Nitro radicals

It was recognized as early as 1968 [16] that the interaction in aqueous solution of these radicals with nitroaromatics can lead to two types of (transient) product alkoxynitroxyl radicals (produced by addition to the nitro group), and nitro radical anions (cf. Eqs. 6 and 7) ... 

Wardman P, Clarke ED. 1976. Oxygen inhibition of nitroreductase Electron transfer from nitro radical-anions to oxygen. Biochem Biophys Res Common 69 942. 

The mass spectra of Aristolochia N-containing compounds were first reported by Pailer et al., who studied the electron impact-induced fragmentation of the esters of aristolochic acids. They found that the nitro radical is very easily split off from the molecular ion, giving the base peak (M — 46) +, and then the CH3, CO, etc. were removed. Pailer etal. concluded the fragmentation was as shown in Scheme 3 (26). 

Nitrofurantoin, a anti-microbial agent under investigation for use in cancer therapy, also undergoes bioreduction to a nitro radical anion. Following earlier, contradictory reports, Miller et al. have re-examined the possibility that NF can oxidise GSH. Using three different methods of NF generation, the authors found no evidence for reaction between GSH and the radical.127... 

Biotransformation pathways of nitroaromatic compounds are believed to result from nitroreductases that have the ability to use nitro as either one- or two-electron acceptors. One-electron acceptance by the nitro compounds results in the production of the nitro radical-anion. This nitro radical-anion becomes one of the most aggressive species in biological systems because of its reaction on endogenous molecules (DNA bases) and its well-known catalytic ability to transfer one electron to molecular oxygen with superoxide anion formation. 

In valence isomerization reactions the most common case is the rearrangement of a ligand, as in the example in Figure 4.79 in which a nitro group, N02, isomerizes to a nitrito group, O—N=0. The primary photochemical process is in fact a dissociation of the Co-N bond, with formation of free radicals. The nitro radical isomerized to its nitrito form, then binds again to make the new complex. 

This anomeric stabilization of radicals is also observed using halonitrosugars such as 1-C-nitroglycosyl halides [22] 15. Captodative stabilization of the alcoxy nitro radicals explains the radical-chain substitution with mild nucleophiles such as ma-lonate or nitroalkane anions to form 16 (Scheme 8). 

Scheme 10.35 Solvation of the intermediate nitro radical anion and starting material by H-bonding in methanol.

Solvation of thiolates is similarly low in both protic and dipolar aprotic solvents because of the size and polarisability of the large weakly basic sulfur atom, so is unlikely to contribute appreciably to the observed solvent effect. The intermediate nitro radical anion is stabilised by H-bonding in a manner which retards its dissociation in the SrnI mechanism (upper equation in Scheme 10.35). In contrast, the electron flow in the direct substitution at X (lower equation in Scheme 10.35) is such that solvation by methanol promotes the departure of the nucleofuge. In summary, protic solvation lowers the rate of the radical/radical anion reactions, but increases the rate of the polar abstraction yielding disulfide. 

The electrochemical reduction of 2-nitroimidazole in an aqueous mixed [916] and aprotic [917] medium has been carried out using cyclic voltammetry at a mercury electrode. The voltammetric behavior of 2-nitroimidazole in the aqueous mixed medium is substantially different from that in nonaqueous medium in fact, only in the aqueous medium is it possible to study in isolation the nitro radical anion. 

The reduction of apical nitro substituents to amino groups is a precursor to the synthesis of a large variety of sarcophaginate complexes. The redox behaviour of these nitro substituents is very diverse and complexes with nitro radical anions, nitroso, hydroxylamine and amine substituents were obtained as primary products from such reductions, depending on the t e of reductant, pH, solvent, and the amount of reductant supplied [414]. 

Nitroso Benzene.—The nitroso or nitrous acid derivatives are exactly analogous to the nitro or nitric acid derivatives. As the nitro radical is (AO2), so the nitroso radical is NO) and whenever this radical is present, as we found in the nitroso-amines (p. 61), and as we shall find in some more complex compounds of the dye class, it means nitroso derivative. The simplest representative, viz., nitroso benzene, CeHs—NO, differs from nitro benzene in that it is not formed by the direct action of the acid on the hydrocarbon nor, as shown above, is it able to be isolated as a reduction product of nitro benzene. It is prepared, however, by the oxidation of phenyl hydroxyl amine, either by means of ferric chloride, FeCU, or of chromic acid, CrOa. 

An ET-mechanism would be also in accord with the results (route B). Internal ET within 267 should give the cyclopropyl radical-nitro radical anion species 271 which might easily dimerize to give 272. On addition of electrophiles/oxidants the observed products 268 and 269 would be formed. 

The different steps of the biotransformations that produce a primary amine from an aromatic nitro compound involve a nitro radical-anion, a nitroso derivative, a nitroxyl radical, a hydroxylamine and then the primary amine (Figure 33.15). 

Each of these different intermediates may contribute to the toxicity. Hydroxylamines are often responsible for methemoglobinemia, whereas mutagenic and carcinogenic activity may be due to the combination of nitro radical-anion, nitroso derivatives or esterified hydroxylamine (such as sulfate derivatives) with cellular macromolecules. 

Nitro-radical anions have proved to be especially accessible to ESR study [180-183], The large nitrogen hyperfine splitting in the radical anion often leads to partly or completely resolved hyperfine structure (Fig. 12) that can be analyzed directly or by computer simulation. In the case of the nitro compound furylfuramide (AF-2), the cis-trans isomerization catalyzed by nitro reductases appears to proceed via the radical anion ESR spectra of both cis and trans radical anions have been resolved during reduction of the cis parent compound. 

The trypanocidal action of nifurtimox derives from its ability to undergo activation by partial reduction to nitro radical anions. Transfer of electrons from the activated drug then forms superoxide radical anions and other reactive oxygen species. Reaction of free radicals results in lipid peroxidation and membrane injury, enzyme inactivation, and DNA damage. Benznidazole also requires a one-electron transfer that generates nitro anion radicals, leading to cellular damage that kills the parasites. 

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