Theoretical investigation of mono- and bi-function alkylating agents transformed from nitrosodimethylamine derivatives

In vivo, N-hydroxymethyl-methylnitrosamine (HMMN) and N-acetoxymethyl-methylnitrosamine (AMMN) are the activated derivatives of N-nitrosodimethylamine (NDMA) which is a potent carcinogen. The mechanistic pathway of the transformations of HMMN and AMMN have been investigated at B3LYP/6-311+G(d, p) level. The results show that the decomposition of HMMN to a mono-function alkylating agent proceeds through a stepwise mechanism involving isomerization and retro-ene reaction, in which the former is the rate-determining step in the gas phase with the energy barrier of about 24 kcal/mol. For the transformation of AMMN, a bi-function alkylating agent is produced via an intramolecular rearrangement mechanism which is similar to the Favorskii reaction.