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			{{Short description|Chemical compound}}
	{{distinguish|indene|indigo}}
	{{chembox		{{chembox
			| Watchedfields = changed
	| verifiedrevid = 408567968
			| verifiedrevid = 443872679
	| Name = Indole
	| ImageFile_Ref = {{chemboximage|correct|??}}		| Name = Indole
			| ImageFile_Ref = {{chemboximage|correct|??}}
	| ImageFile = Indole_chemical_structure.png		| ImageFile = Indole 2D numbered.svg
	| ImageSize = 280px		| ImageSize = 160
			| ImageAlt = Skeletal formula with numbering scheme
	| ImageName = Chemical structure of indole
			| ImageClass = skin-invert-image
	| ImageFile2 = Indole.png
			| ImageFile1 = Indole-3D-balls-2.png
	| ImageSize2 = 220px
			| ImageSize1 = 155
	| ImageName2 = Ball-and-stick model of indole
			| ImageAlt1 = Ball-and-stick model of indole
	| IUPACName = Indole
			| ImageFile2 = Indole-3D-spacefill.png
	| OtherNames = 2,3-Benzopyrrole, ketole,<br />1-benzazole
			| ImageSize2 = 145
	| Section1 = {{Chembox Identifiers
			| ImageAlt2 = Space-filling model of indole
			| PIN = 1''H''-Indole<ref>{{cite book |author=] |date=2014 |title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 |publisher=] |pages=213 |doi=10.1039/9781849733069 |isbn=978-0-85404-182-4}}</ref>
			| OtherNames = 2,3-Benzopyrrole, ketole,<br />1-benzazole
			| Section1 = {{Chembox Identifiers
			| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 16881		| ChEBI = 16881
	| SMILES = c1ccc2c(c1)cc2		| SMILES = C12=C(C=CN2)C=CC=C1
	| PubChem = 798		| PubChem = 798
	| UNII_Ref = {{fdacite|correct|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
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	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 15844		| ChEMBL = 15844
			| 3DMet = B01251
			| EC_number = 204-420-7
			| Beilstein = 107693
			| Gmelin = 3477
			| DrugBank = DB04532
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H		| StdInChI = 1S/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H
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	| RTECS = NL2450000		| RTECS = NL2450000
	}}		}}
	| Section2 = {{Chembox Properties		| Section2 = {{Chembox Properties
			| C=8 | H=7 | N=1
	| Formula = C<sub>8</sub>H<sub>7</sub>N
	| MolarMass = 117.15 g/mol
	| Appearance = White solid		| Appearance = White solid
			| Odor = Fecal or jasmine like (at extremely low concentrations)
	| Density = 1.1747 g/cm<sup>3</sup>, solid
			| Density = 1.1747&nbsp;g/cm<sup>3</sup>, solid
	| Solubility = 0.19 g/100 ml (20 °C)<br />Soluble in hot water
			| Solubility = 0.19&nbsp;g/100&nbsp;ml (20&nbsp;°C)<br />Soluble in hot water
	| MeltingPt = 52–54 °C
			| MeltingPtC = 52 to 54
	| BoilingPt = 253–254°C (526 K)
			| MeltingPt_notes =
			| BoilingPtC = 253 to 254
			| BoilingPt_notes =
	| pKa = 16.2<!-- Joule & Mills --><br />(21.0 in ])<!-- http://www.chem.wisc.edu/areas/reich/pkatable/ -->		| pKa = 16.2<!-- Joule & Mills --><br />(21.0 in ])<!-- http://www.chem.wisc.edu/areas/reich/pkatable/ -->
	| pKb = 17.6		| pKb = 17.6
			| MagSus = -85.0·10<sup>−6</sup> cm<sup>3</sup>/mol }}
	}}
	| Section3 = {{Chembox Structure		| Section3 = {{Chembox Structure
	| MolShape = Planar		| MolShape = Planar
	| CrystalStruct = Pna2<sub>1</sub>		| CrystalStruct = Pna2<sub>1</sub>
	| Dipole = 2.11 ] in ]		| Dipole = 2.11&nbsp;] in ]
	}}		}}
	| Section7 = {{Chembox Hazards		| Section7 = {{Chembox Hazards
	| ExternalMSDS =		| ExternalSDS =
	| MainHazards =		| MainHazards = Skin sensitising
	| FlashPt = 121 °C		| FlashPtC = 121
			| GHSPictograms = {{GHS06}}{{GHS07}}
	| RSPhrases = R: 21/22-37/38-41-50/53<br /> S: 26-36/37/39-60-61
			| GHSSignalWord = Danger
			| HPhrases = {{H-phrases|302|311}}
			| PPhrases = {{P-phrases|264|270|280|301+312|302+352|312|322|330|361|363|405|501}}
	}}		}}
	| Section8 = {{Chembox Related		| Section8 = {{Chembox Related
			| OtherCations = ]
	| Function = ]
			| OtherFunction_label = ]
	| OtherFunctn = ], ],<br />], ],<br />], ],<br />], ],<br />], ],<br />]}}
			| OtherFunction = ], ],<br />], ],<br />], ],<br />],<br />], ],<br />], ],<br />], ]}}
	}}		}}
