EVIDENCE FOR INTERMEDIATES AND A CHANGE IN RATE-LIMITING STEP IN THE AMINOLYSIS OF THE CARCINOGEN N-METHYL-N'-NITRO-N-NITROSOGUANIDINE BY CYCLIC AMINES

Rate constants and products are reported for the decomposition of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stimulated by cyclic amines in aqueous solutions at 40-degrees-C, ionic strength 1 M (KCl). Plots of k(obs) against nucleophile are linear to a concentration of nucleophile up to 0.3 M. The slopes of the plots change as a function of pH. There is no evidence of significant buffer catalysis of the reactions in control experiments containing up to 0.5 M buffer. In the pH region from 4 to 8.5, the second-order rate constants, corrected for concentration of the acid form of MNNG and free base of the amine, increase with increasing pH and level off to a pH-independent reaction in the cases of imidazole, 3,5-dimethylpyrazole, and pyrazole. The downward break in the pH rate profiles and the absence of buffer catalysis require a change in the rate-limiting step involving two, presumably tetrahedral, intermediates that are in protonic equilibrium in the pH-dependent region. It is concluded that the rate-limiting step for the pH-independent reaction involves nucleophilic attack on MNNG while leaving group expulsion from an anionic intermediate, T-, is rate-limiting for the pH-dependent region. This represents the first evidence for reaction intermediates in the nucleophile-stimulated decomposition of MNNG. The corrected second-order rate constants for the reactions of 1,2,3- and 1,2,4-triazoles are strictly pH-dependent over the same pH range. A comparison of the rate constants for the reaction of 1,2,4-triazole with those of pyrazole indicates that the reaction of triazoles involves a direct attack of triazole anion on MNNG with subsequent rate-limiting leaving group expulsion from T-. These conclusions require that the N-nitrosomethylamine anion is a worse leaving group from the intermediate T- than the 1,2,4-triazole anion in spite of the fact that the triazole anion is estimated to be more than 3 orders of magnitude more basic. The unreactivity toward MNNG of certain amine nucleophiles, such as 4-(dimethylamino)pyridine, that are incapable of proton loss subsequent to nucleophilic attack further substantiates the conclusion that the N-nitrosomethylamine anion is an unexpectedly poor leaving group.