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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 100.004.019Edit 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/h1-6,9HcheckY
    Key: SIKJAQJRHWYJAI-UHFFFAOYSA-NcheckY
  • 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 117.151g·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 inDMSO)
Basicity(pKb) 17.6
-85.0·10−6cm3/mol
Structure
Pna21
Planar
2.11Dinbenzene
Hazards
Occupational safety and health(OHS/OSH):
Main hazards
 Skin sensitising
GHSlabelling:
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
Othercations
 Indolium
benzene,benzofuran,
carbazole,carboline,
indene,benzothiophene,
indoline,
isatin,methylindole,
oxindole,pyrrole,
skatole,benzophosphole
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).

Indoleis anorganic compoundwith the formulaC6H4CCNH3.Indole is classified as anaromaticheterocycle.It has abicyclicstructure, consisting of a six-memberedbenzenering fused to a five-memberedpyrrolering.Indolesare derivatives of indole where one or more of the hydrogen atoms have been replaced bysubstituentgroups. Indoles are widely distributed in nature, most notably asamino acidtryptophanandneurotransmitterserotonin.[2]

General properties and occurrence

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Indole is asolidat room temperature. It occurs naturally in humanfecesand has an intense fecalodor.At very low concentrations, however, it has a flowery smell,[3]and is a constituent of manyperfumes.It also occurs incoal tar.It has been identified incannabis.[4]It is the main volatile compound instinky tofu.[5]

When indole is asubstituenton a larger molecule, it is called anindolylgroupbysystematic nomenclature.

Indole undergoeselectrophilic substitution,mainly at position 3 (see diagram in right margin).Substitutedindoles are structural elements of (and for some compounds, the synthetic precursors for) the tryptophan-derivedtryptaminealkaloids, which includes theneurotransmitterserotoninand thehormone[6]melatonin,as well as the naturally occurringpsychedelic drugsdimethyltryptamineandpsilocybin.Other indolic compounds include the plant hormoneauxin(indolyl-3-acetic acid,IAA),tryptophol,the anti-inflammatory drugindomethacin,and thebetablockerpindolol.

The nameindoleis aportmanteauof the wordsindigoandoleum,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 dyeindigo.Indigo can be converted toisatinand then tooxindole.Then, in 1866,Adolf von Baeyerreducedoxindoleto indole usingzincdust.[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 importantalkaloids,known asindole alkaloids(e.g.,tryptophanandauxins), and it remains an active area of research today.[9]

Biosynthesis and function

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Indole isbiosynthesizedin theshikimate pathwayviaanthranilate.[2]It is an intermediate in the biosynthesis oftryptophan,where it stays inside thetryptophan synthasemolecule between the removal of 3-phospho-glyceraldehyde and the condensation withserine.When indole is needed in the cell, it is usually produced from tryptophan bytryptophanase.[10]

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

As anintercellular signal molecule,indole regulates various aspects of bacterial physiology, includingsporeformation,plasmidstability,resistance to drugs,biofilmformation, andvirulence.[11]A number of indole derivatives have important cellular functions, includingneurotransmitterssuch asserotonin.[2]

Tryptophan metabolism byhuman gastrointestinal microbiota(
)
The image above contains clickable links
This diagram shows the biosynthesis ofbioactive compounds(indole and certain other derivatives) fromtryptophanby bacteria in the gut.[12]Indole is produced from tryptophan by bacteria that expresstryptophanase.[12]Clostridium sporogenesmetabolizes tryptophan into indole and subsequently3-indolepropionicacid(IPA),[13]a highly potentneuroprotectiveantioxidantthat scavengeshydroxyl radicals.[12][14][15]IPA binds to thepregnane X receptor(PXR) in intestinal cells, thereby facilitating mucosal homeostasis andbarrier function.[12]Followingabsorptionfrom the intestine anddistributionto the brain, IPA confers a neuroprotective effect againstcerebral ischemiaandAlzheimer's disease.[12]Lactobacillaceae(Lactobacilluss.l.) species metabolize tryptophan intoindole-3-aldehyde(I3A) which acts on thearyl hydrocarbon receptor(AhR) in intestinal immune cells, in turn increasinginterleukin-22(IL-22) production.[12]Indole itselftriggers the secretionofglucagon-like peptide-1(GLP-1) inintestinal L cellsand acts as aligandfor AhR.[12]Indole can also be metabolized by the liver intoindoxyl sulfate,a compound that is toxic in high concentrations and associated withvascular diseaseandrenal dysfunction.[12]AST-120 (activated charcoal), an intestinalsorbentthat istaken by mouth,adsorbsindole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[12]

