Origins of regio- and stereoselectivity in acid-promoted reactions of alpha-lactams

alpha-Lactams (aziridinones) have been shown to react with nucleophiles at both the acyl (C-2) and alpha (C-3) carbons. Products of C-2 attack are obs erved with strong nucleophiles, and products of C-3 attack are observed wit h weak nucleophiles in the presence of Bronsted and Lewis acids. C-3 attack proceeds with inversion of configuration at the C-3 carbon. A cationic int ermediate activated toward C-3 attack has been implicated in this substitut ion process, but the structure of this intermediate is unknown. Density fun ctional theory calculations (at the B3LYP/6-31G(d) level) were used to exam ine various candidate structures for this intermediate and to assess their reactivity. Initial protonation on oxygen or nitrogen leads to several cycl ic cations with relative energies within several kcal/mol of each other. Di rect nucleophilic attack at both C-2 and C-3 of these structures was examin ed, and the substitution transition state with the lowest relative energy c orresponds to C-3 attack on the O-protonated species with inversion of conf iguration at C-3. This mechanism is consistent with the experimental result s.