O-Nitrotoluene,

Uses O-Nitrotoluene is a yellow liquid. The compound is used for the synthesis of a variety of industrial products (e.g., azo dyes, agricultural chemicals, explosives, sulfur dyes, and rubber chemicals). 

Toxicity O-Nitrotoluene causes adverse effects to animals and humans. Acute and chronic exposure causes irritation to skin and mucous membranes, hypoxia, anemia, and depression in workers.86 More reports are available regarding the genotoxicity, carcinogenicity, and reproductive effects of O-Nitrotoluene in experimental animals.87,88 

Uses The technical-grade dinitrotoluene is an oily liquid and is easily combustible. Essentially, dinitrotoluene is used in large volume during the manufacture of polyurethane foams and polymers, in the production of toluene diisocyanates, and in manufacturing explosives. 

Toxicity Dinitrotoluene is known to cause a variety of adverse effects in animals and humans. Workers come in contact with dinitrotoluene through all three major routes (oral, dermal, inhalation). The acute oral LD50 in rats ranges from 568 to 650 mg/kg female rats are more resistant to the chemical. The acute inhalation LC50 (1 hour) in rats is less than 2 mg/L. Acute and repeated exposures to the compound are known to cause hypoxia, dyspnea, headache, dizziness, joint pain, optic neuritis, cyanosis, jaundice, and anemia among workers.78 83 

Studies have indicated that repeated exposure of dinitrotoluene has resulted in testicular atrophy and disturbances in the spermatogenesis cycle in experimental mice, rats, and dogs. Female mice also revealed nonfunctioning ovaries 89,90 Conflicting reports regarding the potential reproductive toxicity of dinitrotoluene among workers demand more confirmatory data 91,92 NIOSH has classified technical dinitrotoluene as a human reproductive health hazard in industrial workplaces. Isomers of dinitrotoluene have caused complete liver cancers in animals, but technical-grade dinitrotoluene failed to induce any kind of hepatic cancer in humans.37,93 

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The reduction of o-nitrophenyl acetic acids or esters leads to cyclization to oxindoles. Several routes to o-nitrophenylacetic acid derivatives arc available, including nitroarylation of carbanions with o-nitroaryl halides[2l,22] or trif-late[23] and acylation of o-nitrotoluenes with diethyl oxalate followed by oxidation of the resulting 3-(u-nitrophenyl)pyruvate[24 26]. 

Reductive Gyclizations. The Batcho-Leimgmber protocol involves condensation of an o-nitrotoluene with a dimethylformamide acetal to form a P-( nitrophenyl)enamine (27). A reducing agent then affects the reductive cycli2ation to an indole. 

Properties. o-Nitiotoluene [88-72-2] is a clear yeUow liquid. The solid is dimorphous and the melting points of the a- and P-forms ate —9.55 and —3.85 C, respectively. o-Nitrotoluene is infinitely soluble in benzene, diethyl ether, and ethanol. It is soluble in most organic solvents and only slightly soluble in water (0.065 g in 100 g of water at 30°C). The physical properties of o-nitrotoluene are hsted in Table 9. 

The separation of the isomers is carried out by a combination of fractional distillation and crystallization. In a fractional vacuum distillation step, the distillate, obtained at a head temperature of 96—97°C at 1.6 kPa (12 mm Hg), is fairly pure o-nitrotoluene and can be purified further by crystallization. The meta isomer is distilled from a mixture of m- and -nitrotoluene and can be purified further by additional distillation and crystallization steps. The bottoms product from the distillation steps is cooled in a crystallizer to obtain nitrotoluene. 

If pure isomers are required, the ortho and meta compounds can be prepared by indirect methods. o-Nitrotoluene can be obtained by treating 2,4-dinitrotoluene with ammonium sulfide followed by diazotization and boiling with ethanol. / -Nitrotoluene can be prepared from -toluidine by acetylation, nitration deacetylation, diazotization, and boiling with ethanol. A fairly pure -nitrotoluene, which has been isolated from the isomeric mixture, can be purified further by repeated crystallization. 

Analytical and Test Methods. o-Nitrotoluene can be analyzed for purity and isomer content by infrared spectroscopy with an accuracy of about 1%. -Nitrotoluene content can be estimated by the decomposition of the isomeric toluene diazonium chlorides because the ortho and meta isomers decompose more readily than the para isomer. A colorimetric method for determining the content of the various isomers is based on the color which forms when the mononitrotoluenes are dissolved in sulfuric acid (45). From the absorption of the sulfuric acid solution at 436 and 305 nm, the ortho and para isomer content can be deterrnined, and the meta isomer can be obtained by difference. However, this and other colorimetric methods are subject to possible interferences from other aromatic nitro compounds. A titrimetric method, based on the reduction of the nitro group with titanium(III) sulfate or chloride, can be used to determine mononitrotoluenes (32). Chromatographic methods, eg, gas chromatography or high pressure Hquid chromatography, are well suited for the deterrnination of mononitrotoluenes as well as its individual isomers. Freezing points are used commonly as indicators of purity of the various isomers. 