Detection methods

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Common classical methods applied for the detection of extracellular and environmental indoles, areSalkowski,Kovács,Ehrlich’sreagent assays andHPLC.[16][17][18]For intracellular indole detection and measurement genetically encoded indole-responsivebiosensoris applicable.[19]

Medical applications

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Indoles and their derivatives are promising againsttuberculosis,malaria,diabetes,cancer,migraines,convulsions,hypertension,bacterial infections of methicillin-resistantStaphylococcus aureus(MRSA) and evenviruses.[20][21][22][23][24]

Synthetic routes

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

The main industrial routes start fromanilinevia vapor-phase reaction withethylene glycolin the presence ofcatalysts:

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 includeformyltoluidine,2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergocyclizations.[28]


Leimgruber–Batcho indole synthesis

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Main article:Leimgruber–Batcho indole synthesis
The Leimgruber–Batcho indole synthesis

TheLeimgruber–Batcho indole synthesisis 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 thepharmaceutical industry,where many pharmaceuticaldrugsare 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 theFischer indole synthesis,developed in 1883 byEmil 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 reactingphenylhydrazinewithpyruvic acidfollowed bydecarboxylationof the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.[30]

Other indole-forming reactions

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Chemical reactions of indole

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Basicity

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Unlike mostamines,indole is notbasic:just likepyrrole,the aromatic character of the ring means that thelone pairof electrons on the nitrogen atom is not available for protonation.[33]Strong acids such ashydrochloric acidcan, however,protonateindole. Indole is primarily protonated at the C3, rather than N1, owing to theenamine-like reactivity of the portion of the molecule located outside of thebenzenering. The protonated form has apKaof −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 forelectrophilic aromatic substitutionis C3, which is 1013times more reactive thanbenzene.For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan.Vilsmeier–Haackformylationof 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 aMannich reactionof indole withdimethylamineandformaldehyde.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 pKaof 21 inDMSO,so that verystrong basessuch assodium hydrideorn-butyl lithiumand water-free conditions are required for completedeprotonation.The resultingorganometalicderivatives can react in two ways. The moreionicsalts such as thesodiumorpotassiumcompounds tend to react withelectrophilesat nitrogen-1, whereas the morecovalentmagnesium compounds (indoleGrignard reagents) and (especially)zinccomplexes tend to react at carbon 3 (see figure below). In analogous fashion,polaraproticsolventssuch asDMFandDMSOtend to favour attack at the nitrogen, whereas nonpolar solvents such astoluenefavour 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 ofN-protected indoles withbutyl lithiumorlithium diisopropylamideresults 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 easilyoxidized.Simple oxidants such asN-bromosuccinimidewill selectively oxidize indole1tooxindole(4and5).

Oxidation of indole by N-bromosuccinimide

Cycloadditions of indole

[edit]

Only the C2–C3pi bondof indole is capable ofcycloaddition reactions.Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwaet al.[39]have developed thisDiels-Alder reactionto form advancedstrychnineintermediates. In this case, the 2-aminofuran is thediene,whereas the indole is thedienophile.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 thePictet-Spengler reactionbetweentryptophanderivatives andaldehydes,[44]which produces a mixture ofdiastereomers,leading to reducedyieldof the desired product.

Hydrogenation

[edit]

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

See also

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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.ISBN978-0-85404-182-4.
  2. ^abcNelson, David L.; Cox, Michael M. (2005).Principles of Biochemistry(4th ed.). New York: W. H. Freeman.ISBN0-7167-4339-6.
  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.Retrieved20 October2020.
  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/acs Omega.3c04496.ISSN2470-1343.PMC10601067.PMID37901519.
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  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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    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
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    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.ISBN978-0-12-676945-6.
  • Joule, J. A.; Mills, K. (2000).Heterocyclic Chemistry.Oxford, UK: Blackwell Science.ISBN978-0-632-05453-4.
  • Joule, J. (2000). E. J., Thomas (ed.).Science of Synthesis.Vol. 10. Stuttgart: Thieme. p. 361.ISBN978-3-13-112241-4.
  • 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.PMID22540677.
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