Nitroarenes

The nitroarenes, picric acid and TNT, have been used as explosives since the late 1800 s (Fig. 3). At temperatures over which the thermal stability 

Range of activation energies (Ea) are given for reports of multiple compounds. 

Nitrotoluenes including 2,4,6-trinitrotoluene (TNT) are important components of explosives and several nitroarenes including the antibacterial nitrofurans have established mntagenicity (Purohit and Basu 2000). Substantial effort has been directed to the degradation of nitroarenes, and to their reduction to amines. Although nitroarene reductases, noted in Chapter 3, Part 3, are distribnted in a range of biota, the products may not necessarily represent intermediates in the degradation 

7V-acetylation to neutral acetanilides that are terminal metabolites (Noguera and Freedman 1996) 

Dimerization of partially reduced intermediates to nitroazoxytoluenes (Dayman and Radkar 1997) 

Association with organic matter in soil to produce nonextractable residues (Thorn and Kennedy 2002). 

A wide range of mechanisms are involved in the degradation and transformation of aromatic compounds with nitro substituents. These include reduction of the nitro group, and dioxygenation, monooxygenation, and reduction of the aromatic ring. A review devoted to 2,4,6-trinitrotolune is available (Esteve-Nunez et al. 2001). 

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Siace nitroarenes are reported to be catalyst poisons (18), the concentration of DNT ia the reaction medium is kept as low as is practical with regard to production goals and catalyst usage. The pubHshed kinetic studies are of Htde iadustrial value siace they describe batch processes with high DNT catalyst ratios (18—21). The effects of important process variables, such as temperature and pressure, can only be iaferred from descriptions ia the patent Hterature. 

International Agency for Research on Cancer (1989). Diesel and Gasoline Engine Exhausts ami Some Nitroarenes. lARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 46. International Agency for Research on Cancer, Lyon, France. 

Control of the regioselecdvity of VNS is important. It is governed by three major factors the stnicture of the nitroarene the nature of the nucleophile, and the reacdon condidons, especially solvent and base. The different effect of methoxy and hydroxy groups is interesdng the reacdon of Tmethoxy-2,4-dinitrobenzene vdth cbloromethyl phenyl sulfone proceeds in... 

The anion produced by VNS of nitroarenes andct-chloro esters is hydroxylated by the ac of air and benzaldehyde, thereby producing ct-hydroxy esters fEq 9 37,... 

Carbo- and heterocyclic nitroarenes react v/ith anions of rerr-butyl and cumyl hydroperoxides in the presence of strong bases to form snbsdtuted o- and -nitrophenols Regiochemistry of the hydtoxyladon can be controlled to a snbstandM extent by selecdon of proper conthdons fEq 9 53 ... 

Because the nucleophiles can be introduced at the orr/io-posidon of the nitro group, various heterocycles can be prepared via VNS and related reacdons. Indoles and related compounds are prepared via the VNS reacdon and subsequent cyclizadon. The VNS reaction of nitroarenes followed by cyclizadon v/ithEt- N-Me SiCl gives 1-hydroxyindoles fEq. 9.53. Cyclizadon is Mso catrilyzed on treatment v/ith bases, in which nitroso intermediates are postidated. 

The novel cyclizadon takes places by the silane-mediated condensadon of nitroarenes with allylic carbanions, in which a sLx-membered nitrogen-containing ting is constnicted fEq. 9.54. ... 

The foregoing examples show that the nucleophilic attack to nitroarenes at theorr/io-posidcn followed by cyclizadon is a generid method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion dedved from ethyl isocyanoacetate as the reacdve anion for the preparadon of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyriirddines depending on the stnicture of nitroarenes fEqs. 9.56 and9.57. The synthesis of pyrroles is discussed in detail in Chapter 10. 

The cyanomethyladon of nitroarenes followed by alkyladon and reducdve cyclizadon yields indoles ("see Chapter 9, which discusses the VNS reacdonsi fEq 10 56 ... 

Iron, reaction with nitroarenes, 928 lron(lll) bromide, aromatic bromination and, 548 Iron sulfate, LD5q of, 26 Isoamyl group, 89 lsobutane, molecular model of, 80 lsobutyl group, 84... 

Staggered conformation, 94 molecular model of, 94 Stannous chloride, reaction with nitroarenes, 928 Starch, 1—>4- -links in, 1000 structure of, 1000 Stationary phase, chromatography and, 432... 

Nitration of aromatic rings by nitronium tetrafluoroborate is a general method. Fifty-seven arenes, haloarenes, nitroarenes,... 

