Indole
472625
224747744
2008-07-10T06:50:45Z
194.128.151.241
{{Chembox new
| Name = Indole
| ImageFile = Indole_chemical_structure.png
| ImageSize = 280px
| ImageName = Chemical structure of indole
| IUPACName = Indole
| OtherNames = 2,3-Benzopyrrole, ketole,<br />1-benzazole
| Section1 = {{Chembox Identifiers
| SMILES = C1(NC=C2)=C2C=CC=C1
| CASNo = 120-72-9
| RTECS = NL2450000
}}
| Section2 = {{Chembox Properties
| Formula = C<sub>8</sub>H<sub>7</sub>N
| MolarMass = 117.15 g/mol
| Appearance = White solid
| Density = 1.22 g/cm<sup>3</sup>, solid
| Solubility = 0.19 g/100 ml (20 °C)<br />Soluble in hot water
| MeltingPt = 52 - 54°C (326 K)
| BoilingPt = 253 - 254°C (526 K)
| pKa = 16.2<!-- Joule & Mills --><br />(21.0 in [[dimethyl sulfoxide|DMSO]])<!-- http://www.chem.wisc.edu/areas/reich/pkatable/ -->
| pKb = 17.6
}}
| Section3 = {{Chembox Structure
| MolShape = Planar
| CrystalStruct = ?
| Dipole = 2.11 [[Debye|D]] in [[benzene]]
}}
| Section7 = {{Chembox Hazards
| ExternalMSDS = [http://msds.chem.ox.ac.uk/IN/indole.html]
| MainHazards =
| FlashPt = 121°C
| RSPhrases = R: 21/22-37/38-41-50/53<br /> S: 26-36/37/39-60-61
}}
| Section8 = {{Chembox Related
| Function = [[aromatic compound|aromatic<br />compounds]]
| OtherFunctn = [[benzene]], [[benzofuran]],<br />[[carbazole]], [[carboline]],<br />[[indene]], [[indoline]],<br />[[isatin]], [[methylindole]],<br />[[oxindole]], [[pyrrole]],<br />[[skatole]]}}
}}
'''Indole''' is an [[aromatic]] [[Heterocyclic compound|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 (chemistry)|base]], and it does not behave like a simple [[amine]].
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<ref name="smell">http://www.leffingwell.com/olfact5.htm<!-- there might be better references for its odor properties --></ref>, and is a constituent of many flower [[scent]]s (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 [[alkaloid]]s, and in [[pigment]]s.
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 [[Psychedelics, Dissociatives and Deliriants|hallucinogen]]s [[psilocybin]], [[Dimethyltryptamine|DMT]], [[5-MeO-DMT]], or the [[ergoline]]s like [[LSD]]. Other indolic compounds include the plant hormone [[Auxin]] (indolyl-3-acetic acid, [[Indole-3-acetic acid|IAA]]), the anti-inflammatory drug [[indomethacin]], and the [[betablocker]] [[pindolol]].
The name ''indole'' is a [[portmanteau]] of the words ''[[indigo dye|'''ind'''igo]]'' and ''[[oleum|'''ole'''um]]'', since indole was first isolated by treatment of the indigo dye with oleum.
==History==
[[Image:Baeyer indole structure.png|left|thumb|120px|Baeyer's original structure for indole, 1869]]
Indole chemistry began to develop with the study of the dye [[indigo dye|indigo]]. This was converted to [[isatin]] and then to [[oxindole]]. Then, in [[1866]], [[Adolf von Baeyer]] reduced oxindole to indole using [[zinc]] dust.<ref name="baeyer1866">[[Adolf von Baeyer|Baeyer, A.]] ''Ann.'' '''1866''', ''140'', 295.</ref> In 1869, he proposed the formula for indole (left) that is accepted today.<ref name="baeyer1869">[[Adolf von Baeyer|Baeyer, A.]]; Emmerling, A. ''[[Chemische Berichte]]'' '''1869''', ''2'', 679.</ref>
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 [[alkaloid]]s, as well is in [[tryptophan]] and [[auxin]]s, and it remains an active area of research today.<ref name="vanorder1942">R. B. Van Order, H. G. Lindwall ''[[Chem. Rev.]]'' '''1942''', ''30'', 69-96. (Review) ({{DOI|10.1021/cr60095a004}})</ref>
==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.<ref name="gribble2000">Gribble G. W. ''J. Chem. Soc. Perkin Trans. 1'' '''2000''', 1045-1075. (Review) ({{DOI|10.1039/a909834h}})</ref><ref name="cacchi2005">Cacchi, S.; Fabrizi, G. ''[[Chem. Rev.]]'' '''2005''', ''105'', 2873-2920. (Review) ({{DOI|10.1021/cr040639b}})</ref><ref name="humphrey2006">Humphrey, G. R.; Kuethe, J. T. ''[[Chem. Rev.]]'' '''2006''', ''106'', 2875-2911. (Review) ({{DOI|10.1021/cr0505270}})</ref>
<!-- Significant synthetic methods -->
===Leimgruber-Batcho indole synthesis===
{{main|Leimgruber-Batcho indole synthesis}}
:[[Image:Leimgruber-Batcho Indole Scheme.png|500px|The 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 [[medication|drugs]] are comprised of specifically substituted indoles.
