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Indole

Names
IUPAC name Indole
Other names 2,3-Benzopyrrole, ketole, 1-benzazole
Identifiers
CAS Number	120-72-9
3D model (JSmol)	Interactive image
ChEBI	CHEBI:16881
ChEMBL	ChEMBL15844
ChemSpider	776
ECHA InfoCard	100.004.019
KEGG	C00463
PubChem CID	798
RTECS number	NL2450000
UNII	8724FJW4M5
CompTox Dashboard (EPA)	DTXSID0020737
InChI InChI=1S/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9HKey: SIKJAQJRHWYJAI-UHFFFAOYSA-N InChI=1/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9HKey: SIKJAQJRHWYJAI-UHFFFAOYAI
SMILES c1ccc2c(c1)cc2
Properties
Chemical formula	C8H7N
Molar mass	117.15 g/mol
Appearance	White solid
Density	1.1747 g/cm, solid
Melting point	52–54 °C
Boiling point	253–254°C (526 K)
Solubility in water	0.19 g/100 ml (20 °C) Soluble in hot water
Acidity (pKa)	16.2 (21.0 in DMSO)
Basicity (pKb)	17.6
Structure
Crystal structure	Pna21
Molecular shape	Planar
Dipole moment	2.11 D in benzene
Hazards
Flash point	121 °C
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). Y verify (what is  ?) Infobox references

Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an indole ring are called indoles. The indolic amino acid tryptophan is the precursor of the neurotransmitter serotonin.

General properties and occurrence

Indole is a solid at room temperature. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar.

The corresponding substituent is called indolyl.

Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, and melatonin. Other indolic compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally occurring hallucinogen dimethyltryptamine (N,N-DMT).

The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum.

History

Indole chemistry began to develop with the study of the dye indigo. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. In 1869, he proposed a formula for indole (left).

Certain indole derivatives were important dyestuffs until the end of the 19th century. In the 1930s, interest in indole intensified when it became known that the indole nucleus is present in many important alkaloids, as well as in tryptophan and auxins, and it remains an active area of research today.

Synthesis of indoles

Indole is a major constituent of coal-tar, and the 220–260 °C distillation fraction is the main industrial source of the material. Indole and its derivatives can also be synthesized by a variety of methods. The main industrial routes start from aniline.

Illustrative of such large-scale syntheses, indole (and substituted derivatives) form via vapor-phase reaction of aniline with ethylene glycol in the presence of catalysts:

In general, reactions are conducted between 200 and 500 °C. Yields can be as high as 60%. Other precursors to indole include formyltoluidine, 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergo cyclizations. Many other methods have been developed that are applicable.

Leimgruber-Batcho indole synthesis

The Leimgruber-Batcho indole synthesis is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are made up of specifically substituted indoles.

Fischer indole synthesis

One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis, developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions. Indole can still be synthesized, however, using the Fischer indole synthesis by reacting phenylhydrazine with pyruvic acid followed by decarboxylation of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.

Other indole-forming reactions

• Bartoli indole synthesis
• Bischler-Möhlau indole synthesis
• Fukuyama indole synthesis
• Gassman indole synthesis
• Hemetsberger indole synthesis
• Larock indole synthesis
• Madelung synthesis
• Nenitzescu indole synthesis
• Reissert indole synthesis
• Baeyer-Emmerling indole synthesis
• In the Diels-Reese reaction dimethyl acetylenedicarboxylate reacts with diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2,3-dicarboxylate and aniline. With other solvents, other products are formed: with glacial acetic acid a pyrazolone, and with pyridine a quinoline.

Chemical reactions of indole

Basicity

Unlike most amines, indole is not basic. The bonding situation is completely analogous to that in pyrrole. Very strong acids such as hydrochloric acid are required to protonate indole. The protonated form has an pK_a of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.

Electrophilic substitution

The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 10 times more reactive than benzene. For example, Vilsmeier-Haack formylation of indole will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole acetic acid and synthetic tryptophan.

Nitrogen-H acidity and organometallic indole anion complexes

The N-H center has a pK_a of 21 in DMSO, so that very strong bases such as sodium hydride or butyl lithium and water-free conditions are required for complete deprotonation. The resulting alkali metal derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents) and (especially) zinc complexes tend to react at carbon-3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C-3 attack.

Carbon acidity and C-2 lithiation

After the N-H proton, the hydrogen at C-2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C-2 position. This strong nucleophile can then be used as such with other electrophiles.

Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole.

Alan Katritzky also developed a technique for lithiating the 2-position of unsubstituted indole.

Oxidation of indole

Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

Cycloadditions of indole

Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intermolecular cycloadditions are not favorable, whereas intramolecular variants are often high-yielding. For example, Padwa et al. have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile.

