Indole is an
organic compound with the formula C6H4CCNH3. Indoles are derivatives of indole where one or more H's have been replaced by other groups. Indole is classified as an
aromaticheterocycle. It has a
bicyclic structure, consisting of a six-membered
benzene ring fused to a five-membered
pyrrole ring. Indoles are widely distributed in nature, most notably as
amino acidtryptophan and
neurotransmitterserotonin.[2]
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,[3] and is a constituent of many
perfumes. It also occurs in
coal tar. It has been identified in
cannabis.[4] It is the main volatile compound in
Stinky tofu.[5]
The name indole is a
portmanteau of the words indigo 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. Indigo can be converted to
isatin and then to
oxindole. Then, in 1866,
Adolf von Baeyer reduced
oxindole to indole using
zinc 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 important
alkaloids, known as
indole alkaloids (e.g.,
tryptophan and
auxins), and it remains an active area of research today.[9]
Common classical methods applied for the detection of extracellular and environmental indoles, are
Salkowski,
Kovács,
Ehrlich’s reagent assays and
HPLC.[16][17][18] For intracellular indole detection and measurement genetically encoded indole-responsive
biosensor is applicable.[19]
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.[28]
The
Leimgruber–Batcho indole synthesis is 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 the
pharmaceutical industry, where many pharmaceutical
drugs are made up of specifically substituted indoles.
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.[30]
Unlike most
amines, 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.[33] Strong acids such as
hydrochloric acid can, however,
protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the
enamine-like reactivity of the portion of the molecule located outside of the
benzene ring. The protonated form has a
pKa of −3.6. The sensitivity of many indolic compounds (e.g.,
tryptamines) under acidic conditions is caused by this 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–Haackformylation of indole[34] 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.[35]
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 pKa of 21 in
DMSO, so that very
strong bases such as
sodium hydride or
n-butyl lithium and water-free conditions are required for complete
deprotonation. The resulting
organometalic derivatives can react in two ways. The more
ionic salts such as the
sodium or
potassium compounds tend to react with
electrophiles at nitrogen-1, whereas the more
covalent magnesium compounds (indole
Grignard reagents) and (especially)
zinc complexes tend to react at carbon 3 (see figure below). In analogous fashion,
polar aprotic
solvents such as
DMF and
DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as
toluene favour C3 attack.[36]
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
butyl lithium 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,[37] as did Katritzky.[38]
Oxidation of indole
Due to the electron-rich nature of indole, it is easily
oxidized. 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.[39] 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. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.
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