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Indole

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Indole
Skeletal formula with numbering scheme
Ball-and-stick model of indole
Space-filling model of indole
Names
Preferred IUPAC name
1H-Indole[1]
Other names
2,3-Benzopyrrole, ketole,
1-benzazole
Identifiers
3D model (JSmol)
3DMet
107693
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.004.019 Edit this at Wikidata
EC Number
  • 204-420-7
3477
KEGG
RTECS number
  • NL2450000
UNII
  • InChI=1S/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H checkY
    Key: SIKJAQJRHWYJAI-UHFFFAOYSA-N checkY
  • InChI=1/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H
    Key: SIKJAQJRHWYJAI-UHFFFAOYAI
  • C12=C(C=CN2)C=CC=C1
Properties
C8H7N
Molar mass 117.151 g·mol−1
Appearance White solid
Odor Fecal or jasmine like (at extremely low concentrations)
Density 1.1747 g/cm3, solid
Melting point 52 to 54 °C (126 to 129 °F; 325 to 327 K)
Boiling point 253 to 254 °C (487 to 489 °F; 526 to 527 K)
0.19 g/100 ml (20 °C)
Soluble in hot water
Acidity (pKa) 16.2
(21.0 in DMSO)
Basicity (pKb) 17.6
-85.0·10−6 cm3/mol
Structure
Pna21
Planar
2.11 D in benzene
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Skin sensitising
GHS labelling:
GHS06: ToxicGHS07: Exclamation mark
Danger
H302, H311
P264, P270, P280, P301+P312, P302+P352, P312, P322, P330, P361, P363, P405, P501
Flash point 121 °C (250 °F; 394 K)
Safety data sheet (SDS) [1]
Related compounds
Other cations
 Indolium
benzene, benzofuran,
carbazole, carboline,
indene, benzothiophene,
indoline,
isatin, methylindole,
oxindole, pyrrole,
skatole, benzophosphole
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Indole is an organic compound with the formula C6H4CCNH3. Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole where one or more of the hydrogen atoms have been replaced by substituent groups. Indoles are widely distributed in nature, most notably as amino acid tryptophan and neurotransmitter serotonin.[2]

General properties and occurrence

[edit]

Indole is a 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,[3] and is a constituent of many perfumes. It also occurs in coal tar. It has been identified in cannabis.[4] It is the main volatile compound in stinky tofu.[5]

When indole is a substituent on a larger molecule, it is called an indolyl group by systematic nomenclature.

Indole undergoes electrophilic substitution, mainly at position 3 (see diagram in right margin). Substituted indoles are structural elements of (and for some compounds, the synthetic precursors for) the tryptophan-derived tryptamine alkaloids, which includes the neurotransmitter serotonin and the hormone[6] melatonin, as well as the naturally occurring psychedelic drugs dimethyltryptamine and psilocybin. Other indolic compounds include the plant hormone auxin (indolyl-3-acetic acid, IAA), tryptophol, 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.

History

[edit]
Baeyer's original structure for indole, 1869

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.[7] In 1869, he proposed a formula for indole.[8]

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 substituent is present in many important alkaloids, known as indole alkaloids (e.g., tryptophan and auxins), and it remains an active area of research today.[9]

Biosynthesis and function

[edit]

Indole is biosynthesized in the shikimate pathway via anthranilate.[2] It is an intermediate in the biosynthesis of tryptophan, where it stays inside the tryptophan synthase molecule between the removal of 3-phospho-glyceraldehyde and the condensation with serine. When indole is needed in the cell, it is usually produced from tryptophan by tryptophanase.[10]

Indole is produced via anthranilate and reacts further to give the amino acid tryptophan.

As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence.[11] A number of indole derivatives have important cellular functions, including neurotransmitters such as serotonin.[2]

Tryptophan metabolism by human gastrointestinal microbiota (
)
The image above contains clickable links
This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.[12] Indole is produced from tryptophan by bacteria that express tryptophanase.[12] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),[13] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[12][14][15] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[12] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.[12] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.[12] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.[12] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.[12] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[12]

Detection methods

[edit]

Common classical methods applied for the detection of extracellular and environmental indoles, are Salkowski, Kovács, Ehrlich’s reagent assays and HPLC.[16][17][18] For intracellular indole detection and measurement genetically encoded indole-responsive biosensor is applicable.[19]

Medical applications

[edit]

Indoles and their derivatives are promising against tuberculosis, malaria, diabetes, cancer, migraines, convulsions, hypertension, bacterial infections of methicillin-resistant Staphylococcus aureus (MRSA) and even viruses.[20][21][22][23][24]

Synthetic routes

[edit]

Indole and its derivatives can also be synthesized by a variety of methods.[25][26][27]

The main industrial routes start from aniline via vapor-phase reaction with ethylene glycol in the presence of catalysts:

Reaction of aniline and ethylene glycol to give indole.

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.[28]


Leimgruber–Batcho indole synthesis

[edit]
Main article: Leimgruber–Batcho indole synthesis
The Leimgruber–Batcho indole synthesis

The Leimgruber–Batcho indole synthesis is an efficient method of synthesizing indole and substituted indoles.[29] 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

[edit]
Main article: Fischer indole synthesis
The Fischer indole synthesis
One-pot microwave-assisted synthesis of indole from phenylhydrazine and pyruvic acid

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.[30]

Other indole-forming reactions

[edit]

Chemical reactions of indole

[edit]

Basicity

[edit]

Unlike most amines, indole is not basic: just like pyrrole, the aromatic character of the ring means that the lone pair of electrons on the nitrogen atom is not available for protonation.[33] Strong acids such as hydrochloric acid can, however, protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the enamine-like reactivity of the portion of the molecule located outside of the benzene ring. The protonated form has a pKa of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.

