Model Reactions for the Degradation of DNA-4′ Radicals in Aqueous Solution. Fast Hydrolysis of α-Alkoxyalkyl Radicals with a Leaving Group in β-Position Followed by Radical Rearrangement and Elimination Reactions

Abstract

α-Alkoxyalkyl radicals with a leaving group L = Cl or OCOCH3 in β-position are produced by H-abstraction from the corresponding saturated substrates by ·OH, SO·4- or (CH3)3CO· radicals. From ESR spectroscopic observations it is concluded that in aqueous solution at pH 5 -9 the following fast hydrolysis reactions take place: The rate constants of these reactions and for the hydrolysis of CH3O-ĊH-CH2Cl are k ≥ 106 s-1, whereas the rate constant for CH3O-ĊH-CH2OCOCH3 was determined to be ≈ 2 × 103 s-1 at room temperature. The radicals with L = Cl cannot be scavenged by O2 which fact leads to a value of k ≥ 2 × 10-7 s-1. α-Alkoxyalkene radical cations are assumed as intermediates in the hydrolysis reactions. The radicals with L = OCOCH3 and the radical CH3O--ĊH-CH2Cl are observable in acetone solution ESR spectroscopically. In aqueous solution at pH below 3 proton catalyzed reactions are observed by ESR spectroscopy: Radicals resulting from H-abstraction at the CH3O-groups of the substrates or at the 5-positions of the cyclic ethers are also observed. The ESR parameters and the pH-ranges of existence of the above radicals are given. Support of the reported reactions comes from quantitative analysis of stable products such as H+, Cl- or CH3OH after 60Co-γ-irradiation of N2O saturated aqueous solutions of the substrates. The behaviour of the radicals is used as a model to describe a modified version of the degradation of DNA-4′ radicals in aqueous solution in the absence of oxygen.

Chemistry of β-(Acyloxy)alkyl and β-(Phosphatoxy)alkyl Radicals and Related Species: Radical and Radical Ionic Migrations and Fragmentations of Carbon−Oxygen Bonds

“…Support was subsequently provided by semiempirical molecular orbital calculations (INDO). 203 Later work by Beckwith and Brumby 204 and the Schulte-Frohlinde group 111 confirmed this observation, which is rationalized in terms of a stabilizing "extended anomeric interaction" between a lone pair on the R-oxygen, the singly occupied p-orbital, and the σ*-orbital of the -C-O bond (483). The same effect is observed in carbohydrate based radicals, wherein the tetraacetyl-1-glucopyranosyl radical has been shown to adopt a flattened, possibly deformed, B 2,5 boat conformation (75) to accommodate this extended anomeric interaction.…”

“…These examples are characterized by the use of protic solvents, usually water, and acidic media. 111,127,[224][225][226][227][228] These entirely reasonable, acid-or base-catalyzed mechanisms, however, do not account satisfactorily for the diol dehydrase promoted version of this same reaction. Labeling studies indicated that, in the enzyme catalyzed reaction, up to 50% of the oxygen from the hydroxy group to the radical is retained in the carbonyl group of the product.…”

Radical Rearrangements of Esters

“…Schulte-Frohlinde and coworkers also observed that the more highly substituted 2-acetoxy-1 -methoxy-1 -propyl and the 1 -acetoxy-2-methoxy-2-propyl radicals underwent solvolysis by water more rapidly than the lower homolog (13) in Scheme 21. This again is indicative of a dissociative rather than a 'Zipse-like' associative phenomenon [43].…”

Reactivity of Nucleic Acid Radicals

“…35,101 Stabilized radicals containing β-leaving groups undergo heterolytic fragmentation to produce radical cations, a process that is facilitated in polar solvents such as water. 102–106 …”