Indole

Indole
Gerd Collin, DECHEMA e.V., Frankfurt/Main, Federal Republic of Germany (Chaps. 2 5) Hartmut Hoke, Weinheim, Federal Republic of Germany (Chap. 6)

1. 2. 3. 4.

Introduction Properties . . Production . Derivatives .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

1 1 1 1

5. Uses . . . . . . . . . . . . . . . . . . . . . . . . 6. Toxicology ................... 7. References . . . . . . . . . . . . . . . . . . .

2 3 4

1. Introduction
Indole [120-72-9], 1-benzo[b]pyrrole, C8 H7 N, was discovered by A. v. Baeyer and C. A. Knop in 1866 as the basic structure of the natural dye, indigo, from which it was obtained. In 1910, R. Weissgerber found indole in coal tar.

2. Properties
Physical Properties. Indole, M r 117.15, mp 52.5 C, bp 254.7 C (101.3 kPa), d 1.22 g/cm3 (18 C), forms colorless, shiny akes with a slight jasmine aroma. It is readily soluble in ethanol, diethyl ether, and benzene, soluble in hot water, slightly soluble in cold water, and volatile in steam. The heat of combustion is 3.650 kJ/kg (25 C), the enthalpy of vaporization 597.5 kJ/kg (10.3 27.4 C), and the dipole moment 2.11 D (benzene). Chemical Properties. As a secondary amine, indole has a hydrogen atom which can be substituted by alkali metals. Oxidation leads to indigo, mild hydrogenation to 2,3-dihydroindole (indoline). Diindole, triindole, and resinication products are obtained upon treatment with acids.

the indole is concentrated in a biphenyl indole fraction which boils between 245 and 255 C. Following extraction of phenols and bases, the indole is isolated from this fraction and separated from the other major component biphenyl, whose boiling point is only 0.3 C higher. This is achieved by melting with potassium hydroxide to give the potassium salt of indole, by azeotropic distillation with diethylene glycol, or by extraction with selective solvents (e.g., glycols, aqueous dimethyl sulfoxide, or monoethanolamine). The crude indole can then be puried by crystallization from aliphatic hydrocarbon solvents. In addition to its recovery from coal tar, indole is also synthesized in technical quantities. Methods used include Madelung synthesis of formyltoluidine (from o-toluidine and formic acid), followed by cyclization [810], dehydrogenating cyclization of 2-ethylaniline [1120], cyclocondensation of aniline and ethylene glycol in the liquid or gas phase [2123], and cyclization of 2-(2-nitrophenyl)ethanol [24].

4. Derivatives
3-Methylindole [83-34-1], skatole, C9 H9 N, M r 131.18, mp 95 C, bp 266.4 C (101.3 kPa), forms colorless akes which are soluble in ethanol and slightly soluble in water. It can be recovered from coal tar or synthesized by Fischer reaction from the phenylhydrazone of propionaldehyde or, together with indole, by catalytic dehydration of 2-(2-aminophenyl)-1,3-propanediol [25].

3. Production
High-temperature coal tar contains on average just under 0.2 % indole. In coal tar distillation,
c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 10.1002/14356007.a14 167

Indole colorless needles. It is readily soluble in ethanol and acetone, and slightly soluble in water, diethyl ether, chloroform, and benzene. It can be produced by reacting indole with ethylene imine, by catalytic hydrogenation of indole-3-acetonitrile, or by reacting phenylhydrazine with 4-aminobutyraldehyde diethyl acetal. Tryptamine is used to synthesize the vasodilator and antihypertensive, Vincamine.

3-(Dimethylaminomethyl)indole [87-52-5], gramine, C11 H14 N2 , M r 174.25, mp 138 139 C, forms colorless needles. The compound is soluble in ethanol, diethyl ether, and chloroform and insoluble in water. It can be synthesized from indole by the Mannich reaction with dimethyl-amine and formaldehyde. Gramine is used to synthesize d,l-tryptophan, the plant growth regulators indole-3-acetic acid and indole-3-butanoic acid as well as the intermediate tryptamine.

Indole-3-aldehyde [487-89-8], C9 H7 NO, M r 145.16, mp 194 C, forms colorless crystals. It is readily soluble in ethanol and slightly soluble in cold water. It can be produced by Vilsmeier reaction of indole with formylmethylaniline or with dimethylformamide and phosphorus oxychloride. Indole-3-aldehyde can be used to make d,l-tryptophan and cyanine dyes.

