Indole

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. The participation of the nitrogen lone electron pair in the aromatic ring means that indole is not a base, and it does not behave like a simple amine.

Indole is solid at room temperature. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell^[1], and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar.

The indole structure can be found in many organic compounds like the amino acid tryptophan and in tryptophan-containing protein, in alkaloids, and in pigments.

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, melatonin, the hallucinogens psilocybin, DMT, 5-MeO-DMT, or the ergolines like LSD. Other indolic compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory drug indomethacin, and the betablocker pindolol.

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.

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History

Indole chemistry began to develop with the study of the dye indigo. This was converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.^[2] In 1869, he proposed the formula for indole (left) that is accepted today.^[3]

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 is in tryptophan and auxins, and it remains an active area of research today.^[4]

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.^[5][6][7]

Leimgruber-Batcho indole synthesis

Main article: 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 comprised of specifically substituted indoles.

Fischer indole synthesis

Main article: 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.

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
• In the Diels-Reese reaction^[8][9] 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

Nitrogen basicity

Although the indole N-1 nitrogen atom has a lone pair of electrons, indole is not basic like amines and anilines because the lone pair is delocalised and contributes to the aromatic system. The protonated form has an pK_a of -3.6, so that very strong acids like hydrochloric acid are needed to protonate a substantial amount of indole. 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 10¹³ times more reactive than benzene. For example, Vilsmeier-Haack formylation of indole^[10] will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, nucleophilic 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.

Nitrogen-H acidity and organometallic indole anion complexes

The N-H proton has a pK_a of 21 in DMSO, so that very strong bases like sodium hydride or butyl lithium and water-free conditions are needed for complete deprotonation. Salts of the resulting indole anion can react in two ways. Highly-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). For the same reason, 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.^[11]

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.^[12]

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.^[13] 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 [2+3] and [2+2] 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

• 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.; Mills, K. (2000). Heterocyclic Chemistry. Oxford, UK: Blackwell Science. ISBN 0-632-05453-0. 

• 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. Ann. 1866, 140, 295.
3. ^ Baeyer, A.; Emmerling, A. Chemische Berichte 1869, 2, 679.
4. ^ R. B. Van Order, H. G. Lindwall Chem. Rev. 1942, 30, 69-96. (Review) (doi:10.1021/cr60095a004)
5. ^ Gribble G. W. J. Chem. Soc. Perkin Trans. 1 2000, 1045-1075. (Review) (doi:10.1039/a909834h)
6. ^ Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-2920. (Review) (doi:10.1021/cr040639b)
7. ^ Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875-2911. (Review) (doi:10.1021/cr0505270)
8. ^ 0. Diels and J. Reese, Ann., 511, 168 (1934).
9. ^ An Extension of the Diels-Reese Reaction Ernest H. Huntress, Joseph Bornstein, and William M. Hearon J. Am. Chem. Soc.; 1956; 78(10) pp 2225 - 2228; doi:10.1021/ja01591a055
10. ^ James, P. N.; Snyder, H. R. (1959). "Indole-3-aldehyde". Organic Syntheses 39: 30.
11. ^ Heaney, H.; Ley, S. V. (1974). "1-Benzylindole". Organic Syntheses 54: 58.
12. ^ Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495 - 2497. (doi:10.1021/jo00034a058)
13. ^ Lynch, S. M. ; Bur, S. K.; Padwa, A.; Org. Lett. 2002, 4, 4643 - 4645. (doi:10.1021/ol027024q)

See also

• Indole-3-butyric acid