Site of protonation of carboxylic and non-carboxylic amides in the gas phase and in water

The site of protonation of several types of amide bases (carboxylic amides and thioamides, sulfenamides, sulfinamides, sulfonamides, nitrosamides, nit ramides, cyanamides, and phosphorous and phosphoric acid triamides) has bee n investigated through a combination of quantum chemical calculations and h eteronuclear NMR measurements. Relative energies of tautomeric ions derivin g from protonation at the various sites were determined both in the gas pha se (by MP2 calculations) and in water (by the IPCM continuum solvation meth od). Relevant NMR properties of the involved heteronuclei (nuclear shieldin g and electric field gradient) were calculated at the GIAO-HF level, and co mpared with chemical shifts and relaxation rates experimentally measured in N-14,O-17, and P-31 spectra. It is shown that such a combination of theore tical and experimental tools allows a dependable prediction of spectral par ameters and ultimately of the protonation site of amides. The reliability o f common assumptions, like the comparison of spectral parameters of polyfun ctional bases and monofunctional models, is also scrutinized and tested.