3-(2-Hydroxyethyl)indole [526-55-6], tryptophol, C10 H11 NO, M r 161.20, mp 59 C, bp 174 C, (2 kPa) forms colorless prisms or akes that are readily soluble in methanol, ethanol, diethyl ether, chloroform, and acetone, soluble in benzene, and slightly soluble in water. It is produced by reacting methyl1H-indole-3-acetate with lithium aluminum hydride, or through reduction of methyl-1Hindole-3-glyoxylate with sodium borohydride. The antihypertensive Indoramin is produced from tryptophol.

5. Uses
2,3-Dihydroindole [495-15-1], indoline C8 H9 N, M r 119.16, bp 229 230 C (101.3 kPa), is a colorless liquid, which is volatile in steam and soluble in diethyl ether, acetone, and benzene, but only slightly soluble in water. Indoline is obtained by hydrogenation of indole or by catalytic cyclodehydration of 2-(2-aminophenyl)ethanol. A range of pharmaceuticals, as well as fungicides and bactericides, can be produced from indoline. In line with its natural occurrence as a component of jasmine oil and orange-blossom oil, indole has been used for many years to x fragrances and is therefore found in many perfumes [26]. A further important application is the production of the essential amino acid tryptophan ( Amino Acids, Chap. 3.2.17. ). Tryptophan can be synthesized from indole by chemical reactions as a racemate (via the indole derivatives gramine and indole-3-aldehyde). It is also produced by biotechnology in the enantiomerically pure l-form (e.g., from indole and l-serine). Indole is also used as a feedstock in the synthesis of plant growth regulators, such as indole3-acetic acid [6250-86-8] ( heteroauxin) and

3-(2-Aminoethyl)indole [61-54-1], tryptamine, C10 H12 N2 , M r 160.22, mp 118 C, forms

Indole indole-3-butanoic acid [3127-44-4] ( Plant Growth Regulators). Fungicidal and bactericidal plant protectives are synthesized from indoline [27]. Derivatives of indole-3-acetic acid nd application as mild analgesics, e.g., indomethacin, ( Anti-inammatory Antirheumatic Drugs). Indole and its derivatives are basic building blocks for many other pharmaceuticals. Thus, for example, indoline is used to synthesize analgesics [28] and antihypertensives [29], and tryptamine [61-54-1] [3-(2-aminoethyl)indole] for the synthesis of the vasodilator and antihypertensive, Vincamine [30]. Tryptophol [526-55-6] [3-(2-hydroxyethyl)indole] is used to prepare the antihypertensive Indoramin [31] ( Antihypertensives, Chap. 4.2.2.2.). (Pyridylalkyl)indoles can be produced from indole and can be used as antidepressants, antihistamines, and antihypertensives [3234]. 3Piperidinylindoles can be obtained via the Grignard reaction of 4-chloroindole with 3piperidinone, and can be used in the prevention of anoxia [35]. Indole-2-carboxylic acid derivatives are useful, e.g., as antihypertensives [3638]. 5-Chloroindole [17422-32-1] can be synthesized from indoline via the intermediates 1-acylindoline, 1-acyl-5-chloroindoline, and 5-chloroindoline [39]. It can be used as an intermediate in the production of 5chlorotryptamine (for the production of tranquilizers and blood pressure lowering agents), as well as in the production of antidepressives, antiemetics, and drugs for the treatment of Parkinsons disease [4042]. 2-Methylindole [95-20-5] (as the heterocyclic coupling component) is a starting material for commercially important cationic diazo dyes. Cyanine dyes are synthesized from 2-methylindole, 1-methyl-2-phenylindole, 2-methylindole-3aldehyde, and indole-3-aldehyde ( Methine Dyes and Pigments). In addition, indolylmethane dyes are produced from 1-methyl-2phenylindole ( Triarylmethane and Diarylmethane Dyes). Reacting indole with 3,6-bis(2-carboxybenzoyl)carbazole affords carbazole phthalein dyes, which are used as optical lter agents in photographic emulsions [43].