	'''Indole''' is an ] ] ]. It has a bicyclic structure, consisting of a six-membered ] ring fused to a five-membered ]-containing ] 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 ] is the precursor of the neurotransmitter ].		'''Indole''' is an ] with the formula {{chem2|C6H4CCNH3}}. Indole is classified as an ] ]. It has a ] structure, consisting of a six-membered ] ring fused to a five-membered ] ring. '''Indoles''' are derivatives of indole where one or more of the hydrogen atoms have been replaced by ] groups. Indoles are widely distributed in nature, most notably as ] ] and ] ].<ref name=Lehninger/>
	==General properties and occurrence==		== General properties and occurrence ==
			Indole is a ] at room temperature. It occurs naturally in human ] and has an intense fecal ]. At very low concentrations, however, it has a flowery smell,<ref name="smell">{{cite web | last1=Purves | first1=Dale | last2=Augustine | first2=George J | last3=Fitzpatrick | first3=David | last4=Katz | first4=Lawrence C | last5=LaMantia | first5=Anthony-Samuel | last6=McNamara | first6=James O | last7=Williams | first7=S Mark | title=Olfactory Perception in Humans | website=Olfactory Perception in Humans | url=https://www.ncbi.nlm.nih.gov/books/NBK11032/ | access-date=20 October 2020}}</ref> and is a constituent of many ]. It also occurs in ]. It has been identified in ].<ref>{{Cite journal |last1=Oswald |first1=Iain W. H. |last2=Paryani |first2=Twinkle R. |last3=Sosa |first3=Manuel E. |last4=Ojeda |first4=Marcos A. |last5=Altenbernd |first5=Mark R. |last6=Grandy |first6=Jonathan J. |last7=Shafer |first7=Nathan S. |last8=Ngo |first8=Kim |last9=Peat |first9=Jack R. |last10=Melshenker |first10=Bradley G. |last11=Skelly |first11=Ian |last12=Koby |first12=Kevin A. |last13=Page |first13=Michael F. Z. |last14=Martin |first14=Thomas J. |date=2023-10-12 |title=Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis |journal=ACS Omega |volume=8 |issue=42 |pages=39203–39216 |language=en |doi=10.1021/acsomega.3c04496 |pmid=37901519 |pmc=10601067 |issn=2470-1343|doi-access=free }}</ref> It is the main volatile compound in ].<ref>{{cite journal |last1=Liu |first1=Yuping |last2=Miao |first2=Zhiwei |last3=Guan |first3=Wei |last4=Sun |first4=Baoguo |title=Analysis of Organic Volatile Flavor Compounds in Fermented Stinky Tofu Using SPME with Different Fiber Coatings |journal=Molecules |date=26 March 2012 |volume=17 |issue=4 |pages=3708–3722 |doi=10.3390/molecules17043708 |pmid=22450681 |pmc=6268145 |doi-access=free }}</ref>
	Indole is a ] at room temperature. Indole can be produced by ] as a degradation product of the ] ]. It occurs naturally in human ] and has an intense fecal ]. 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 ]s (such as orange blossoms) and ]. It also occurs in ].
	The corresponding substituent is called '''indolyl'''.		When indole is a ] on a larger molecule, it is called an '''''indolyl''' group'' by ].
	Indole undergoes ], mainly at position 3. ] are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived ] alkaloids like the ] ], and ].		Indole undergoes ], mainly at position 3 (see diagram in right margin). ] indoles are structural elements of (and for some compounds, the synthetic precursors for) the tryptophan-derived ] alkaloids, which includes the ] ] and the ]<ref>{{cite journal |last1=Lee |first1=Jung Goo |title=The Neuroprotective Effects of Melatonin: Possible Role in the Pathophysiology of Neuropsychiatric Disease |journal=Brain Sciences |date=21 October 2019 |volume=9 |issue=285 |page=285 |doi=10.3390/brainsci9100285 |pmid=31640239 |pmc=6826722 |doi-access=free }}</ref> ], as well as the naturally occurring ] ] and ]. Other indolic compounds include the plant hormone ] (indolyl-3-acetic acid, ]), ], the anti-inflammatory drug ], and the ] ].
	Other indolic compounds include the plant hormone ] (indolyl-3-acetic acid, ]), the anti-inflammatory drug ], the ] ], and the naturally occurring hallucinogen ] (N,N-DMT).
	The name ''indole'' is a ] of the words '']'' and '']'', since indole was first isolated by treatment of the indigo dye with oleum.		The name ''indole'' is a ] of the words '']'' and '']'', since indole was first isolated by treatment of the indigo dye with oleum.
