Oxidation of cyclic dipeptide radicals in aqueous solution: the rapid hydration of the intermediate 1,6-dihydropyrazine-2,5-diones (cyclic dehydrodipeptides). A pulse-radiolysis study

Abstract

The lifetimes of radiolytically generated 1,6-dihydropyrazine-2,5-diones (cyclic dehydrodipeptides) in aqueous solution have been studied by pulse radiolysis.

Hydroxyl radicals were allowed to react with the 2,5-dioxopiperazines glycine anhyride (1) and alanine anhydride (2). The resulting 3-yl radicals (4) and (5) have been oxidized by IrCl₆^2– in a diffusioncontrolled reaction [k(4)= 3.1 × 10⁹; k(5)= 3.0 × 10⁹ dm³ mol^–1 s^–1], which yielded the corresponding carbocations which rapidly deprotonate at N-4 (pK_a < 2) to form the short-lived 1,6-dihydropyrazine-2,5-diones (6) and (7).

At neutrality, spontanous addition of water to the –CN– bond [k(6)= 640; k(7)= 5 ± 2 s^–1] prevents the isomerisation of (6) and (7) into their tautomeric 2,5-dihydroxypyrazines. In acidic and basic solutions a proton-catalysed [k(6)= 6.3 × 10⁶; k(7)= 3.7 × 10⁶ dm³ mol^–1 s^–1] and a basecatalysed [k(6)= 1.4 × 10⁷; k(7)= 2.0 × 10⁵ dm³ mol^–1 s^–1] addition of water is observed.

The 3-yl (8)(79%) and N-methyl (9)(21%) radicals resulting from H abstraction from sarcosine anhydride are also readily oxidized by IrCl₆^2–(k= 3.6 × 10⁹ dm³ mol^–1 s^–1). Blocking of N-1 and N-4 by methyl groups prevents deprotonation of the resulting carbocations (12) and (14) and their reaction with water can be monitored directly by pulsed-conductivity measurements. The positive charge on the exocyclic carbocation (14) is effectively stabilized by nitrogen and thus addition of water proceeds only slowly [k(14)= 150 s^–1]. However, in the case of the endocyclic carbocation (12), which is destabilized by the carbonyl group next to C-3, the reaction with water is fast [k(12)= 2.3 × 10⁶ s^–1].

The instability of (6) towards attack by water (possibly attended by a general sensitivity towards nucleophiles), may be the reason why no successful synthesis of the tautomeric parent 2,5-dihydroxypyrazine has been reported so far.