6. Toxicology
Apart from contact during production and manufacture of indole, human exposure results from smoking and intestinal degradation of nutritional l-tryptophan. Indole is readily absorbed from the gastrointestinal tract and rapidly converted by the liver, e.g., to indican and oxindole, which are excreted mainly into the urine [44], [45]. The acute oral LD50 is 1000 1100 mg/kg in rats [46], [47] and about 500 mg/kg in mice [48]. Autopsy after acute exposure revealed hemorrhages and hyperemia of inner organs and tissues. Upon application to the skin and eyes of rabbits, slight temporary irritation was observed [49], [50]. Unlike 3-methylindole (skatole), indole does not induce pulmonary injury in cattle after repeated oral application [51]. At high chronic dosage (20 200 mg kg1 d1 orally and subcutaneously in mice, rats, rabbits, and dogs for more than three months), indole resulted in a shift in the blood cell differential picture (anemia, leukocytosis, or leukopenia) ; with persistently high intoxication, the development of leukemia cannot be ruled out [5254]. In cattle, hemolysis and hemoglobinuric nephrosis were observed after several oral doses of indole (100 or 200 mg/kg) [51]. Although there is no other experimental evidence for its cancerogenic potential [55], indole may inuence the formation of tumors caused by other agents. Thus, very high oral doses (800 mg kg1 d1 ) have been reported to accelerate the development of tar-induced skin tumors in mice [53] and 2-acetylaminouorene-induced bladder carcinomas in hamsters and rats [56]. On the other hand, it simultaneously seemed to suppress 2-acetylaminouorene-induced hepato-carcinogenesis [56]. A genotoxic effect of indole was conrmed in the Ames test in combination with other mutagenic agents [57]. However, indole itself was neither mutagenic in the Ames test [57], [58], nor in a cell transformation test [59], although in a DNA repair assay with Bacillus subtilis, indole caused reparable DNA damage [59].

Indole
24. Bofors, DE 2 052 678, 1970 (J. M. Bakke, H. E. Heikmann). 25. R tgerswerke, DE 2 328 330, 1973 (G. u Grigoleit, R. Oberkobusch, G. Collin). 26. G. T. Walker, Seifen ole Fette Wachse 100 (1974) 375 377. 27. Pzer, GB 1 394 373, 1975; GB 1 394 374, 1975 (R. J. Bass, R. C. Koch, H. C. Richards, J. E. Thorpe). 28. Hoechst-Roussel Pharmaceuticals, US 4 448 784 784, 1982 (E. J. Glamkowski, J. M. Fortunato). 29. Science Union, FR 2 003 311, 1968 (L. Beregi, P. Hugon, M. Laubie). 30. Roussel-UCLAF, DE 2 115 718, 1970 (J. Warnant, A. Farcilli, E. Toromnoff). 31. Wyeth, GB 1 399 608, 1971 (J. L. Archibald). 32. Pharmindustrie, EP 65 907, 1982 (F. Audiau, G. R. Le Fur). 33. Boehringer Ingelheim, EP 58 975, 1982 (K. Freter, V. Fuchs, J. T. Oliver). 34. Wyeth, EP 2 886, 1979 (J. L. Archibald, T. J. Ward). 35. Roussel-UCLAF, EP 21 924, 1981 (J. Guillaume, L. Nedelec, C. Dumont, R. Fournex). 36. Hoechst, DE 3 151 690, 1981 (H. Urbach, R. Henning, V. Teetz, R. Geiger, R. Becker). 37. McNeilab, US 4 529 724, 1983 (C. Y. Ho). 38. American Cyanamid, US 4 619 941, 1984 (W. B. Wright, J. B. Press). 39. R tgerswerke, DE 3 035 403, 1980 (M. u Maurer, W. Orth, W. Fickert). 40. MARPHA, DE 2 618 152, 1977 (A. Champseix, C. Gueremy, G. Le Fur). 41. Roussel-UCLAF, DE 2 719 294, 1977 (F. Clemence, D. Humbert). 42. Roussel-UCLAF, DE 2 738 646, 1978 (C. Dumont, J. Guillaume, L. Nedelec). 43. Polaroid, US 3 932 455, 1976 (R. C. Bilofsky, R. D. Cramer). 44. A. H. Beckett, D. M. Morton, Biochem. Pharmacol. 15 (1966) 937 946. 45. L. J. King, D. V. Parke, R. T. Williams, Biochem. J. 98 (1966) 266 277. 46. National Institute for Occupational Safety and Health (NIOSH): Registry of Toxic Effects of Chemical Substances, US Government Printing Ofce, Washington D.C. 1987, p. 12992. 47. Huntingdon Research Centre, R tgerswerke u Order No. 338 a, 1979, M nster, Federal u Republic of Germany.

