxygen) was investigated through quantum chemical calculations and heteronuclear NMR measurements. The relative energies of the various ions deriving from protonation at each site were calculated both in the gas phase and in water, and NMR properties of the involved heteronuclei (nuclear shielding and electric field gradient) were also calculated and compared with chemical shins and relaxation rates experimentally measured in N-14, O-17 and P-31 spectra. It is shown that such a combination of theoretical and experimental tools allows the reliable prediction of spectral parameters and ultimately of the protonation site. In general, amides are protonated at the acyl group, with the exception of (a) when the parent acid is strong (for which the preference is not marked), (b) the protonation site of sulfinamides may easily shift from N to O as a result of slight structural changes and (c) sulfenamides behave as substituted amines and are nitrogen bases.