	==History==		==History==
	]		]
	Indole chemistry began to develop with the study of the dye ]. Indigo can be converted to ] and then to ]. Then, in 1866, ] reduced oxindole to indole using ] dust.<ref name="baeyer1866">{{cite journal|author = ]|journal = ]|year = 1866|volume = 140|pages = 295|doi = 10.1002/jlac.18661400306|title = Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub|issue = 3}}</ref> In 1869, he proposed a formula for indole (left).<ref name="baeyer1869">{{cite journal|author = ]; Emmerling, A.|journal = ]|year = 1869|volume = 2|pages = 679|doi = 10.1002/cber.186900201268|title = Synthese des Indols}}</ref>		Indole chemistry began to develop with the study of the dye ]. Indigo can be converted to ] and then to ]. Then, in 1866, ] reduced ] to indole using ] dust.<ref name="baeyer1866">{{cite journal|author-link = Adolf von Baeyer|last=Baeyer |first=A.|journal = Annalen der Chemie und Pharmacie|year = 1866|volume = 140|pages = 295–296|doi = 10.1002/jlac.18661400306|title = Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub|trans-title=On the reduction of aromatic compounds by means of zinc dust|issue = 3|url=https://archive.org/stream/annalenderchemi11liebgoog#page/n690/mode/2up}}</ref> In 1869, he proposed a formula for indole.<ref name="baeyer1869">{{cite journal|author-link = Adolf von Baeyer|last1=Baeyer |first1=A. |last2=Emmerling |first2=A.|journal = Berichte der Deutschen Chemischen Gesellschaft|year = 1869|volume = 2|pages = 679–682|doi = 10.1002/cber.186900201268|title = Synthese des Indols|trans-title=Synthesis of indole|url=http://babel.hathitrust.org/cgi/pt?id=uc1.b3481747;view=1up;seq=709}}</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 ]s, as well as in ] and ]s, and it remains an active area of research today.<ref name="vanorder1942">{{cite journal|author = R. B. Van Order, H. G. Lindwall|journal = ]|year = 1942|volume = 30|pages = 69–96|doi = 10.1021/cr60095a004|title = Indole}}</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 substituent is present in many important ]s, known as ]s (e.g., ] and ]s), and it remains an active area of research today.<ref name="vanorder1942">{{cite journal|first1=R. B. |last1=Van Order |first2=H. G. |last2=Lindwall |journal = ]|year = 1942|volume = 30|pages = 69–96|doi = 10.1021/cr60095a004|title = Indole}}</ref>
			{{clear left}}
	==Synthesis of indoles==		==Biosynthesis and function==
			Indole is ] in the ] via ].<ref name=Lehninger>{{Lehninger4th}}</ref> It is an intermediate in the biosynthesis of ], where it stays inside the ] molecule between the removal of 3-phospho-glyceraldehyde and the condensation with ]. When indole is needed in the cell, it is usually produced from tryptophan by ].<ref>{{Cite book|url=https://books.google.com/books?id=9mGzkso4NVQC&pg=PA251|title=Metabolic Engineering: Principles and Methodologies|last1=Stephanopoulos|first1=George|last2=Aristidou|first2=Aristos A.|last3=Nielsen|first3=Jens|date=1998-10-17|publisher=Academic Press|isbn=9780080536286|pages=251|language=en}}</ref>
	Indole is a major constituent of ], 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">{{cite journal|author = Gribble G. W.|journal = ] |year = 2000|doi = 10.1039/a909834h|title = Recent developments in indole ring synthesis—methodology and applications|pages = 1045|issue = 7}}</ref><ref name="cacchi2005">{{cite journal|author = Cacchi, S.; Fabrizi, G.|journal = ]|doi = 10.1021/cr040639b|pmid = 16011327|title = Synthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions|year = 2005|volume = 105|issue = 7|pages = 2873}}</ref><ref name="humphrey2006">{{cite journal|author = Humphrey, G. R.; Kuethe, J. T.|journal = ]|doi = 10.1021/cr0505270|pmid = 16836303|title = Practical Methodologies for the Synthesis of Indoles|year = 2006|volume = 106|issue = 7|pages = 2875}}</ref> The main industrial routes start from aniline.
			:]{{clear left}}
			As an ], indole regulates various aspects of bacterial physiology, including ] formation, ] stability, ], ] formation, and ].<ref name="LeeLee2010">{{cite journal|last1=Lee|first1=Jin-Hyung|last2=Lee|first2=Jintae|title=Indole as an intercellular signal in microbial communities|journal=FEMS Microbiology Reviews|volume=34|issue=4|pages=426–44|year=2010|issn=0168-6445|doi=10.1111/j.1574-6976.2009.00204.x|pmid=20070374|doi-access=free}}</ref> A number of indole derivatives have important cellular functions, including ]s such as ].<ref name="Lehninger" />
	Illustrative of such large-scale syntheses, indole (and substituted derivatives) form via vapor-phase reaction of ] with ] in the presence of ]s:
			<!-- -->
			{{Tryptophan metabolism by human microbiota|align=left}}
			{{clear left}}
			== Detection methods ==
	:] and ] to give indole.]]
