Novel bridgehead bicyclic lactams: (a) Molecules predicted to have O-protonated and N-protonated tautomers of comparable stability; (b) hyperstable lactams and their O-protonated tautomers

• We may have found examples of lactams that protonate on nitrogen and oxygen in equilibrium.
• Larger bicyclic lactams are predicted to be hyperstable in O-protonation.
• Winkler–Dunitz parameters may predict when the switch from O-protonation to N-protonation occurs.

The N- and O-protonated tautomers of 1-azabicyclo[3.3.1]nonan-2-one are predicted computationally to be comparable in stability. This was experimentally verified. The same theoretical models are employed to explore a wider range of bridgehead bicyclic lactams. Some additional examples are identified: some slightly preferring N-protonation and some O-protonation. Winkler–Dunitz parameters are employed to see if a pattern in geometry would emerge to help in the prediction of protonation preference. A number of larger bicyclic lactams are identified as possibly being hyperstable in O-protonation.