Photolyses of 3-substituted phenyl azides 53 in hot diethylamine containing pyrene, a singlet sensitizer, furnish mixtures of the 4- and 6-substituted 3ff-azepines 54 and 55. The isomers, however, were not separated and the yields were based on quantitative GC analysis of the reaction mixtures.176 Of mechanistic significance is that the ratios of the isomeric azepines obtained compare favorably with those observed in the deoxygenation of 3-nitroarenes with trivalent phosphorus compounds. 

Diethyl methylphosphonite in refluxing dialkylamine is the favored method for the formation of 37/-azepines from nitroarenes,75,176,207 although tributylphosphane and tri-piperidinophosphane are recommended for the deoxygenation of nitrobenzene in piperidine.79 Deoxygenation of nitrobenzene in diethylamine furnishes Ar,Ar-diethyl-3/f-azepin-2-amine, and a range of 5-substituted 3//-azepines 97 have been prepared in a similar manner from 4-sub-stituted nitroarenes.79,176 Curiously, the corresponding 2-substituted nitroarenes, with the exception of 2-nitrotoluene, yield only tarry products. 

V,/V-Diethyl-3//-azepin-2-amines 97 from Nitroarenes General Procedure 176... 

As expected, similar treatment of 3-nitroarenes furnishes mixtures of 4- and 6-substituted 3H-azepines, 54 and 55, respectively.176 Comparable yields of mixed azepines were also obtained by deoxygenation of 3-nitroarenes with alkylphophorous triamides, formed in situ from hexa-methylphosphorous triamide and excess of a secondary amine.66 In a few cases the 3//-azepines were separated by fractional crystallization of their oxalate salts66 but, in general, pure isomers were not isolated and the yields cited in the table were determined by HNMR spectroscopy. 

Attempts to prepare 2-butoxy-3//-azepines by heating nitro compounds with tris(di-ethylamino)phosphane in /m-butyl alcohol failed, as diethylamine, liberated by alcoholysis of the aminophosphane, reacts in preference with the alcohol (vide supra) to give the Ar,/V-di-ethyl-3//-azepin-2-amine in good yield.176 However, the deoxygenation of nitroarenes with tributylphosphane in the presence of primary and secondary alcohols furnishes 2-alkoxy-3//-azepines 98 in practicable yields.79... 

Alkoxy-3//-azepines 98 by Deoxygenation of Nitroarenes in Alcohol Solution Typical Procedures 79 Method A 2-Methoxy-3//-azepine (98, R = Me) ... 

Deoxygenation of the nitroarene in the presence of phenol or an enol (acetyl acetone) fails to yield the 3//-azepine. On the basis of these studies it is concluded that there is a correlation between azepine formation and the p/(a of the hydroxy compound and only those hydroxy compounds of pATa >12 yield 3//-azepines. The detrimental effect of acid conditions on 3H-azepine formation has been referred to earlier.214... 

The deoxygeneration of nitroarenes by trivalent phosphorus compounds in the presence of amines is a useful route to 3/f-azepin-2-amines (cf. compounds 32, Section 3.1.1.4.2.2.). Subsequently, it has been shown, by carrying out the reaction in strongly basic solution, that the process can be extended to the synthesis of 1H-. 3H- and 5//-2-benzazepines from nitronaph-thalenes 43 For example, 1-nitronaphthalenes 3 with dimethyl phosphite in the presence of sodium methoxide and a primary or secondary aliphatic amine, yield the dimethyl 5//-2-ben-zazepin-3-yl phosphonates 4 accompanied, in some cases, by the isomeric 3//-2-bcnzazepin-3-yl phosphonates 5. 

The reaction with nitrite proceeds smoothly and with relatively high yields of the corresponding nitroarene (see Sec. 10.6). Obviously a major part of the driving force of this reaction is the formation of a stable, i. e., an energetically favorable, radical, nitrogen dioxide. With the hydroxide ion — a much stronger nucleophile than the nitrite ion — the reaction is expected to produce very unstable radicals, the hydroxy radical OH and the oxygen radical anion O, from the diazohydroxide (Ar - N2 — OH) and the diazoate (Ar-N20 ) respectively. Consequently, dediazoniation in alkaline aqueous solution does not follow the simple Scheme 8-41 with Yn = OH, but instead involves diazoanhydrides (Ar — N2 —O —N2 —Ar) as intermediates (see Sec. 8.8). 

Alkylation of carbanions of a-halogenomethyl sulphoxides enables one to elongate the alkyl chain403-406 (equations 175 and 176). a-Chlorosulphoxides react with nitroarenes in... 

The carbanion of 2,3-dimethylthiazolidine-4-one reacted with nitroarenes to give either a ting opened product (50) via a VNS (vicarious nucleophilic substitution) reaction or a product resulting from oxidative nucleophilic substitution of hydrogen (51). Ring opening VNS reactions with 5-membered 5-heterocycles are limited to those heterocycles which show some conformational flexibility <96TL983>. 

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