Radical-Stimulated Nucleophile Release

Abstract

Supporting Information ABSTRACT. Experimental and computational results had shown that deprotonation was enhanced for precursors containing radical centers (RED-shift). An examination of whether the inverse heterolytic dissociations that release nucleophiles instead of electrophiles could also be stimulated by suitably sited radicals is reported in this paper. A DFT method was employed to assess the free energies of heterolytic dissociations releasing C-centered and O-centered nucleophiles. In most instances a radical adjacent to the incipient positive charge in the precursors led to significant enhancement of heterolytic dissociation; but inhibition was found in some cases. Greater enhancements were obtained with C-centered, rather than O-centered radicals. Exergonic dissociations for both O-and C-centered nucleophiles could be achieved with fluorenylmethyl-and cyclohepta-2,4,6-trienylmethyl-containing precursors. Heterolytic phosphate release from ribose and deoxyribose nucleotide C4' radicals was also found to be enhanced. This provided supporting evidence of the importance of these radicals in DNA and RNA strand breaking. The effect of ethyne, ethene and phenyl spacer units between the radical 2 center and the incipient positive charge was examined. Evidence was obtained that the key factor promoting heterolytic dissociation was the resonance stabilization of the co-released radical-cations.

Dissociations of free radicals to generate protons, electrophiles or nucleophiles: role in DNA strand breaks

“…Heterolytic dissociations of radical precursors were computed to be inhibited by introduction of the CH 2 unit, or longer hydrocarbon chains, between the formal site of an upe and the nucleophile. 60 The same was true for the bicyclo[1.1.1]pentane spacer. Unlike the cases of proton or cation release, the simple ethynyl spacer was usually ineffective too.…”

“…To circumvent this problem the CH 2 CRC-, CH 2 CHQCH-and CH 2 C 6 H 6units, where the upe resides in a p-orbital available for conjugation with its neighbour bonds, were examined as spacers (Scheme 13). 60 With trifluoroacetate as the attached nucleophile heterolyses were endergonic or only marginally exergonic, irrespective of chain length, for these three spacers. Interestingly, however, release of trifluoroacetate was enhanced, relative to the corresponding models, for all three types of spacer.…”

“…26,69 Both heterolyses became less favourable as the solvent polarity decreased from water through methanol, acetonitrile and THF to n-heptane. 60 The free energies of heterolysis became less favourable fairly smoothly as the Hildebrand solvent parameters d decreased. Trifluoroacetate release was exergonic in methanol and acetonitrile as well as in water.…”

“…We used our DFT computational method to explore the types of radicals for which release of nucleophiles would be spontaneous. 60 For useful releases of nucleophiles, that would be concerted with radical generation, heterolyses that were enhanced (DDG positive) and also exergonic DG Ã R negative À Á were sought. Strongly stabilised nucleophiles would be needed to achieve this so the 'Meldrumate' anion (Mm) was chosen for C-centred nucleophiles and the 2,2,2trifluoroacetate anion (Tfa) was selected to represent O-centred nucleophiles (see Scheme 10).…”

“…65 To investigate the role of radical enhancement of these strand breaks the energetics of dissociation of the phosphatesubstituted deoxyribose radicals 52, depicted in Scheme 12, were computed. 60 Scheme 11 Energetics of heterolytic dissociations of dihydronaphthalenyl-linked nucleophiles. In mode (a), dissociation of the C5 0 -phosphate linkage of the C4 0 -radical (52) yields a phosphate anion [L n P 5À ], together with the exocyclic radical-cation 53.…”