The site of protonation of a distorted bicyclic lactam: Nitrogen vs oxygen

Protonation of typical unstrained amides and lactams is favored at oxygen. Protonation of highly distorted lactams such as 1-azabicyclo[2.2.2]octan-2-one is favored at nitrogen. Density function theory calculations at the B3LYP/6-31G* level, as well as QCISD(T)/6-31G* calculations, predict that 1-azabicyclo[3.3.1]nonan-2-one favors protonation at nitrogen only very slightly (\u3c2.0 kcal/mol; gas phase ) over protonation at oxygen. 1H and 13C NMR as well as ultraviolet (UV) studies of this lactam, confirm the lactam is primarily protonated at the nitrogen. Experimental spectra clearly support the N-protonated boat-chair, in contrast the calculations show the N-protonated chair-chair conformation is lower in energy. Broadened resonances in the 13C NMR spectrum suggest an exchange phenomenon. Variable-temperature studies of the 13C NMR spectra support dynamic exchange between the major tautomer (N-protonated) and the minor tautomer (O-protonated) in a roughly 4:1 mixture