Nitroaromatics

3-Dinitrobenzene, which is used widely in the production of pesticides and dyes, causes testicular cancer in the rat. The compound displays the prototypical aerobic metabolism of the nitroaromatics, namely bioreduction to a radical anion, followed by electron transfer to oxygen  

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 

Nirofuran compounds are also effective anti-parasitic drugs. Nifurtimox, for example, is used to treat Chagas disease (caused by Trypansoma cruzi) but has side effects. In exploring the use of alternatives to nifurtimox, Olea-Azar et al. have examined radical formation from two analogues. Radical anions were observed upon electrolytic reduction of the compounds and a nitroxide, believed to be the glutathionyl radical-adduct, was detected upon electrolysis in the presence of DMPO and GSH. Radical adducts were also detected upon incubation of one of the analogues with microsomes from T. Cruzi.m A novel endo-peroxide reductase has been isolated from T. Cruzi. Whereas the flavoenzyme was found to reduce quinones to their semiquinones, nifurtimox underwent a direct, two-electron reduction, without the formation of radicals.129 

Olea-Azar et al. have also explored the use of 1,2,5-oxadiazole N-oxides in the treatment of Chagas disease. Spectra of radicals were obtained by both electrochemical and microsomal reduction. The calculated electron affinities of the compounds correlated well with the measured reduction potentials, which were 

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Explosives for Use at High Temperatures. Explosives that can withstand prolonged exposure to elevated temperatures without detonating find considerable use ia such appHcations as detonators for deep oil wells, space travel, and componentry for specialised appHcations. The explosives developed for this purpose are primarily nitroaromatic compounds, the most important of which are hexanitrostilbene and... 

Fluorodenitration of nitroaromatics represents an exchange duorination technique with commercial potential. For example, y -duoronittoben2ene [402-67-5] from y -dinitroben2ene [99-65-0] and KF in the presence of various promoters can be reali2ed (69—72). This is not feasible under Halex conditions with y -chlotonittoben2ene [121 -73-3]. 

Substituted aromatics, eg, aLkylbenzenes, sometimes experience attack at the substituent position by NO/ (7). A cyclohexadienyl cation is formed it is unstable and the nitro group migrates on the ring to a carbon atom that is attached to a hydrogen. Loss of the proton results in a stable nitroaromatic. 

The danger of an explosion of a nitrated product generally increases as the degree of nitration increases, eg, trinitroaromatics are more hazardous as compared to dinitroaromatics or especially mononitroaromatics. Nitroaromatics and some polynitrated paraffins are highly toxic when inhaled or when contacted with the skin. AH nitrated compounds tend to be highly flammable. 

Most derivatives of aniline are not obtained from aniline itself, but ate prepared by hydrogenation of their nitroaromatic precursors. The exceptions, for example, /V-a1ky1ani1ines, /V-ary1ani1ines, sulfonated anilines, or the A/-acyl derivatives, can be prepared from aniline and have been discussed. Nitroanilines are usually prepared by ammonolysis of the corresponding chloronitroben2ene. Special isolation methods may be requited for some derivatives if the boiling points are close and separation by distillation is not feasible. Table 6 Hsts some of the derivatives of aniline that are produced commercially. 

Both chloramphenicol and thiamphenicol cause reversible bone marrow suppression (9). The irreversible, often fatal, aplastic anemia, however, is only seen for chloramphenicol (9). This rare (1 in 10,000—45,000) chloramphenicol toxicity has been linked to the nitroaromatic function (1,9). Thiamphenicol, which is less toxic than chloramphenicol in regard to aplastic anemia, lacks potency as can be seen in Table 1, and thiamphenicol has never found much usage in the United States. An analogue of thiamphenicol having antimicrobial potencies equivalent to chloramphenicol was sought. Florfenicol (2) was selected for further development from a number of closely related stmctures. 