7. References
General References 1. Beilstein, 20 304, 20(1) 121, 20(2) 196, 20(3) 3176 3180. 2. H. J. V. Winkler: Der Steinkohlenteer und seine Aufarbeitung, Verlag Gl ckauf, Essen u 1951, pp. 146 148, 151 152. 3. R tgerswerke, Erzeugnisse aus u Steinkohlenteer, 1958, Frankfurt, Federal Republic of Germany. 4. H.-G. Franck, G. Collin: Steinkohlenteer, Springer Verlag, Berlin 1968, pp. 60 61, 180 181. 5. H.-G. Franck, J. W. Stadelhofer: Industrial Aromatic Chemistry, Springer Verlag, Berlin 1988, pp. 417 418. 6. R. J. Sundberg: The Chemistry of Indoles, Academic Press, New York 1970. 7. W. J. Houlihan: Indoles, John Wiley & Sons, New York 1972. Specic References 8. Mitsui Toatsu, JP 74 20 587, 1970 (R. Fujiwars, Y. Yamada, N. Kuroda). 9. Kyowa Fermentation Industry, JP 73 76 864, 1972 (T. Yamauchi, S. Yada, S. Kudo). 10. Ube Industries, JP 78 95 965, 1977 (M. Nakai, T. Komata, M. Oda). 11. R tgerswerke, DE 2 224 556, 1972; u DE 2 401 017, 1974 (G. Grigoleit, R. Oberkobusch, G. Collin). 12. Houdry, US 2 891 965, 1956 (S. E. Voltz, J. H. Krause, W. E. Erner). 13. Snam Progetti, DE 2 148 961, 1971 (M. M. Mauri, P. Moggi). 14. Teijin, JP 73 76 862, 1972 (T. Fukada, K. Tanaka). 15. E. I. du Pont de Nemours, US 2 409 676, 1944 (W. F. Grasham, W. M. Brunner). 16. Socony Mobil Oil, NL 6 505 911, 1965. 17. Lonza, DE 2 441 439, 1974 (C. OMurchu). 18. Soci t Nationale Elf Aquitaine, ee DE 2 328 284, 1973 (M. Petinaux, J. Metzger, J.-P. Aune, H. Knoche). 19. Sumitomo Chemical, JP 7 831 660, 1976 (M. Tamura). 20. Mitsui Toatsu, JP 76 113 868, 1975 (K. Yamamoto, K. Nitta, S. Ichikawa). 21. Mitsui Toatsu, EP 86 239, 1982 (T. Honda, K. Terada). 22. Ube Industries, JP 83 128 371, 1982 (N.N.). 23. Keishitsu Ruibun Shinyoto Kaihatsu Gijutsu Kenkyu Kumiai, JP 86 44 862, 1984 (M. Imanari, T. Seto).

Indole
48. G. J. Martin, E. H. Rennebaum, M. R. Thompson, Ann. Intern. Med. 18 (1943) 57 71. 49. Huntingdon Research Centre, R tgerswerke u Order No. 338 b, 1979, M nster, Federal u Republic of Germany. 50. Huntingdon Research Centre, R tgerswerke u Order No. 338 c, 1979, M nster, Federal u Republic of Germany. 51. A. C. Hammond, J. R. Carlson, Vet. Rec. 107 (1980) 344 346. 52. W. T. Taylor, Med. Ann. D. C. 8 (1939) 362 363.

53. K. Kaiser, Z. Krebsforsch. 59 (1953) 448 495. 54. H. Ehrhart, W. Stich, Klin. Wochenschr. 35 (1957) 504 511. 55. M. J. Shear, J. Leiter, J. Natl. Cancer. Inst. (US) 2 (1941) 241 258. 56. M. Matsumoto, M. L. Hopp. R. Oyasu, Invest. Urol. 14 (1976) 206 209. 57. T. Matsumoto, D. Yoshida, S. Mizusaki, Mutat. Res. 56 (1977) 85 88. 58. M. Curvall, J. Florin, T. Jansson, Toxicology 23 (1982) 1 10. 59. T. Osawa, M. Namiki, K. Suzuki, T. Mitsuoka, Mutat. Res. 122 (1983) 299 304.

Industrial Hygiene

Occupational Health and Safety