			Common classical methods applied for the detection of extracellular and environmental indoles, are ], ], ] reagent assays and ].<ref>{{Cite journal |last=Ehmann |first=Axel |date=1977-02-11 |title=The van URK-Salkowski reagent — a sensitive and specific chromogenic reagent for silica gel thin-layer chromatographic detection and identification of indole derivatives |url=https://www.sciencedirect.com/science/article/pii/S0021967300893000 |journal=Journal of Chromatography A |language=en |volume=132 |issue=2 |pages=267–276 |doi=10.1016/S0021-9673(00)89300-0 |pmid=188858 |issn=0021-9673}}</ref><ref>{{Cite journal |last1=Darkoh |first1=Charles |last2=Chappell |first2=Cynthia |last3=Gonzales |first3=Christopher |last4=Okhuysen |first4=Pablo |date=December 2015 |editor-last=Schloss |editor-first=P. D. |title=A Rapid and Specific Method for the Detection of Indole in Complex Biological Samples |journal=Applied and Environmental Microbiology |language=en |volume=81 |issue=23 |pages=8093–8097 |doi=10.1128/AEM.02787-15 |issn=0099-2240 |pmc=4651089 |pmid=26386049|bibcode=2015ApEnM..81.8093D }}</ref><ref>{{Cite journal |last1=Gilbert |first1=Sarah |last2=Xu |first2=Jenny |last3=Acosta |first3=Kenneth |last4=Poulev |first4=Alexander |last5=Lebeis |first5=Sarah |last6=Lam |first6=Eric |date=2018 |title=Bacterial Production of Indole Related Compounds Reveals Their Role in Association Between Duckweeds and Endophytes |journal=Frontiers in Chemistry |volume=6 |page=265 |doi=10.3389/fchem.2018.00265 |issn=2296-2646 |pmc=6052042 |pmid=30050896 |bibcode=2018FrCh....6..265G |doi-access=free }}</ref> For intracellular indole detection and measurement genetically encoded indole-responsive ] is applicable.<ref>{{Cite journal |last1=Matulis |first1=Paulius |last2=Kutraite |first2=Ingrida |last3=Augustiniene |first3=Ernesta |last4=Valanciene |first4=Egle |last5=Jonuskiene |first5=Ilona |last6=Malys |first6=Naglis |date=January 2022 |title=Development and Characterization of Indole-Responsive Whole-Cell Biosensor Based on the Inducible Gene Expression System from Pseudomonas putida KT2440 |journal=International Journal of Molecular Sciences |language=en |volume=23 |issue=9 |pages=4649 |doi=10.3390/ijms23094649 |issn=1422-0067 |pmc=9105386 |pmid=35563040 |doi-access=free }}</ref>
			==Medical applications==
	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.<ref>Gerd Collin and Hartmut Höke “Indole” Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. {{DOI|10.1002/14356007.a14_167}}.</ref> Many other methods have been developed that are applicable.
			Indoles and their derivatives are promising against ], ], ], ], ], ], ], bacterial infections of methicillin-resistant '']'' (]) and even ].<ref>{{cite journal |last1=Ramesh |first1=Deepthi |last2=Joji |first2=Annu |last3=Vijayakumar |first3=Balaji Gowrivel |last4=Sethumadhavan |first4=Aiswarya |last5=Mani |first5=Maheswaran |last6=Kannan |first6=Tharanikkarasu |title=Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis |journal=European Journal of Medicinal Chemistry |date=15 July 2020 |volume=198 |pages=112358 |doi=10.1016/j.ejmech.2020.112358 |pmid=32361610 |s2cid=218490655 |language=en |issn=0223-5234|doi-access=free }}</ref><ref>{{cite journal |last1=Qin |first1=Hua-Li |last2=Liu |first2=Jing |last3=Fang |first3=Wan-Yin |last4=Ravindar |first4=L. |last5=Rakesh |first5=K. P. |title=Indole-based derivatives as potential antibacterial activity against methicillin-resistance Staphylococcus aureus (MRSA) |journal=European Journal of Medicinal Chemistry |date=15 May 2020 |volume=194 |pages=112245 |doi=10.1016/j.ejmech.2020.112245 |pmid=32220687 |s2cid=214695328 |url=https://doi.org/10.1016/j.ejmech.2020.112245 |language=en |issn=0223-5234}}</ref><ref>{{cite journal |last1=Thanikachalam |first1=Punniyakoti Veeraveedu |last2=Maurya |first2=Rahul Kumar |last3=Garg |first3=Vishali |last4=Monga |first4=Vikramdeep |title=An insight into the medicinal perspective of synthetic analogs of indole: A review |journal=European Journal of Medicinal Chemistry |date=15 October 2019 |volume=180 |pages=562–612 |doi=10.1016/j.ejmech.2019.07.019 |pmid=31344615 |s2cid=198911553 |url=https://doi.org/10.1016/j.ejmech.2019.07.019 |language=en |issn=0223-5234}}</ref><ref>{{cite journal |last1=Kumari |first1=Archana |last2=Singh |first2=Rajesh K. |title=Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives |journal=Bioorganic Chemistry |date=1 August 2019 |volume=89 |pages=103021 |doi=10.1016/j.bioorg.2019.103021 |pmid=31176854 |s2cid=182950054 |url=https://doi.org/10.1016/j.bioorg.2019.103021 |language=en |issn=0045-2068}}</ref><ref>{{cite journal |last1=Jia |first1=Yanshu |last2=Wen |first2=Xiaoyue |last3=Gong |first3=Yufeng |last4=Wang |first4=Xuefeng |title=Current scenario of indole derivatives with potential anti-drug-resistant cancer activity |journal=European Journal of Medicinal Chemistry |date=15 August 2020 |volume=200 |pages=112359 |doi=10.1016/j.ejmech.2020.112359 |pmid=32531682 |s2cid=219021072 |url=https://doi.org/10.1016/j.ejmech.2020.112359 |language=en |issn=0223-5234}}</ref>
