Density functional calculations on dissociation reactions of radical anions of 5-fluorouracil derivatives

Abstract

Fragmentation reactions upon electron attachment to 5-fluorouracil with CH₂R substituents at N₁ have been evaluated by means of density functional calculations. The present results show that electron attachment to R = F, HCO or CN derivatives follows a stepwise pathway with radical anions as intermediates. For these compounds, the most stable species formed is the π radical anion which bears an unpaired spin density at the C₆C₅–C₄O π-conjugated system of the uracil ring. Cleavage of the N₁–CH₂R or N₁CH₂–R bond of these intermediates proceeds through the mixing of the π and σ states by means of proper geometrical fluctuations along the reaction coordinate. No σ radical anion could be characterised on any of these σ basal potential surfaces. A noticeable decrease in the activation energy for the N₁–CH₂R bond dissociation was observed for R = H–CO or CN. Therefore, such derivatives with unsaturated groups positioned vicinal to the N₁–C₁′ bond are identified as targets for the development of novel radiation-activated antitumour drugs. On the other hand, the electron transfer to the compounds with R = Cl, Br is dissociative, i.e. it occurs without the mediation of radical anions. For compounds with R = halides or R = NO₂, the fragmentation of the N₁CH₂–R bond is the preferred dissociation pathway.