Dihydrophenazine oxidation

Nitrogen Compound Autoxidation. CycHc processes based on the oxidation of hydrazobenzene and dihydrophenazine to give hydrogen peroxide and the corresponding azobenzene—phenazine were developed in the United States and Germany during World War II. However, these processes could not compete economically with the anthrahydroquinone autoxidation process. 

As observed, aromatic hydrocarbons gave products of protonation on dissolution in hydrofluoric acid. Oxidation into aromatic cation-radicals did not take place (Kon and Blois 1958). Trifluoro-acetic acid is able to transform aromatics into cation-radicals. This acid is considered a middle-powered one-electron oxidant (Eberson and Radnor 1991). Its oxidative ability can be enhanced in the presence of lead tetraacetate. This mixture, however, should be used carefully to avoid oxidation deeper than the one-electron removal. Thus, oxidation of 1,2-phenylenediamine by the system Pb(OCOCH3)4 -I- CE3COOH -P CH2CI2 leads to the formation of either primary or secondary cation-radicals. The primary product is the cation radical of initial phenylenediamine, whereas the secondary product is the cation radical of dihydrophenazine (Omelka et al. 2001). Sulfuric acid is also used as an one-electron oxidant, especially for aromatic hydrocarbons. In this case, generation of cation radicals proceeds simultaneously with the hydrocarbon protonation and sulfonation (Weissmann et al. 1957). 

Oxidation of 5,10-dialkyl-5,10-dihydrophenazines with hydrobromic acid in DMSO gives 10-alkyl-2(10/7)-phena-zinone in 52-79% yields (Equation 17) <1999JHC1057>. Depending on the alkyl substituents on C-5 and C-10 carbons, the parent phenazine is generated as the by-product. 

A major group of photochemical reduction reactions are oxidation-reduction processes. As typical examples, phenazine (CXXI) and alloxan (CXXIII) are reduced by ethanol to give dihydrophenazine (CXXIl)/ 2 and alloxantin (CXXIV).42 Isatin (CXXV) in the presence of ace-naphthene (CXXVI) is reduced to isatide (CXXVII).204 The photoreaction proceeds at the expense of the alcohol, or (CXXVI) acetaldehyde and acenaphthylene (CXXVIII), are formed as by-products respectively. The formation of CXXVII may be due to the interaction of CXXV with the intermediate oxindole (CXXIX). 

The anodic oxidation of phenazine N,AT-dioxide at a platinum anode in benzonitrile led to the intermediate radical-cation, which dimerizes.320,321 5-Substituted 5,10-dihydrophenazines are oxidized in two successive one-electron steps or one two-electron step in aqueous acetone.322 The corresponding phenazinium salts were formed as the ultimate oxidation products. 

Superoxide ion is an effective hydrogen-atom oxidant for substrates with coupled heteroatom (O or N) dihydro groups such as 3,5-di-t-butylcatechol (DTBCH,), ascorbic acid(H2Asc), 1,2-disubstituted hydrazines, dihydrophenazine (H2Phen), and dihydrolumiflavin (H2Fl)." d56.i57... 

With 1,2-diphenylhydrazine (PhNHNHPh), the azobenzene anion radical is rapidly oxidized by dioxygen to azobenzene, which also is true for the phenazine and lumi-flavin anion radicals. Hence, 02 acts as an initiator for the autoxidation of these compounds (equation 153). For 1,2-diphenylhydrazine, turnover numbers in excess of 200 substrate molecules per 02 have been observed. The 1,2-diphenylhydrazine autoxidation cycle can be initiated by HO , which indicates that 02 is formed in the HO initiated process. Superoxide ion also initiates the autoxidation of dihydrophenazine, which is a model for dihydroflavin. For example, the addition of 1 mM (Me4N)02 in DMF to 10 mM H2Phen in an 02-saturated DMF solution results in the complete oxidation of the substrate (about 80% recovered as phenazine) and the production of 9 -10 mM HOOH. 

When both benzene rings are amino-substituted in the ortho positions, phenazines are easily formed in good yield with the elimination of an ortho group. Reaction of 2,2 -diaminodiphenyl-amines 3 with iron(III) chloride in dilute hydrochloric acid affords initially, by a cyclization reaction with concomitant elimination of ammonia, dihydrophenazines which undergo rapid oxidation in air to the corresponding phenazines 4 in almost quantitative yields. 

Condensation of benzene-l,2-diamine (25) with cyclohexadiene-1,2-dione (30) in a sealed tube gives in low yield initially a 5,10-dihydrophenazine which can be oxidized to the phenazine 31. Several substituted derivatives have been prepared by this method - (see also Houben-Weyl, Vol. 11/1, p 164). The most ready conversion into phenazine is by oxidative sublimation. ... 

Oxidation of diethyl 5,10-dihydrophenazine-l,4-dicarboxylate with sodium dichromate in glacial acetic acid at room temperature or by catalytic dehydrogenation with palladium/calci-um carbonate in refluxing nitrobenzene yields diethyl phcnazinc-l,4-dicarboxylatc. ... 

The primary process for the oxidation by O2 - of dihydrophenazine and dihydro-lumiflavin must be analogous to that for PhNHNHPh (Scheme 7-14) to give the anion radicals of phenazine (Phen ) and lumiflavin (Fl ). These in turn react with O2 to give O2 - plus phenazine and lumiflavin, respectively the process is analogous to that for the anion radical of azobenzene (PhN NPh), The oxidation potentials (Ep,a) for PhN NPh, Phen - and Fl - in Me2SO are -1.1 V versus NHE, -0.9 V, and -0.6 V, respectively. Each value is sufficiently negative to reduce O2 to O2 - (-0.5 V versus NHE in Me2SO). Hence, the (O2 )-induced auto-oxidation of PhNHNHPh also is thermodynamically feasible for dihydrophenazine and dihydro-lumiflavin and does occur for these two model substrates of reduced flavoproteins (Table 7-3). Such an auto-oxidation reaction sequence may be relevant to the fractional yield of 02 - from the flavin-mediated activation of 02 ° and the auto-oxidation of xanthine [catalyzed by xanthine oxidase (XO), a flavoprotein]. ... 

Perhaps the most significant aspect of the superoxide-, hydroxide-, or electron-induced auto-oxidation of donor molecules (1,2-diphenylhydrazine, dihydrophenazine, dihydro-lumiflavin, and reduced flavoproteins) is the activation of dioxygen to hydrogen peroxide in biological matrices. Thus, within the normal cytochrome P-450 metabolic cycle, either hydroxide ion or an electron-transfer co-factor acts as an initiator (probably to produce Fl -) and reduced flavoproteins act as the H-atom donor. In contrast, the introduction of 02 - or hydrated electrons (from ionizing radiation or a disease state) into a biological matrix that contains donor molecules leads to the uncontrolled formation of hydrogen peroxide. If reduced metal ions are present, Fenton... 

Fig. 5 Oxidative coupling forming diphenylamine, dihydrophenazine and phenazine linkages...

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