Indole is asolid at room temperature. It occurs naturally in humanfeces and 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]
Indole chemistry began to develop with the study of the dyeindigo. Indigo can be converted toisatin and then tooxindole. In 1866,Adolf von Baeyer reducedoxindole to indole usingzinc 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 importantalkaloids, known asindole alkaloids (e.g.,tryptophan andauxins), and it remains an active area of research today.[9]
Common classical methods applied for the detection of extracellular and environmental indoles, areSalkowski,Kovács,Ehrlich's reagent assays andHPLC.[16][17][18] For intracellular indole detection and measurement genetically encoded indole-responsivebiosensor is applicable.[19]
Indole and its derivatives can also be synthesized by a variety of methods.[25][26][27] According to a 2011 review, all known syntheses fall into 9 categories.[28]
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.[29]
TheLeimgruber–Batcho indole synthesis is an efficient method of synthesizing indole and substituted indoles.[30] 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 pharmaceuticaldrugs are made up of specifically substituted indoles.
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 reactingphenylhydrazine withpyruvic acid followed bydecarboxylation of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.[31]
Unlike mostamines, indole is notbasic: just likepyrrole, the aromatic character of the ring means that thelone pair of electrons on the nitrogen atom is not available for protonation.[34] Strong acids such ashydrochloric acid can, however,protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to theenamine-like reactivity of the portion of the molecule located outside of thebenzene ring. The protonated form has apKa of −3.6. The sensitivity of many indolic compounds (e.g.,tryptamines) under acidic conditions is caused by this protonation.
The most reactive position on indole forelectrophilic aromatic substitution is C3, which is 1013 times more reactive thanbenzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan.Vilsmeier–Haackformylation of indole[35] 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.[36]
After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction ofN-protected indoles withbutyl lithium orlithium diisopropylamide 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,[39] as did Katritzky.[40]
Due to the electron-rich nature of indole, it is easilyoxidized. Simple oxidants such asN-bromosuccinimide will selectively oxidize indole1 tooxindole (4 and5).
Only the C2–C3pi bond of indole is capable ofcycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwaet al.[41] have developed thisDiels-Alder reaction to form advancedstrychnine intermediates. In this case, the 2-aminofuran is thediene, whereas the indole is thedienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.
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^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 October 2020.
^Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (July 1999)."Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid".J. Biol. Chem.274 (31):21937–21942.doi:10.1074/jbc.274.31.21937.PMID10419516.S2CID6630247.[Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
^Qin, Hua-Li; Liu, Jing; Fang, Wan-Yin; Ravindar, L.; Rakesh, K. P. (15 May 2020). "Indole-based derivatives as potential antibacterial activity against methicillin-resistance Staphylococcus aureus (MRSA)".European Journal of Medicinal Chemistry.194 112245.doi:10.1016/j.ejmech.2020.112245.ISSN0223-5234.PMID32220687.S2CID214695328.
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^Noland, W. E.; Rush, K. R.; Smith, L. R. (1966). "Nitration of Indoles. IV. The Nitration of 2-Phenylindole".J. Org. Chem.31:65–69.doi:10.1021/jo01339a013.
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^Katritzky, Alan R.; Li, Jianqing; Stevens, Christian V. (1995). "Facile Synthesis of 2-Substituted Indoles and Indolo[3,2-b]carbazoles from 2-(Benzotriazol-1-ylmethyl)indole".J. Org. Chem.60 (11):3401–3404.doi:10.1021/jo00116a026.
^Lynch, S. M.; Bur, S. K.; Padwa, A. (2002). "Intramolecular Amidofuran Cycloadditions across an Indole π-Bond: An Efficient Approach to theAspidosperma andStrychnosABCE Core".Org. Lett.4 (26):4643–5.doi:10.1021/ol027024q.PMID12489950.
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