Miscellaneous Dyes. Other classes of dyes that stiU have some importance are the stilbene dyes and the forma2an dyes. Stilbene ( es are in most cases mixtures of dyes of indeterminate constitution that are formed from the condensation of sulfonated nitroaromatic compounds ia aqueous caustic alkah either alone or with other aromatic compounds, typically arylarnines (5). The sulfonated nitrostilbene [128-42-7] (79) is the most important nitroaromatic, and the aminoa2oben2enes are the most important arylarnines. Cl Direct Orange 34 [2222-37-6] (Cl 40215-40220), the condensation product(s) of (79) and the aminoa2oben2ene [104-23-4] (80), is a typical stilbene dye. 

The range of nueleophiles whieh have been observed to partieipate in nueleophilie aromatie substitution is similar to that for S[, 2 reactions and includes alkoxides, phenoxides, sulftdes, fluoride ion, and amines. Substitutions by earbanions are somewhat less common. This may be because there are frequently complications resulting from eleetron-transfer proeesses with nitroaromatics. Solvent effects on nucleophilic aromatic substitutions are similar to those discussed for S 2 reactions. Dipolar... 

Potassium nitrite by-product can react with nitroaromatic substrate to suppress yields of aryl fluorides Modest yields (40-60%) of fluorophthafic anhydride are obtained from 3- or 4-nitiophthalic anhydride and potassium fluonde due to formation of by-product dipotassium salt of 3- or 4-nitrophtlialic acid [1/3,114, 115] (equation 33) Higher yields (93%) of 3-fluorophfhalic anhydride can be realized by regenera tion of 3-nitrophthalic anhydride from the dipotassium salt with thionyl chloride, followed by addition of fresh potassium fluoride [7/5] (equation 33)... 

Nitro functions are easily reductively alkylated and a number of alkylated anilines are made industrially starting with the appropriate nitroaromatic in the ketone as solvent. The addition reaction can occur at the hydroxylamine intermediate as well as the aniline. A process step is saved by beginning with the nitro compound. 

Aromatic nitroso compounds usually are considered to be intermediates in the hydrogenation of a nitroaromatic compound to the aromatic hydroxyl-amine or amine. However, nitroso compounds do not accumulate in these reductions, suggesting that they are reduced more easily than are nitro compounds. Catalysts effective for the nitro group should also be effective for nitroso. 

Molecular ion The mass spectra of nitroaromatic compounds are characterized by intense molecular ions. 

Moisture—when purchased dry - max 0.20 percent when purchased wet - max 22.0 percent Ash - Max 0.1 percent Insoluble matter — Max 0.1 percent Acidity - total sulfuric acid - max 0.1 percent nitric acid - none Lead - max 0.004 percent Analytical A qualitative test for PA depends on its reaction with aq KCN to form a red colored salt, the so-called isopurpuric acid . The reactions involved in this test are still in doubt (see Ref 35, p 492). PA is one of the few tri-nitroaromatics that does not produce a reddish coloration with strong alkalis (Ref 46). It has... 

Reduction of the nitroaromatic with NaBH4 in DMSO or Zn in NaOH/EtOH leads to the hydrazo derivative and treatment with aqueous HC1 gives benzidine rearrangement.115... 

Under the chosen conditions aromatic compounds are nitrated to nitroaromatics [1]. The detection of rotenone [1] (see below) depends on the reduction of silver ions, incorporated into the layer, to metallic silver in the presence of ammonia [4]. The mechanism of the reaction of many substances leading to fluorescent derivatives has not yet been elucidated [2],... 

Brief exposure to nitrous fumes (up to 3 min) leaves the fluorescent power of the acid-instable fluorescence indicator 254. incorporated into most TLC layers, largely unaffected, so that the nitroaromatics so formed can be detected as dark zones on a green fluorescent background [1]. For purposes of in situ quantitation it is recommended that the fluorescence indicator be destroyed by 10 min exposure to nitrous fumes in order to avoid difficulties in the subsequent evaluation [1]. 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

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