===Fischer indole synthesis===
{{main|Fischer indole synthesis}}
:[[Image:Fischer Indole Reaction Scheme.png|400px|The 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===
<!-- Minor synthetic methods -->
* [[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'''<ref>0. Diels and J. Reese, Ann., 511, 168 ('''1934''').</ref><ref>''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}}</ref> [[dimethyl acetylenedicarboxylate]] reacts with [[hydrazine|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 [[electron]]s, indole is not [[Base (chemistry)|basic]] like [[amine]]s and [[aniline]]s because the lone pair is delocalised and contributes to the aromatic system. The protonated form has an [[Acid dissociation constant|pK<sub>a</sub>]] of -3.6, so that very strong acids like [[hydrochloric acid]] are needed to [[Protonation|protonate]] a substantial amount of indole. The sensitivity of many indolic compounds (e.g., [[tryptamine]]s) 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<sup>13</sup> times more reactive than [[benzene]]. For example, [[Vilsmeier-Haack reaction|Vilsmeier-Haack]] [[formylation reaction|formylation]] of indole<ref name="james1959">{{cite journal|author=James, P. N.; Snyder, H. R.|year=1959|title=Indole-3-aldehyde |journal=[[Organic Syntheses]]|volume=39|pages=30| url=http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0539}}</ref> 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.
[[Image:Indole Vilsmeyer-Haack Formylation.png|center|300px|The Vilsmeyer-Haack formylation of indole]]
[[Gramine]], a useful synthetic intermediate, is produced via a [[Mannich reaction]] of indole with [[dimethylamine]] and [[formaldehyde]].
[[Image:Gramine From Indole Scheme.png|center|250px|Synthesis of Gramine from indole]]
===Nitrogen-H acidity and organometallic indole anion complexes===
The N-H proton has a pK<sub>a</sub> of 21 in [[dimethyl sulfoxide|DMSO]], so that very [[strong base]]s like [[sodium hydride]] or [[butyl lithium]] and water-free conditions are needed for complete [[deprotonation]]. [[Salt]]s of the resulting indole anion can react in two ways. Highly-[[ionic bond|ionic]] salts such as the [[sodium]] or [[potassium]] compounds tend to react with [[electrophile]]s at nitrogen-1, whereas the more [[Covalent bond|covalent]] magnesium compounds (''indole [[Grignard reaction|Grignard reagents]]'') and (especially) [[zinc]] complexes tend to react at carbon-3 (see figure below). For the same reason, [[polarity|polar]] aprotic [[solvent]]s such as [[dimethylformamide|DMF]] and [[Dimethyl sulfoxide|DMSO]] tend to favour attack at the nitrogen, whereas nonpolar solvents such as [[toluene]] favour C-3 attack.<ref name="heaney1974">{{cite journal|author=Heaney, H.; Ley, S. V.|year=1974|title=1-Benzylindole |journal=[[Organic Syntheses]]|volume=54|pages=58| url=http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0104}}</ref>
[[Image:Indole anion reactions.png|center|400px|Formation and reactions of the indole anion]]
===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.<ref name="bergman1992">Bergman, J.; Venemalm, L. ''[[J. Org. Chem.]]'' '''1992''', ''57'', 2495 - 2497. ({{DOI|10.1021/jo00034a058}})</ref>
[[Image:Bergman Indole Lithiation.png|center|400px|2-position lithiation of indole]]
===Oxidation of indole===
Due to the electron-rich nature of indole, it is easily [[redox|oxidized]]. Simple oxidants such as [[N-Bromosuccinimide|''N''-bromosuccinimide]] will selectively oxidize indole '''1''' to [[oxindole]] ('''4''' and '''5''').
[[Image:Indole NBS Oxidation.png|center|600px|Oxidation of indole by N-bromosuccinimide]]
===Cycloadditions of indole===
Only the C-2 to C-3 pi-bond of indole is capable of [[cycloaddition reaction]]s. Intermolecular cycloadditions are not favorable, whereas intramolecular variants are often high-yielding. For example, Padwa ''et al.''<ref name="lynch2002">Lynch, S. M. ; Bur, S. K.; Padwa, A.; ''[[Org. Lett.]]'' '''2002''', ''4'', 4643 - 4645. ({{DOI|10.1021/ol027024q}})</ref> 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]].
[[Image:Indole Cycloaddition Padwa.png|center|250px|Example of a cycloaddition of indole]]
Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.
== Applications ==
Natural [[jasmine]] [[Essential oil|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<!-- in whose currency? -->, 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]]
* [[Tryptamine]]s
== General references ==
* ''Indoles Part One'', W. J. Houlihan (ed.), Wiley Interscience, New York, 1972.<!-- need ISBN # -->
* {{cite book|first=R. J.|last=Sundberg|year=1996|title=Indoles|publisher=Academic Press|location=San Diego|id=ISBN 0-12-676945-1}}
* {{cite book|first=J. A.|last=Joule|coauthors=Mills, K.|year=2000|title=Heterocyclic Chemistry|publisher=Blackwell Science|location=Oxford, UK|id=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 ==
<references/>
== See also ==
* [[Indole-3-butyric acid]]
* [[Indole test]] - biochemical test for bacterial identification
== External links ==
* [http://chemistry.tidalswan.com/index.php?title=Heteroaromatics#Indoles Synthesis and reactivity of indoles] (doesn't work)
* [http://www.organic-chemistry.org/synthesis/heterocycles/indoles.shtm Synthesis of indoles (overview of recent methods)]
[[Category:Flavors]]
[[Category:Indoles| ]]
[[Category:Nitrogen heterocycles]]
[[Category:Aromatic compounds]]
[[Category:Heterocyclic compounds]]
[[Category:Simple aromatic rings]]
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