			{{clear left}}
			==Synthetic routes==
			Indole and its derivatives can also be synthesized by a variety of methods.<ref name="gribble2000">{{cite journal|last = Gribble|first= G. W.|journal = ] |year = 2000|doi = 10.1039/a909834h|title = Recent developments in indole ring synthesis—methodology and applications|page = 1045|issue = 7}}</ref><ref name="cacchi2005">{{cite journal|last1=Cacchi |first1=S. |last2=Fabrizi |first2=G. |journal = ]|doi = 10.1021/cr040639b|pmid = 16011327|title = Synthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions|year = 2005|volume = 105|issue = 7|pages = 2873–2920|hdl=11573/232340 }}</ref><ref name="humphrey2006">{{cite journal|last1=Humphrey |first1=G. R. |last2=Kuethe |first2=J. T. |journal = ]|doi = 10.1021/cr0505270|pmid = 16836303|title = Practical Methodologies for the Synthesis of Indoles|year = 2006|volume = 106|issue = 7|pages = 2875–2911}}</ref>
			The main industrial routes start from ] via vapor-phase reaction with ] in the presence of ]s:
			:] and ] to give indole.]]
			In general, reactions are conducted between 200 and 500&nbsp;°C. Yields can be as high as 60%. Other precursors to indole include ], 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergo ].<ref>{{Ullmann|first1=Gerd |last1=Collin |first2=Hartmut |last2=Höke |title=Indole |doi=10.1002/14356007.a14_167}}</ref>
	<!-- Significant synthetic methods -->		<!-- Significant synthetic methods -->
	===Leimgruber-Batcho indole synthesis===		===Leimgruber–Batcho indole synthesis===
	{{main|Leimgruber-Batcho indole synthesis}}		{{main|Leimgruber–Batcho indole synthesis}}
	:]		:]
	The ] 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 ], where many pharmaceutical ] are made up of specifically substituted indoles.		The ] is an efficient method of synthesizing indole and substituted indoles.<ref>{{Cite web|url=https://nsp-sun.com/wp-content/uploads/2020/02/indol.pdf|title=Indol NSP}}</ref> Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the ], where many pharmaceutical ] are made up of specifically substituted indoles.
	===Fischer indole synthesis===		===Fischer indole synthesis===
	{{main|Fischer indole synthesis}}		{{main|Fischer indole synthesis}}
	:]		:]
	] One of the oldest and most reliable methods for synthesizing substituted indoles is the ], developed in 1883 by ]. 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 ] with ] followed by ] of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.<ref>{{cite journal|last1=Bratulescu|first1=George|title=A new and efficient one-pot synthesis of indoles|journal=Tetrahedron Letters|volume=49|pages=984|year=2008|doi=10.1016/j.tetlet.2007.12.015|issue=6 }}</ref>		]
			One of the oldest and most reliable methods for synthesizing substituted indoles is the ], developed in 1883 by ]. 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 ] with ] followed by ] of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.<ref>{{cite journal|last1=Bratulescu|first1=George|title=A new and efficient one-pot synthesis of indoles|journal=Tetrahedron Letters|volume=49|page=984|year=2008|doi=10.1016/j.tetlet.2007.12.015|issue=6 }}</ref>
	===Other indole-forming reactions===		===Other indole-forming reactions===
	<!-- Minor synthetic methods -->		<!-- Minor synthetic methods -->
	* ]		* ]
	* ]		* ]
			* ]
	* ]		* ]
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	* In the '''Diels-Reese reaction'''<ref>{{cite journal|doi = 10.1002/jlac.19345110114|journal = ]|title = Synthesen in der hydroaromatischen Reihe. XX. Über die Anlagerung von Acetylen-dicarbonsäureester an Hydrazobenzol|year = 1934|author = Diels, Otto|volume = 511|pages = 168|last2 = Reese|first2 = Johannes}}</ref><ref>{{cite journal|title = An Extension of the Diels-Reese Reaction|author = Ernest H. Huntress, Joseph Bornstein, and William M. Hearon|journal = ]|doi = 10.1021/ja01591a055|year = 1956|volume = 78|pages = 2225|issue = 10}}</ref> ] reacts with ] to an adduct, which in ] gives ''dimethyl indole-2,3-dicarboxylate'' and ]. With other solvents, other products are formed: with ] a ], and with ] a ].		* In the ]<ref>{{cite journal|doi = 10.1002/jlac.19345110114|journal = Justus Liebig's Annalen der Chemie|title = Synthesen in der hydroaromatischen Reihe. XX. Über die Anlagerung von Acetylen-dicarbonsäureester an Hydrazobenzol|trans-title=Syntheses in the hydroaromatic series. XX. The addition of acetylene dicarboxylic acid ester to hydrazobenzene|year = 1934|last1 = Diels |first1=Otto|volume = 511|page = 168|last2 = Reese|first2 = Johannes}}</ref><ref>{{cite journal|title = An Extension of the Diels-Reese Reaction|first1=Ernest H. |last1=Huntress |first2=Joseph |last2=Bornstein |first3=William M. |last3=Hearon |journal = ]|doi = 10.1021/ja01591a055|year = 1956|volume = 78|page = 2225|issue = 10|bibcode=1956JAChS..78.2225H }}</ref> ] reacts with ] to an adduct, which in ] gives dimethyl indole-2,3-dicarboxylate and ]. With other solvents, other products are formed: with ] a ], and with ] a ].
