Toluidine hydrochloride

Dissolve 1 g. of the sulphonic acid or its sodium salt in the minimum volume of boiling water and add a saturated aqueous solution of 1 g. of p-toluidine hydrochloride. Cool, Alter off the precipitate of the p-tolu-idine salt, and recrystallise it from hot water or from dilute ethanol. 

Dissolve 36 g. of p-toluidine in 85 ml. of concentrated hydrochloric acid and 85 ml. of water contained in a 750 ml. conical flask or beaker. Cool the mixture to 0° in an ice-salt bath with vigorous stirring or shaking and the addition of a httle crushed ice. The salt, p-toluidine hydrochloride, will separate as a finely-divided crystalline precipitate. Add during 10-15 minutes a solution of 24 g. of sodium nitrite in 50 ml. of water (1) shake or stir the solution well during the diazotisation, and keep the mixture at a temperature of 0-5° by the addition of a httle crushed ice from time to time. The hydrochloride wUl dissolve as the very soluble diazonium salt is formed when ah the nitrite solution has been introduced, the solution should contain a trace of free nitrous acid. Test with potassium iodide - starch paper (see Section IV,60). 

A good 3ueld of 5-iodo-2-aminotoluene may be obtained by intimately mixing o-toluidine hydrochloride, iodine and calcium carbonate, and then adding water to the mixture. The liberated hydriodic acid reacts at once with the Calcium carbonate and the lij driodide of the base is not formed. 

Triturate 20 g. of dry o-toluidine hydrochloride and 35 5 g. of powdered iodine in a mortar and then grind in 17 -5 g. of precipitated calcium carbonate. Transfer the mixture to a conical flask, and add 100 ml. of distilled water with vigorous shaking of the flask. Allow the mixture to stand for 45 minutes with occasional agitation, then heat gradually to 60-70° for 5 minutes, and cool. Transfer the contents of the flask to a separatory funnel, extract the base with three 80 ml. portions of ether, diy the extract with anhydrous calcium chloride or magnesium sulphate, and remove the excess of solvent. The crude 5-iodo-2-aminotoluene separates in dark crystals. The yield is 32 g. Recrystallise from 50 per cent, alcohol nearly white crystals, m.p. 87°, are obtained. 

Scheme 13.2 Deuteration of o-toluidine hydrochloride under microwave conditions.

Goodman, D.G., J.M.Ward, and W.D.Reichardt. 1984. Splenic fibrosis and sarcomas in F344 rats fed diets containing aniline hydrochloride, p-chloroaniline, azobenzene, o-toluidine hydrochloride, 4,4 -sulfonyldianiline, or D C red no. 9. J. Natl. Cancer Inst. 73 265-273. 

While the cuprous cyanide solution is warmed gently (to 60°-70°) on the water bath, a solution of p-tolyldiazonium chloride is prepared as follows Heat 20 g. of p-toluidine with a mixture of 50 g. of concentrated hydrochloric acid and 150 c.c. of water until dissolution is complete. Immerse the solution in ice-water and stir vigorously with a glass rod so that the toluidine hydrochloride separates as far as possible in a microcrystalline form. Then cool the mixture in ice and diazotise with a solution of 16 g. of sodium nitrite in 80 c.c. of water, added until the nitrous acid test with potassium iodide-starch paper persists. The diazonium chloride solution so obtained is poured during the course of about ten minutes into the warm cuprous cyanide solution, which is meanwhile shaken frequently. After the diazo-solution has been added the reaction mixture is heated under an air condenser on the water bath fox a further quarter of an hour, and then the toluic nitrile is separated by distillation with steam (fume chamber, HCN ). The nitrile (which passes over as a yellowish oil) is extracted from the distillate with ether, the p-cresol produced as a by-product is removed by shaking the ethereal extract twice with 2 A-sodium hydroxide solution, the ether is evaporated,... 

Toxicology. ort/ o-Toluidine causes anoxia due to the formation of methemoglobin and hematuria xA-toluidine hydrochloride is carcinogenic in experimental animals. The meta-and para-isomers are assumed to produce comparable toxic effects however, meta-tolrriAine seems to have no carcinogenic activity. 

The lARC has determined that there is sufficient evidence for carcinogenicity of o-toluidine hydrochloride in animals and that it should be regarded as though it presents a carcinogenic risk to humans." ... 

National Cancer Institute Bioassay of o-Toluidine Hydrochloride for Possible Carcinogenicity, TR-153. DHEW (NIH) Pub No 79-1709, Washington, DC, US Government Printing Office, 1979... 

Hecht SS et al Comparative carcinogenicity of o-toluidine hydrochloride and nitroso-toluene in F-344 Rats. Cancer Lett 16 103-108, 1982... 

B. Preparation of chlorotoluene. In a io-l. stone jar fitted with a mechanical stirrer are placed 2 kg. of commercial 28 per cent hydrochloric acid (sp. gr. 1.14) and 428 g. (4 mols.) of o-toluidine. The mixture is cooled to o° by adding cracked ice (about 1 kg. is required). The o-toluidine hydrochloride separates as a finely divided precipitate. The stirrer is started, and to the cold suspension is added a solution of 280 g. (4.05 mols.) of sodium nitrite in 800 cc. of water the diazotization is carried out at 0-50 and requires about fifteen minutes. Cracked ice is added from time to time to keep the temperature within the proper limits. The volume of the final solution is 5-6 1. 

Information available in 1999 indicated that ort/jo-toluidine was manufactured by 16 companies in China, 11 companies in India, six companies in the United States, three companies each in Germany and Russia, two companies each in Japan and Poland, and one company each in Brazil, France, Italy, Mexico, Romania and Spain, and that ortho-toluidine hydrochloride was manufactured by one company each in Germany and India (Chemical Information Services, 1999). 

Groups of 25 male Sprague-Dawley CD rats, four to six weeks of age, were treated with ort/70-toluidine hydrochloride (purity, 97-99%) in the diet at dose levels of 8000 or 16 000 ppm for three months and then at levels of 4000 or 8000 ppm for a further... 

Male Fischer 344/N rats, 45 days of age, were administered ort/zo-toluidine hydrochloride at a concentration of 5000 ppm in the diet for 13 weeks and then kept for observation for a further 13 weeks, when animals were killed. Mesotheliomas in the epididymis were observed in 2/20 male rats exposed to ort/zo-toluidine hydrocloride. No mesotheliomas were seen in concurrent controls (0/10) (National Toxicology Program, 1996). 

Cheever, K.L., Richards, D.E. Plotnick, H.B. (1980) Metabohsm of ortho-, meta-, and para-toluidine in the adnlt male rat. Toxicol, appl. Pharmacol, 57, 361-369 Cheever, K.L., DeBord D.G, Sweaiengin, T.F. Booth-Jones, A.D. (1992) ortho-Toluidine blood protein addnets HPLC analysis with fluoreseenee deteetion after a single dose in the adult male rat. Fundam. appl Toxicol, 18, 522-531 Chemfinder (2000) ortiho-Toluidine Hydrochloride [http //www.ehemfinder.com/result.asp] Chemieal Information Serviees (1999) Directory of World Chemical Producers (Version 99.1.0) [CD-ROM], Dallas, TX... 

Environmental Protection Agency (1984) Chemical Hazard Information Profile ortho-Toluidine, ortho-Toluidine Hydrochloride, Washington DC, Office of Pesticide Program and Toxic Substances... 

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