Characterization of the 2-(α-Carbolinyl)nitrenium Ion and Its Conjugate Base Produced during the Decomposition of the Model Carcinogen 2-N-(Pivaloyloxy)-2-amino-α-carboline in Aqueous Solution

The kinetics of the decomposition of the model ultimate carcinogen 2-N-(pivaloyloxy)-2-amino-alpha-carboline (4a), and its 9-methyl analogue (4b), in 20 vol % CH3CN-H2O, mu = 0.5 (NaClO4) at 20 degrees C, are consistent with the uncatalyzed N-O bond heterolysis of the neutral esters. The protonated ester 4aH(+) (pK(a) = 1.6), detected kinetically and by spectrophotometric titration, is unreactive under these conditions. Spectrophotometric titration of 4b also indicates that a protonated species, 4bH(+) (pK(a) = 0.9), is formed under acidic conditions. Both 4a and 4b produce electrophilic intermediates, identified as the nitrenium ions 5a and 5b, that are efficiently trapped by N-3(-), Br-, and 2'-deoxyguanosine, d-G, without an increase in the overall rate of decomposition of the esters. N-3(-) and d-G trapping efficiencies, k(az)(+)/k(s)(+) and k(d-G)(+)/k(s)(+), for 5a and 5b are very similar to each other and are within a factor of 4 of the trapping efficiencies with N-3(-) and d-G previously measured for the 2-fluorenylnitrenium ion (6). The trapping efficiencies for 5a, but not 5b, decrease with increasing pH. These results indicate that 5a is deprotonated at the indolyl nitrogen to produce a neutral intermediate (7a) that retains reduced reactivity with Br-, N-3(-), and d-G in an aqueous environment. The neutral 7a undergoes reduction and dimerization reactions in the absence of nonsolvent nucleophiles much more efficiently than its conjugate acid. Microscopic rate constants for trapping of 5a and 7a by the three nucleophiles and the pK(a) for ionization of 5a to produce 7a have been estimated from experimental data, from the assumption of diffusion control of the reaction of 5a with N-3(-), and by analogy to the reactions of structurally related species. The relatively low mutagenicity and carcinogenicity of the parent amine, 2-amino-alpha-carboline (3a), may be related to the fact that the less selective neutral species 7a is responsible for the reaction with nucleophiles at neutral pH.