	==Chemical reactions of indole==		==Chemical reactions of indole==
	===Basicity===		===Basicity===
	Unlike most ]s, indole is not ]. The bonding situation is completely analogous to that in ]. Very strong acids such as ] are required to ] indole. The protonated form has an ] of −3.6. The sensitivity of many indolic compounds (e.g., ]s) under acidic conditions is caused by this protonation.		Unlike most ]s, indole is not ]: just like ], the aromatic character of the ring means that the ] of electrons on the nitrogen atom is not available for protonation.<ref>{{Cite book|url=https://books.google.com/books?id=RrKgfuRwsqsC&pg=PA143|title=Essentials of Organic Chemistry: For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry|last=Dewick|first=Paul M.|date=2013-03-20|publisher=John Wiley & Sons|isbn=9781118681961|pages=143|language=en}}</ref> Strong acids such as ] can, however, ] indole. Indole is primarily protonated at the C3, rather than N1, owing to the ]-like reactivity of the portion of the molecule located outside of the ] ring. The protonated form has a ] of −3.6. The sensitivity of many indolic compounds (e.g., ]s) under acidic conditions is caused by this protonation.
	===Electrophilic substitution===		===Electrophilic substitution===
	The most reactive position on indole for ] is C-3, which is 10<sup>13</sup> times more reactive <!--toward what--> than ]. <!--one cannot compare a site and a molecule--> For example, ] ] of indole<ref name="james1959">{{cite journal|author=James, P. N.; Snyder, H. R.|year=1959|title=Indole-3-aldehyde |journal=]|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, electrophilic substitution of the carbocyclic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.		The most reactive position on indole for ] is C3, which is 10<sup>13</sup> times more reactive <!--toward what--> than ]. <!--one cannot compare a site and a molecule--> For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan. ] ] of indole<ref name="james1959">{{cite journal|last1=James |first1=P. N. |last2=Snyder |first2=H. R. |year=1959|title=Indole-3-aldehyde |journal=]|volume=39|page=30| url=http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0539|doi=10.15227/orgsyn.039.0030}}</ref> will take place at room temperature exclusively at C3.
	:]		:]
			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.<ref name="noland1966">{{cite journal |last1=Noland |first1=W. E. |last2=Rush |first2=K. R. |last3=Smith |first3=L. R. |year=1966 |title=Nitration of Indoles. IV. The Nitration of 2-Phenylindole. |journal=] |volume=31 |pages=65–69 |doi=10.1021/jo01339a013}}</ref>
	], a useful synthetic intermediate, is produced via a ] of indole with ] and ]. It is the precursor to indole acetic acid and synthetic tryptophan.
			], a useful synthetic intermediate, is produced via a ] of indole with ] and ]. It is the precursor to indole-3-acetic acid and synthetic tryptophan.
