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Quantum Chemical Characterization of the Reactions of Guanine with the Phenylnitrenium Ion

Parks, J. M.; Ford, G. P.; Cramer, C. J.
J. Org. Chem. 2001, 66, 8997.

Density functional calculations at the B3LYP/6-311+G(2d,p)//pBP/DN* level predict all cationic adducts combining guanine, at either its N2, O6, N7, or C8 positions, with phenylnitrenium ion, at either its N, 2, or 4 positions, to be lower in energy than the separated reactants. This relative stability of all adducts is preserved after addition of aqueous solvation free energies computed at the SM2 level, although some leveling of the adduct relative energies one to another is predicted. Cations having the lowest relative energies in solution correspond structurally to those adducts most commonly found when guanine reacts with larger, biologically relevant nitrenium ions in vitro and in vivo. One of these, the N-C8 adduct, is stabilized both by a re-aromatized phenyl ring and by the operation of an anomeric effect not found in any of the others. Based on energetic analysis, direct conversion of an N-N7 cation to an N-C8 cation according to a previously proposed mechanism is unlikely, however an alternative rearrangement converting a 2-N7 cation to a N-C8 cation via the intermediacy of a 5-membered ring may be operative in nitrenium ions with aromatic frameworks able to stabilize endocyclic cationic charge better than phenyl.

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