1997 Alfred Bader Award Lecture Reactivities of arylnitrenium ions with guanine derivatives and other nucleophiles

The carcinogens 4-aminobiphenyl and 2-aminofluorene are metabolized to hydroxylamine esters that undergo N-O heterolysis to produce arylnitrenium ions that react with DNA, especially at guanine residues. These nitrenium ions and a number of their derivatives have been studied by the laser flash photolysis technique, to provide direct kinetic information about the lifetimes of the electrophiles in water and their reactivities with added nucleophiles. Arylnitrenium ions ArNH + are longer-lived in water than arylcarbenium analogs ArCH 2 + , in some cases significantly longer-lived. The nitrenium ions do react with azide ion at the diffusion limit (providing the cation is not highly stabilized). This behaviour completely parallels that of carbenium ions. The biphenylyl- and fluorenylnitrenium ions react with guanine derivatives such as 2-deoxyguanosine (dG) with rate constants that are close to or at the diffusion limit (2 × 10 9 M -1 s -1 ) for the more reactive cations. Thus, in spite of cation lifetimes of the order of 100 ns to a millisecond in water, dG effectively competes with the solvent. The product is a C8 adduct, the same adduct observed with carcinogenic arylamines and DNA. With delocalized carbenium ions that have similar lifetimes, guanine derivatives compete very poorly with water. Thus, arylnitrenium ions have high dG:water selectivities; arylcarbenium ions have low selectivities. Nitrenium ions and carbenium ions do have parallel reactivities with primary alkyl amines. More reactive cations show a greater reactivity with less basic amines and the rate constants level below the diffusion limit. This can be explained by hydrogen bonding of the amine lone pair. Using the NH 2 group of the alkyl amines as a model for the C 2 -NH 2 group of guanine shows why nitrenium ions show no detectable reactivity at this site. The rate constant for the nitrenium-guanine reaction that forms the C8 adduct is at least an order of magnitude greater than that of a nitrenium-NH 2 reaction. Nitrenium ions do form a guanine-NH 2 adduct in DNA, suggesting that incorporation into the polymer changes reactivity patterns. With imidazoles, nitrenium ions show reactivity trends that parallel the nitrenium-dG reaction, with rate constants levelling at the 2 × 10 9 limit for the more reactive cations. Imidazole itself and 1-methylimidazole are generally less reactive than dG, while 2-methylimidazole and 1,2-dimethylimidazole are very similar. A Brönsted-like plot incorporati