Thiolytic decomposition of the carcinogen N-methyl-N′-nitro-N-nitrosoguanidine. A change in rate-limiting step with nucleophile basicity controls alkylating activity

Article abstract of DOI:10.1021/ja00049a017

The kinetics of the reaction of seven alkanethiolates with N-methyl-N′-nitro-N-nitrosoguanidine over the pH range 3-8.5 at 40 °C, ionic strength 1 M (KCl), are reported. Plots of k_obs against total thiol concentration are linear, and the slopes of these plots change as a function of pH. The changes in slope with pH are well-described by a rate law for decomposition of MNNG that is first-order in thiolate ion and first-order in neutral MNNG. Rate constants k₂′ for the reaction of the thiolates are determined. There is no significant buffer catalysis of the reactions of any of the thiolates in the pH range studied. In the case of the reactions of propanethiolate and trifluoroethanethiolate, two products, methylnitroguanidine (MNG) and the thiol ((RS)-N-nitroformamidine) adducts 1, were found to account quantitatively (98 ± 3%) for the nitroguanidine skeleton of the starting material. In the case of the other five thiolates, the percent yield of MNG was determined. The yields of MNG are independent of thiolate ion concentration or buffer concentration. The yield of MNG changes from 5% for the reaction of propanethiolate, the most basic thiolate, to 90% for the reaction of pentafluoropropanethiolate, the least basic thiolate. On the basis of the yields of MNG, which indicate the extent of reaction at the nitroso nitrogen for the different thiolates, specific second-order rate constants for the thiolate ion reaction at the nitroso nitrogen, k_DN, and for the thiolate ion reaction at the guanidino carbon, k_DA, are calculated from the total second-order rate constant, k₂′. The plot of log k_DN against pK_aRSH is linear with a slope β_nuc = 0.54 ± 0.02. A similar plot for log k_DA shows a downward break with decreasing thiol pK_a. The plot is consistent with a reaction that involves an anionic intermediate, T^-, the formation of which is rate-limiting for basic thiolates and the decomposition of which is rate-limiting for weakly basic thiolates. Limiting values of β_nuc consistent with the data were determined to be β_nuc = 0.70 ± 0.12 and 2.4 ± 0.2 for rate-limiting formation and breakdown reactions, respectively. The latter value is attributed to a late transition state for leaving group expulsion with a large imbalance in which C-N double bond formation lags behind leaving group expulsion. The results represent a good chemical model for the recently reported chemoprotective denitrosation reaction between glutathione and MNNG that is catalyzed by a glutathione S-transferase.