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

Abstract

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 ArCH2+, 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 × 109 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 NH2 group of the alkyl amines as a model for the C2-NH2 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-NH2 reaction. Nitrenium ions do form a guanine-NH2 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 × 109 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 incorporating points for dG, primary amines and imidazoles shows no correlation of nitrenium rate constants with nitrogen basicity. This is true even if only dG and imidazoles are considered. Thus a previous correlation of nitrenium reactivity with purine N7 basicity is suspect. The conclusion is that there is some feature of guanine that makes its reaction with nitrenium ions unusually fast. The reasons for this are not immediately apparent, especially since there is conflicting evidence as to the detailed nature of the mechanism of the reaction that forms the C8 adduct. Key words: nitrenium, aryl azide, guanine, DNA, carcinogen.

Singlet and triplet states in the reactions of nitrenium ions

“…This type of DNA damage can, under certain circumstances, convert a healthy cell into a cancer cell. This proposal has been discussed at length in a number of recent articles and reviews [3][4][5][6][7][8][9][10] and it will not be considered further here other than to note that the relevant reactions appear to be characteristic of the singlet state (see below).…”

General Photo‐Patterning of Polyelectrolyte Thin Films via Efficient Ionic Bis(Fluorinated Phenyl Azide) Photo‐Crosslinkers and their Post‐Deposition Modification

“…For example, laser flash photolysis has established that solvation in MeOH causes rapid intersystem crossing, probably through hydrogen-bonding stabilization of the triplet state in solution, [36] while solvation in H 2 O causes protonation of the singlet nitrene which is then attacked by H 2 O to give imine and quinone intermediates. [34,35] It will not be surprising that these occur here in the solid-state as well, thereby depleting the singlet nitrene population. Figure 6.…”

“…This indicates significant loss of the nitrene intermediate to side-reactions, which could include solid-state protonation of the nitrene intermediate, analogous to that already known in acid solutions [33] and pure water, [34] followed by nucleophilic degradation. [35] Nevertheless reproducible crosslinking of this material can still be achieved at practical levels of ionic bisFPAs.…”

Aryl Nitrenium Ions in Aqueous Solution

“…The suggestion in the late 1960s that 1 is the reactive intermediate responsible for the carcinogenicity of metabolites of aromatic amines, 12 and the substantiation of that proposal during the 1990s, [13][14][15][16][17] spurred research into the reactions of 1 in water. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] Many reactive examples of 1 have lifetimes in water in the microsecond range making it possible to detect and characterize the cations during laser flash photolysis experiments.…”

“…22,30 Aryl nitrenium ions can be generated in water by heterolytic cleavage of NÀ ÀX bonds under solvolysis conditions, and by photolysis of various precursors. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Under solvolysis conditions, 1 is generated as a steady-state intermediate that does not reach directly detectable concentrations, but it can be studied by indirect methods. 13,14,18,19,27,29 Laser flash photolysis provides the opportunity to directly observe the cation.…”