Electrophilic substitution

[edit]

The most reactive position on indole for electrophilic aromatic substitution is C3, which is 1013 times more reactive than benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan. Vilsmeier–Haack formylation of indole[34] will take place at room temperature exclusively at C3.

The Vilsmeyer–Haack formylation of indole

Since the pyrrolic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring generally takes place only after N1, C2, and C3 are substituted. A noteworthy exception occurs when electrophilic substitution is carried out in conditions sufficiently acidic to exhaustively protonate C3. In this case, C5 is the most common site of electrophilic attack.[35]

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan.

Synthesis of gramine from indole

N–H acidity and organometallic indole anion complexes

[edit]

The N–H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or n-butyl lithium and water-free conditions are required for complete deprotonation. The resulting organometalic 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 C3 attack.[36]

Formation and reactions of the indole anion

Carbon acidity and C2 lithiation

[edit]

After the N–H proton, the hydrogen at C2 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 C2 position. This strong nucleophile can then be used as such with other electrophiles.

2-position lithiation of indole

Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole,[37] as did Katritzky.[38]

Oxidation of indole

[edit]

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).

Oxidation of indole by N-bromosuccinimide

Cycloadditions of indole

[edit]

Only the C2–C3 pi bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa et al.[39] 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.

Example of a cycloaddition of indole

Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.[40][41][42][43] One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes,[44] which produces a mixture of diastereomers, leading to reduced yield of the desired product.

Hydrogenation

[edit]

Indoles are susceptible to hydrogenation of the imine subunit[45] to give indolines.

See also

[edit]

References

[edit]
  1. ^ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 213. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4.
  2. ^ a b c Nelson, David L.; Cox, Michael M. (2005). Principles of Biochemistry (4th ed.). New York: W. H. Freeman. ISBN 0-7167-4339-6.
  3. ^ Purves, Dale; Augustine, George J; Fitzpatrick, David; Katz, Lawrence C; LaMantia, Anthony-Samuel; McNamara, James O; Williams, S Mark. "Olfactory Perception in Humans". Olfactory Perception in Humans. Retrieved 20 October 2020.
  4. ^ Oswald, Iain W. H.; Paryani, Twinkle R.; Sosa, Manuel E.; Ojeda, Marcos A.; Altenbernd, Mark R.; Grandy, Jonathan J.; Shafer, Nathan S.; Ngo, Kim; Peat, Jack R.; Melshenker, Bradley G.; Skelly, Ian; Koby, Kevin A.; Page, Michael F. Z.; Martin, Thomas J. (2023-10-12). "Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis". ACS Omega. 8 (42): 39203–39216. doi:10.1021/acsomega.3c04496. ISSN 2470-1343. PMC 10601067. PMID 37901519.
  5. ^ Liu, Yuping; Miao, Zhiwei; Guan, Wei; Sun, Baoguo (26 March 2012). "Analysis of Organic Volatile Flavor Compounds in Fermented Stinky Tofu Using SPME with Different Fiber Coatings". Molecules. 17 (4): 3708–3722. doi:10.3390/molecules17043708. PMC 6268145. PMID 22450681.
  6. ^ Lee, Jung Goo (21 October 2019). "The Neuroprotective Effects of Melatonin: Possible Role in the Pathophysiology of Neuropsychiatric Disease". Brain Sciences. 9 (285): 285. doi:10.3390/brainsci9100285. PMC 6826722. PMID 31640239.
  7. ^ Baeyer, A. (1866). "Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub" [On the reduction of aromatic compounds by means of zinc dust]. Annalen der Chemie und Pharmacie. 140 (3): 295–296. doi:10.1002/jlac.18661400306.
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  9. ^ Van Order, R. B.; Lindwall, H. G. (1942). "Indole". Chem. Rev. 30: 69–96. doi:10.1021/cr60095a004.
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  12. ^ a b c d e f g h i Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi:10.1186/s13073-016-0296-x. PMC 4840492. PMID 27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
  13. ^ Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A. 106 (10): 3698–3703. Bibcode:2009PNAS..106.3698W. doi:10.1073/pnas.0812874106. PMC 2656143. PMID 19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes.
    IPA metabolism diagram
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General references

[edit]
  • Houlihan, W. J., ed. (1972). Indoles Part One. New York: Wiley Interscience.[ISBN missing]
  • Sundberg, R. J. (1996). Indoles. San Diego: Academic Press. ISBN 978-0-12-676945-6.
  • Joule, J. A.; Mills, K. (2000). Heterocyclic Chemistry. Oxford, UK: Blackwell Science. ISBN 978-0-632-05453-4.
  • Joule, J. (2000). E. J., Thomas (ed.). Science of Synthesis. Vol. 10. Stuttgart: Thieme. p. 361. ISBN 978-3-13-112241-4.
  • Schoenherr, H.; Leighton, J. L. (2012). "Direct and Highly Enantioselective Iso-Pictet-Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures". Org. Lett. 14 (10): 2610–3. doi:10.1021/ol300922b. PMID 22540677.
[edit]
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