Indoles also undergo intramolecular and cycloadditions.

Applications

Natural jasmine oil, used in the perfume industry, contains around 2.5% of indole. Since 1 kilogram of the natural oil requires processing several million jasmine blossoms and costs around $10,000, indole (among other things) is used in the manufacture of synthetic jasmine oil (which costs around $10/kg).

See also

• Isoindole
• Martinet dioxindole synthesis
• Skatole (3-methylindole)
• Stollé synthesis
• Tryptamines

General references

• Indoles Part One, W. J. Houlihan (ed.), Wiley Interscience, New York, 1972.
• Sundberg, R. J. (1996). Indoles. San Diego: Academic Press. ISBN 0-12-676945-1.
• Joule, J. A. (2000). Heterocyclic Chemistry. Oxford, UK: Blackwell Science. ISBN 0-632-05453-0. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
• Joule, J., In Science of Synthesis, Thomas, E. J., Ed.; Thieme: Stuttgart, (2000); Vol. 10, p. 361. ISBN 3-13-112241-2 (GTV); ISBN 0-86577-949-X (TNY).

References

1. http://www.leffingwell.com/olfact5.htm
2. Baeyer, A. (1866). "Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub". Ann. 140 (3): 295. doi:10.1002/jlac.18661400306.
3. Baeyer, A.; Emmerling, A. (1869). "Synthese des Indols". Chemische Berichte. 2: 679. doi:10.1002/cber.186900201268.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. R. B. Van Order, H. G. Lindwall (1942). "Indole". Chem. Rev. 30: 69–96. doi:10.1021/cr60095a004.
5. Gribble G. W. (2000). "Recent developments in indole ring synthesis—methodology and applications". J. Chem. Soc. Perkin Trans. 1 (7): 1045. doi:10.1039/a909834h.
6. Cacchi, S.; Fabrizi, G. (2005). "Synthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions". Chem. Rev. 105 (7): 2873. doi:10.1021/cr040639b. PMID 16011327.{{cite journal}}: CS1 maint: multiple names: authors list (link)
7. Humphrey, G. R.; Kuethe, J. T. (2006). "Practical Methodologies for the Synthesis of Indoles". Chem. Rev. 106 (7): 2875. doi:10.1021/cr0505270. PMID 16836303.{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. Gerd Collin and Hartmut Höke “Indole” Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi:10.1002/14356007.a14_167.
9. Bratulescu, George (2008). "A new and efficient one-pot synthesis of indoles". Tetrahedron Letters. 49 (6): 984. doi:10.1016/j.tetlet.2007.12.015.
10. Diels, Otto; Reese, Johannes (1934). "Synthesen in der hydroaromatischen Reihe. XX. Über die Anlagerung von Acetylen-dicarbonsäureester an Hydrazobenzol". Ann. 511: 168. doi:10.1002/jlac.19345110114.
11. Ernest H. Huntress, Joseph Bornstein, and William M. Hearon (1956). "An Extension of the Diels-Reese Reaction". J. Am. Chem. Soc. 78 (10): 2225. doi:10.1021/ja01591a055.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. James, P. N.; Snyder, H. R. (1959). "Indole-3-aldehyde". Organic Syntheses. 39: 30.{{cite journal}}: CS1 maint: multiple names: authors list (link)
13. Heaney, H.; Ley, S. V. (1974). "1-Benzylindole". Organic Syntheses. 54: 58.{{cite journal}}: CS1 maint: multiple names: authors list (link)
14. Bergman, J.; Venemalm, L. (1992). "Efficient synthesis of 2-chloro-, 2-bromo-, and 2-iodoindole". J. Org. Chem. 57 (8): 2495. doi:10.1021/jo00034a058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
15. Alan R. Katritzky, Jianqing Li, Christian V. Stevens (1995). "Facile Synthesis of 2-Substituted Indoles and Indolo[3,2-b]carbazoles from 2-(Benzotriazol-1-ylmethyl)indole". J. Org. Chem. 60 (11): 3401–3404. doi:10.1021/jo00116a026.{{cite journal}}: CS1 maint: multiple names: authors list (link)
16. Lynch, S. M. ; Bur, S. K.; Padwa, A. (2002). "Intramolecular Amidofuran Cycloadditions across an Indole π-Bond: An Efficient Approach to the Aspidosperma and Strychnos ABCE Core". Org. Lett. 4 (26): 4643. doi:10.1021/ol027024q. PMID 12489950.{{cite journal}}: CS1 maint: multiple names: authors list (link)

See also

• Indole-3-butyric acid
• Indole test – biochemical test for bacterial identification

External links

• Synthesis of indoles (overview of recent methods)

• Indoles
• Foul-smelling chemicals