Nitrosobenzene and Phenylhydroxylamine

Nitroso compounds are of relatively limited importance in aromatic chemistry. However, since the nitroso group is easily reduced to an amino group, they do offer an indirect route to aromatic amines. The nitrosa-tion of phenols and dialkylanilines and the subsequent reduction are pertinent examples. The nitroso group is also readily oxidized to a nitro group. 

Q The nitroso group exhibits similar behaviour to a carbonyl group. Predict the products from the reaction of nitrosobenzene with (a) malononitrile (propane-1,3-dinitrile), (b) hydroxylamine and (c) aniline. Suggest a mechanism for the last reaction. 

Nitrosation of dialkylanilines followed by reduction produces A/,A/-dialkyl-p-phenylenediamines, which are used as developers in colour photography, 

The nitro group is strongly electron withdrawing and directs electrophilic attack, which is significantly more difficult than for benzene, to the met a position. 

Reduction of a nitro group to an amine can be achieved by catalytic hydrogenation, hydrogen transfer and by various combinations of metal and acid. 

Partial reduction of a nitro group to a hydroxylamino function occurs on treatment with zinc dust and aqueous NH4CI. 

Activated aromatic compounds can be nitrosated by the nitro-soniurn ion. NO+. 

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These radical anions have been detected by ESR. This mechanism is consistent with the following result when nitrosobenzene and phenylhydroxylamine are coupled, and N labeling show that the two nitrogens and the two oxygens become equivalent. Unsymmetrical azoxy compounds can be prepared by combination of a nitroso compound with an N,N-dibromoamine. Symmetrical and unsymmetrical azo and azoxy compounds are produced when aromatic nitro compounds react with aryliminodimagnesium reagents, ArN(MgBr>2. ... 

Formation of phenylhydronitroxide radicals, DMPO (5,5-dimethyl-l-pyrroline-7V-oxide)/glutathiyl and DMPO/hemoglobin thiyl free radical adducts has been detected in erythrocytes of rats in vivo after administration of nitrosobenzene and phenylhydroxylamine, respectively92,94. The data, however, could also be interpreted in a different way ... 

Nitrosobenzene and phenylhydroxylamine condense rapidly in alkaline solution to give azoxybenzene. During the reduction of nitrobenzenes at high pH, the phenylhydroxylamine scavenges nitroso compound so that the azoxybenzene becomes... 

Fermenting yeast is able to reduce added nitrobenzene to the corresponding amine, aniline, to quite a considerable extent. Part of the added nitrobenzene remains unattacked, but 70% of it could be converted to aniline. Since a direct reduction of the nitro group to the amino group is improbable, Neuberg and Welde tried phytochemical treatment of the possible intermediaries, namely, nitrosobenzene and phenylhydroxylamine on the one hand and azoxybenzene and azobenzene on the other hand. 

The reduction of nitro groups may also be catalyzed by microsomal reductases and gut bacterial enzymes. The reduction passes through several stages to yield the fully reduced primary amine, as illustrated for nitrobenzene (Fig. 4.39). The intermediates are nitrosobenzene and phenylhydroxylamine, which are also reduced in the microsomal system. These intermediates, which may also be produced by the oxidation of aromatic amines (Fig. 4.21), are involved in the toxicity of nitrobenzene to red blood cells after oral administration to rats. The importance of the gut bacterial reductases in this process is illustrated by the drastic reduction in nitrobenzene toxicity in animals devoid of gut bacteria, or when nitrobenzene is given by the intraperitoneal route. 

The reduction of nitrobenzene follows a well-defined course as shown by Haber.1 Nitrosobenzene is first formed, then phenylhydroxylamine, and finally aniline other products are formed by subsequent condensation. Nitrosobenzene and phenylhydroxylamine condense to azoxybenzene, which becomes reduced to hydrazoben-zene —... 

