Indole is an organic compound with the formula . 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 Indoles are derivatives of indole where one or more of the hydrogen atoms have been replaced by substituent groups.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.[
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General properties and occurrence
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,
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). substituent 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
The name indole is a Portmanteau word of the words indigo dye and oleum, since indole was first isolated by treatment of the indigo dye with oleum.
History
Indole chemistry began to develop with the study of the dye indigo dye. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.
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 , known as (e.g., tryptophan and ), and it remains an active area of research today.
Biosynthesis and function
Indole is Biosynthesis in the shikimate pathway via anthranilic acid.
As an Cell signaling, indole regulates various aspects of bacterial physiology, including Bacterial spore formation, plasmid stability, drug resistance, biofilm formation, and virulence.
Detection methods
Common classical methods applied for the detection of extracellular and environmental indoles, are Salkowski, Kovács, Ehrlich’s reagent assays and HPLC.
Medical applications
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.
Synthetic routes
Indole and its derivatives can also be synthesized by a variety of methods.
The main industrial routes start from aniline via vapor-phase reaction with ethylene glycol in the presence of :
- 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.
Leimgruber–Batcho indole synthesis
The Leimgruber–Batcho indole synthesis is an efficient method of synthesizing indole and substituted indoles.
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. 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.
Other indole-forming reactions
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Bartoli indole synthesis
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Bischler–Möhlau indole synthesis
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Cadogan-Sundberg indole synthesis
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Fukuyama indole synthesis
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Gassman indole synthesis
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Hemetsberger indole synthesis
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Larock indole synthesis
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Madelung synthesis
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Nenitzescu indole synthesis
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Reissert indole synthesis
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Baeyer–Emmerling indole synthesis
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In the Diels–Reese reaction
Chemical reactions of indole
Basicity
Unlike most , 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.
Electrophilic substitution
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
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.
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.
N–H acidity and organometallic indole anion complexes
The N–H center has a p Ka of 21 in DMSO, so that very such as sodium hydride or N-Butyllithium and water-free conditions are required for complete deprotonation. The resulting organometalic derivatives can react in two ways. The more ionic bond salts such as the sodium or potassium compounds tend to react with at nitrogen-1, whereas the more Covalent bond magnesium compounds ( indole Grignard reagents) and (especially) zinc complexes tend to react at carbon 3 (see figure below). In analogous fashion, polar aprotic such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C3 attack.
Carbon acidity and C2 lithiation
After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction of N-protected indoles with N-Butyllithium or lithium 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,
Oxidation of indole
Due to the electron-rich nature of indole, it is easily redox. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole ( 4 and 5).
Cycloadditions of indole
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.
Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.
Hydrogenation
Indoles are susceptible to hydrogenation of the imine subunit[Zhu, G.; Zhang, X. Tetrahedron: Asymmetry 1998, 9, 2415.] to give .
See also
General references
External links
