No abstract

Electrochemical dimerization reactivity has been studied for 5-substituted uracils (5XU) including thymine (1a: X = Me) and 5-halouracil derivatives (1b: X = F; 1c: X = Cl; 1d: X = Br; 1e: X = I). Upon galvanostatic electrolysis of Ar-saturated aqueous solution 1a underwent anodic oxidation to produce N(1)-C(5')- and N(1)-C(6')-linked dimer hydrates, 1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)thymine (5a) and 1-(5'-hydroxy-5',6'-dihydrothymin-6'-yl)thymine (6a), as the major products. These N-C-linked dimerizations were accompanied by the formation of novel stereoisomeric C(5)-C(5')-linked dimers (meso isomer: 13a[meso]; racemic isomer: 13a[rac]) with a condensed tetrahydrofuran ring skeleton. Similar electrolyses of 5-fluorouracil (1b) and 5-chlorouracil (1c) also afforded the corresponding N(1)-C(5')-linked dimer hydrates, 1-(5'-fluoro-6'-hydroxy-5',6'-dihydrouracil-5'-yl)-5-fluorouracil (5b) and 1-(5'-chloro-6'-hydroxy-5',6'-dihydrouracil-5'-yl)-5-chlorouracil (5c), respectively, while resulting in neither N(1)-C(6')-linked dimer analogues nor C(5)-C(5')-linked dimers, unlike the reactivity of 1a. In contrast to 1a-c, no dimeric products were obtained from 5-bromouracil (1d) and 5-iodouracil (1e). The present electrochemical method was applicable to the cross-dimerization into N(1)-C(5')-linked heterodimer hydrates composed of binary 5-substituted uracils that occurred in competition with the formation of homodimer hydrates. A mechanism of the N(1)-C(5')-linked dimerization of 1a-c has been proposed, by which allyl-type radical intermediates with limiting mesomeric forms of N(1)-centered and C(5)-centered pyrimidine radicals (2a-c [N(1)]/2a-c [C(5)]) are generated via anodic one-electron oxidation and subsequent deprotonation at N(1) and undergo a head-to-tail coupling.

Using a redox titration method in the pulse radiolysis of N 2 O-saturated phosphate buffer solution, the redox properties of the intermediate radicals derived from OH radical reactions of 5-substituted uracils 1c-h (R ) F, Cl, Br, NO 2 , NH 2 , OH) have been characterized. While the primary intermediates were oxidizing C(5) radicals 2c-h and reducing C(6) radicals 3c-h of the respective OH adducts, a common allyl-type radical of "redox ambivalence" with limiting mesomeric forms of reducing carbon-centered 5-oxo-5,6-dihydrouracil-6-yl radical (4) and oxidizing oxygen-centered uracil-5-oxyl radical (5) was secondarily formed via elimination of 5-substituents from 3c-h. The rate of 5-substituent elimination decreased with varying structures of the 5-substituents in the order halo > amino, nitro > hydroxy groups. The common radical 4/5 showed weaker reducing/oxidizing abilities than the typical pyrimidine C(6) and C(5) radicals. The product study demonstrated that the one-electron reduction of 5-oxyl radical 5 by N,N,N′,N′-tetramethyl-p-phenylenediamine ((2.0 ( 0.1) × 10 8 dm 3 mol -1 s -1 ) increased the yield of isobarbituric acid (1h), while the one-electron oxidation of 5-oxo C(6) radical 4 by tetranitromethane increased the yield of isodialuric acid (6).

Steady-state gamma-radiolysis, pulse radiolysis, and cyclic voltammetry have been performed to identify the mechanism by which N(1)-C(5')-linked homodimer hydrates [1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)thymine (2a) and [1-(5'-fluoro-6'-hydroxy-5',6'-dihydrouracil-5'-yl)-5-fluorouracil (2b)], N(1)-C(6')-linked dimer hydrate [1-(5'-hydroxy-5',6'-dihydrothymin-6'-yl)thymine (3a)], and N(1)-C(5')-linked heterodimer hydrate [1-(6'-hydroxy-5',6'-dihydrothymin-5'-yl)-5-fluorouracil (2ba)] undergo radiolytic reductive splitting to regenerate the parent monomers in anoxic aqueous solution. Radiolytic reductions of the thymine homodimer hydrates 2a and 3a by hydrated electrons (e(aq)-) regenerated the parent thymine (1a) almost quantitatively, while the 5-fluorouracil homodimer hydrates cis-2b and trans-2b afforded 1-(uracil-5'-yl)-5-fluorouracil efficiently along with a small amount of the parent 5-fluorouracil (1b). In contrast to 2b, the heterodimer hydrate analogue 2ba with noneliminating 5'-methyl substituent releases 5-fluorouracil 1b almost quantitatively in the radiolytic reduction. The pulse radiolysis studies suggested that the electron adducts are produced primarily at the thymine and 5-fluorouracil structural unit in the dimer hydrates 2a,b, respectively, in which the resulting dimer hydrate radical anion of 2b (2b*-) was more stable than that of 2a (2a*-). As characterized by pulse radiolysis and cyclic voltammetry, the 5-fluorouracil homodimer hydrate 2b bearing F-substituent at C(5') undergoes one-electron reduction to eliminate exclusively fluoride ion along with the formation of dimer hydrate C(5') radical (2b(-F)*) with oxidizing property. The formation of a possible dimer hydrate radical intermediate 2b(-F)* was also supported by the effect of amines as the reducing additives on the yields of 1b and 4b in the radiolytic reduction of 2b.

No abstract