Batch syntheses comparable to those used for MDA produce 3,3 -dimethy1methy1enedi(cyclohexylamine) marketed under the trade name Laromia C-260. The starting aromatic diamiae, 3,3 -dimethy1methy1enediani1ine [838-88-0] is prepared from o-toluidine [95-53-4] condensation with formaldehyde. Similarly 3,3 -dimethyldicyclohexylaniiae [24066-10-2] may be produced (38) from o-toHdine [119-93-7] derived from o-nitrotoluene [88-72-2]. The resultant isomer mixtures are dependent on reduction conditions as ia MDA hydrogeaatioa. 

Processes. Toluene is nitrated ia two stages. Mononitration occurs ia mixed acid, 30% HNO and 55% H2SO4, at 30—70°C ia a series of continuous stirred-tank reactors. Heat is Hberated and must be removed. The isomer distribution is approximately 58% o-nitrotoluene 38% -nitrotoluene, and 4% y -nitrotoluene (Fig. 1). 

Certain substituted o-nitrotoluenes can be induced to cyclize, forming 2,1-benzisoxazoles. Bis(2-nitrophenyl)methane when irradiated gave 3-(o-nitrophenyl)-2,l-benzisoxazole. The possible intermediates including a biradical were discussed (74TL4359). 3-(o-Nitrophenyl)-2,1-benzisoxazole was prepared by the acid cyclization of bis(2-nitrophenyl)methanol (Scheme 178) (65RRC1035>. 

Bis(2,4,6-trinitrophenyl)methane when treated with NaAc in acetic acid produced (580) as a thermostable explosive (80MIP41600). The conversion of o-nitrotoluene into 2,1-benzisoxazole was effected by mercury(II) oxide catalysis. A mercury containing intermediate was isolated and was demonstrated to be converted into 2,1-benzisoxazole (67AHC(8)277). The treatment of o-nitrotoluene derivative (581) with sulfuric acid gave (582) in 35% yield (72MI41607). 

Three products are possible from nitration of toluene o-nitrotoluene, rw-nitro-toluene, and p-nitrotoluene. All ar e formed, but not in equal amounts. Together, the ortho-and para-substituted isomers make up 97% of the product mixture the rneta only 3%. 

C-Methylation products, o-nitrotoluene and p-nitrotoluene, were obtained when nitrobenzene was treated with dimethylsulfoxonium methylide (I)." The ratio for the ortho and para-methylation products was about 10-15 1 for the aromatic nucleophilic substitution reaction. The reaction appeared to proceed via the single-electron transfer (SET) mechanism according to ESR studies. 

The Batcho-Leimgruber indole synthesis involves the condensation of o-nitrotoluene derivatives 1 with formamide acetals 2, followed by reduction of the trans-p-dimethylamino-2-nitrostyrene 3 which results to furnish indole derivatives represented by... 

In 1971, Batcho and Leimgruber introduced a new method for the synthesis of indoles. For example, condensation of o-nitrotoluene (5) with N,N-dimethylformamide dimethyl acetal (6) (DMFDMA) was followed by reduction of the rrans-P-dimethylamino-2-nitrostyrene (7) which resulted to provide the indole (8). ... 

The Reissert procedure involves base-catalyzed condensation of an o-nitrotoluene derivative 1 with an ethyl oxalate (2) which is followed by reductive cyclization to an indole-2-carboxylic acid derivative 4, as illustrated below . ... 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

In contrast to the facile condensation of o-nitrotoluene with diethyl oxalate, other a-alky] nitrobenzenes are sluggish to react with diethyl oxalate or fail to react at all. It has been suggested that this is due both to steric and electronic factors effected by the alky] group, which destabilizes the methylene group in regard to formation of the carbanion. ... 

This method has been applied to a large-scale preparation of 6-bromoindole, which reacts with various arylboronic acids via the Suzuki reaction to afford 6-aryhndoles fEq. 10.50. 6-Bromo-5-methoxyindole for use in the synthesis of marine bromoindole " and 5-amino-7-ethoxycarbonyhndole for use in synthesis of l//-pyrrolo[3,2-g quina2ohne ring system fEq. 10.51 " have been prepared from the appropriate o-nitrotoluene. 

Oxidative coupling of o-nitrotoluene gives 4,4 -dinitrodibenzyl which is reduced with hydrogen to the diamine. The diamine is pyrolyzed to give dihydrobenzazepine. This is reacted with N-(3-chloropropvl)-N-methylbenzamine to give N-benzyldesipramine. This is debenzylated by reductive cleavage and then reacted with HCI. 

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