Azoxyhenzene is therefore formed by condensation of nitrosobenzene and phenylhydroxylamine. This reaction, like the production of azobenzene, takes place very rapidly under the influence of sodium ions the ready occurrence of both of these substances in alkaline solution is thus easily explained. Azobenzene is mostly produced by a condensation of nitro-... 

Benzidine.—That nitrobenzene, by electrolytical reduction in acid solution, can directly yield benzidine, was first proved by Hiiussermann,1 who used sulphuric acid. Lob 2 later proved the same to be true for hydrochloric-, acetic- and formic-acid electrolytes. However, several reactions predominate in this direct acid reduction, which prevent the carrying out of the reaction up to hydrazobenzene, or the formation of benzidine. Phenylhydroxylamine may particularly be mentioned in this connection. In alcoholic-acid solution it is partly rearranged to amidophenol or its ethers, and partly reduced to aniline. Azoxybenzene, in acid solution, is the starting-point in the benzidine formation however, in this case, the combining velocity of nitrosobenzene and phenylhydroxylamine is not very great, so that the latter is to a very considerable extent subject to the more rapidly acting influence of the acid. 

These radical anions have been detected by esr. This mechanism is consistent with the following result when nitrosobenzene and phenylhydroxylamine are coupled, 0 and 15n... 

Azoxybenzene arises from the condensation of nitrosobenzene and phenylhydroxylamine. Reaction occurs in both basic and neutral... 

The presence of p-nitrophenol in the urine can be used to indicate exposure to nitrobenzene (Ikeda and Kita 1964). Measurement of p-nitrophenol, however, cannot be used to determine the level of nitrobenzene exposure or if harmful effects can be expected to occur. The nitrobenzene metabolites, nitrosobenzene and phenylhydroxylamine, have been found to bind with hemoglobin in the blood of... 

Biomarkers of Exposure and Effect. The presence of p-nitrophenol in urine serves as a satisfactory biomarker of nitrobenzene exposure. Because nitrobenzene metabolites, nitrosobenzene and phenylhydroxylamine, bind to hemoglobin in the blood of rats and mice, the presence of these hemoglobin adducts in human blood may also serve as biomarkers of nitrobenzene exposure. More information on this possibility would be useful. 

By reduction, it is possible to pass from nitrobenzene to aniline through the intermediate compounds nitrosobenzene and phenyl-hydroxylamine, and by oxidation in the reverse direction. It has been shown that nitrosobenzene and phenylhydroxylamine are formed in the electro-reduction of nitrobenzene, but it is impossible, at present, to effect some of the transformations indicated above in such a way that the reactions can be used as preparative methods. Some, however, can be used for this purpose. Phenylhydroxylamine, for example, is oxidized in the cold by potassium bichromate and sulphuric acid to nitrosobenzene, and is converted by reducng agents into aniline. In certain cases it is possible, by selecting the proper reagent, to effect the change indicated by two of the steps noted above. Phenylhydroxylamine is best prepared by treating with zinc dust a solution of nitrobenzene in dilute alcohol which contains a small amount of calcium chloride. 

These conclusions were supported by work in which and labeled nitrosobenzene and phenylhydroxylamine are coupled and the O and N amounts become equivalent. ... 

Nitrosobenzene is known to react with C02 radical anions with i = 4xl0 ImoP s yielding the nitrosobenzene radical, reaction (R14), which under our experimental conditions is present in its acid form (p Ta= 11-7 ). Further condensation of the acid form of the nitrosobenzene radical with loss of water yields azoxybenzene, reaction (R15). Disproportionation of the conjugate acid of nitrosobenzene radical, reaction (R16), may yield nitrosobenzene and phenylhydroxylamine. The latter product was not observed, however, it may have been further reduced by C02 to the intermediate amine radical, C6H5N H, which subsequently disproportionates to phenylhydroxylamine and aniline, reactions (R17) and (R18), respectively. 

The electrolytic reduction of aromatic nitro-compounds has been studied extensively. Nitrobenzene can be reduced to aniline in three stages, through nitrosobenzene and phenylhydroxylamine ... 

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