	:]
			:]
	===Nitrogen-H acidity and organometallic indole anion complexes===
	The N-H center has a pK<sub>a</sub> of 21 in ], so that very ]s such as ] or ] and water-free conditions are required for complete ]. The resulting alkali metal derivatives can react in two ways. The more ] salts such as the ] or ] compounds tend to react with ]s at nitrogen-1, whereas the more ] magnesium compounds (''indole ]'') and (especially) ] complexes tend to react at carbon-3 (see figure below). In analogous fashion, ] aprotic ]s such as ] and ] tend to favour attack at the nitrogen, whereas nonpolar solvents such as ] favour C-3 attack.<ref name="heaney1974">{{cite journal|author=Heaney, H.; Ley, S. V.|year=1974|title=1-Benzylindole |journal=]|volume=54|pages=58| url=http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0104}}</ref>
			===N–H acidity and organometallic indole anion complexes===
	:]
			The N–H center has a p''K''<sub>a</sub> of 21 in ], so that very ]s such as ] or ] and water-free conditions are required for complete ]. The resulting ] derivatives can react in two ways. The more ] salts such as the ] or ] compounds tend to react with ]s at nitrogen-1, whereas the more ] magnesium compounds (''indole ]'') and (especially) ] complexes tend to react at carbon 3 (see figure below). In analogous fashion, ] aprotic ]s such as ] and ] tend to favour attack at the nitrogen, whereas nonpolar solvents such as ] favour C3 attack.<ref name="heaney1974">{{cite journal|last1=Heaney |first1=H. |last2=Ley |first2=S. V. |year=1974|title=1-Benzylindole |journal=]|volume=54|page=58| url=http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0104|doi=10.15227/orgsyn.054.0058}}</ref>
			:]
	===Carbon acidity and C-2 lithiation===
			===Carbon acidity and C2 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 ] or ] results in lithiation exclusively at the C-2 position. This strong nucleophile can then be used as such with other electrophiles.
			After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction of ''N''-protected indoles with ] or ] results in lithiation exclusively at the C2 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">{{cite journal|author = Bergman, J.; Venemalm, L.|journal = ]|doi = 10.1021/jo00034a058|title = Efficient synthesis of 2-chloro-, 2-bromo-, and 2-iodoindole|year = 1992|volume = 57|pages = 2495|issue = 8}}</ref>
	:]		:]
	Alan Katritzky also developed a technique for lithiating the 2-position of unsubstituted indole.<ref>{{cite journal|title = Facile Synthesis of 2-Substituted Indoles and Indolocarbazoles from 2-(Benzotriazol-1-ylmethyl)indole|author = Alan R. Katritzky, Jianqing Li, Christian V. Stevens|journal = J. Org. Chem.|year = 1995|volume = 60|issue = 11|pages = 3401–3404|doi = 10.1021/jo00116a026|url = http://pubs.acs.org/doi/abs/10.1021/jo00116a026}}</ref>		Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole,<ref name="bergman1992">{{cite journal|author1=Bergman, J. |author2=Venemalm, L. |journal = ]|doi = 10.1021/jo00034a058|title = Efficient synthesis of 2-chloro-, 2-bromo-, and 2-iodoindole|year = 1992|volume = 57|page = 2495|issue = 8}}</ref> as did Katritzky.<ref>{{cite journal|title = Facile Synthesis of 2-Substituted Indoles and Indolocarbazoles from 2-(Benzotriazol-1-ylmethyl)indole|first1=Alan R. |last1=Katritzky |first2=Jianqing |last2=Li |first3=Christian V. |last3=Stevens |journal = J. Org. Chem.|year = 1995|volume = 60|issue = 11|pages = 3401–3404|doi = 10.1021/jo00116a026}}</ref>
	===Oxidation of indole===		===Oxidation of indole===
	Due to the electron-rich nature of indole, it is easily ]. Simple oxidants such as ] will selectively oxidize indole '''1''' to ] ('''4''' and '''5''').		Due to the electron-rich nature of indole, it is easily ]. Simple oxidants such as ] will selectively oxidize indole '''1''' to ] ('''4''' and '''5''').
	:]		:]
	===Cycloadditions of indole===		===Cycloadditions of indole===
	Only the C-2 to C-3 pi-bond of indole is capable of ]s. Intermolecular cycloadditions are not favorable, whereas intramolecular variants are often high-yielding. For example, Padwa ''et al.''<ref name="lynch2002">{{cite journal|author = Lynch, S. M. ; Bur, S. K.; Padwa, A.|journal = ]|doi = 10.1021/ol027024q|pmid = 12489950|title = Intramolecular Amidofuran Cycloadditions across an Indole π-Bond: An Efficient Approach to the ''Aspidosperma'' and ''Strychnos'' ''ABCE'' Core|year = 2002|volume = 4|issue = 26|pages = 4643}}</ref> have developed this ] to form advanced ] intermediates. In this case, the 2-aminofuran is the ], whereas the indole is the ].		Only the C2–C3 ] of indole is capable of ]s. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa ''et al.''<ref name="lynch2002">{{cite journal|last1=Lynch |first1=S. M. |last2=Bur |first2=S. K. |last3=Padwa |first3=A. |journal = ]|doi = 10.1021/ol027024q|pmid = 12489950|title = Intramolecular Amidofuran Cycloadditions across an Indole π-Bond: An Efficient Approach to the ''Aspidosperma'' and ''Strychnos'' ''ABCE'' Core|year = 2002|volume = 4|issue = 26|pages = 4643–5}}</ref> have developed this ] to form advanced ] intermediates. In this case, the 2-aminofuran is the ], whereas the indole is the ]. Indoles also undergo intramolecular and cycloadditions.
