Resonance theory suggests a useful analogy between alkenes and amides (or lactams). Bicyclo[2.2.2]oct-1-ene violates Bredt's rule and is extremely short-lived; derivatives of 1-azabicyclo[2.2.2]octan-2-one are easily hydrolyzed. The resonance energy of 1-azabicyclo[3.3.1]nonan-2-one is about midway between 0 kcal/mol (as in the bridgehead [2.2.2] lactam) and the full 18-20 kcal/mol of an undistorted amide. Hartree-Fock and DFT calculations predict that protonations on N and on O in the [3.3.1] system are nearly isoenergetic and this is confirmed experimentally- the only system in which both tautomers are seen in equilibrium (other potential examples will be presented). Despite the reduced resonance energy, the [3.3.1] molecule is unreactive with dimethyldioxirane, in contrast to the Kirby lactam that appears to form a short-lived lactam N-oxide. Study of the presently unknown 1-methyl-4-silatranone predicts a ground-state lactam structure but a silatrane-like lactam ring inversion transition state. Such a medium-ring bridgehead bicyclic lactam would furnish an analogue to the hyperstable bridgehead alkenes discovered by Maier and Schleyer.

Testing delocalization of the nitrogen lone pair in bridgehead bicyclic lactams

254th National Meeting (2017)

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