	:]		:]
			Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.<ref name="cox1995">{{Cite journal| pages = 1797–1842| year = 1995| doi = 10.1021/cr00038a004| last2 = Cook| last1 = Cox| volume = 95 | first1 = E. D.| journal = Chemical Reviews| first2 = J. M.| title = The Pictet-Spengler condensation: a new direction for an old reaction| issue = 6}}</ref><ref>{{cite journal |last1=Gremmen |first1=C. |last2=Willemse |first2=B. |last3=Wanner |first3=M. J. |last4=Koomen |first4=G.-J. | journal = ] | volume = 2 | year = 2000 | pages = 1955–1958 | doi = 10.1021/ol006034t | title = Enantiopure Tetrahydro-β-carbolines via Pictet–Spengler Reactions with ''N''-Sulfinyl Tryptamines | issue = 13|pmid=10891200 }}</ref><ref>{{cite journal|title=The intermolecular Pictet–Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids|first1=Enrique L.|last1=Larghi|first2=Marcela|last2=Amongero|first3=Andrea B. J.|last3=Bracca|first4=Teodoro S.|last4=Kaufman|journal=]|volume=RL-1554K|pages=98–153|date=2005|issue=12|doi=10.3998/ark.5550190.0006.c09|doi-access=free|hdl=2027/spo.5550190.0006.c09|hdl-access=free}}</ref><ref>{{cite book|first1=Teodoro S.|last1=Kaufman|chapter=Synthesis of Optically-Active Isoquinoline and Indole Alkaloids Employing the Pictet–Spengler Condensation with Removable Chiral Auxiliaries Bound to Nitrogen|title=New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles|editor-first=J. L.|editor-last=Vicario|isbn=978-81-7736-278-7|publisher=Research SignPost|location=Thiruvananthapuram|date=2005|pages=99–147}}</ref> One example is the ] between ] derivatives and ],<ref>{{cite journal |last1=Bonnet |first1=D. |last2=Ganesan |first2=A. | journal = ] | year = 2002 | volume = 4 | issue = 6 | pages = 546–548 | title = Solid-Phase Synthesis of Tetrahydro-β-carbolinehydantoins via the ''N''-Acyliminium Pictet–Spengler Reaction and Cyclative Cleavage | doi = 10.1021/cc020026h |pmid=12425597 }}</ref> which produces a mixture of ], leading to reduced ] of the desired product.
	Indoles also undergo intramolecular and cycloadditions.
	==Applications==		===Hydrogenation===
			Indoles are susceptible to hydrogenation of the imine subunit<ref>Zhu, G.; Zhang, X. ''Tetrahedron: Asymmetry'' '''1998''', ''9'', 2415.</ref> to give ]s.
			]
	Natural ] ], used in the ] 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==		==See also==
			* ]
			* ]
	* ]		* ]
			* ]
	* ]
	* ] (3-methylindole)		* ] (3-methylindole)
	* ]
	* ]s
			==References==
	==General references==
			{{reflist|30em}}
			===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|isbn=0-12-676945-1}}		* {{cite book|title=Indoles Part One|editor-first=W. J.|editor-last=Houlihan|publisher=Wiley Interscience|location=New York|date=1972}}{{ISBN missing}}
	* {{cite book|first=J. A.|last=Joule|coauthors=Mills, K.|year=2000|title=Heterocyclic Chemistry|publisher=Blackwell Science|location=Oxford, UK|isbn=0-632-05453-0}}		* {{cite book|first=R. J.|last=Sundberg|year=1996|title=Indoles|publisher=Academic Press|location=San Diego|isbn=978-0-12-676945-6}}
			* {{cite book|first=J. A.|last=Joule|author2=Mills, K.|year=2000|title=Heterocyclic Chemistry|publisher=Blackwell Science|location=Oxford, UK|isbn=978-0-632-05453-4}}
	* Joule, J., In ''Science of Synthesis'', Thomas, E. J., Ed.; Thieme: Stuttgart, (2000); Vol. 10, p.&nbsp;361. ISBN 3-13-112241-2 (GTV); ISBN 0-86577-949-X (TNY).
			* {{cite book|last=Joule|first=J.|title=Science of Synthesis|editor-first=Thomas|editor-last=E. J.|publisher=Thieme|location=Stuttgart|date=2000|volume=10|page=361|isbn=978-3-13-112241-4}}
			* {{Cite journal|last1=Schoenherr|first1=H.|last2=Leighton|first2=J. L.|title=Direct and Highly Enantioselective Iso-Pictet-Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures|journal=Org. Lett.|date=2012|volume=14|issue=10|pages=2610–3|doi=10.1021/ol300922b|pmid=22540677}}
	==References==		==External links==
			{{Commons category|1H-Indole}}
	{{reflist|2}}
			*
			* at chemsynthesis.com
			{{Simple aromatic rings}}
	==See also==
			{{Authority control}}
	* ]
	* ] – biochemical test for bacterial identification
	==External links==
	{{Commons category|Indoles}}
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