Indole

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Indole
Skeletal formula with numbering scheme
Ball-and-stick model of indole
Space-filling model of indole
Names
Preferred IUPAC name
1H-Indole[1]
Other names
2,3-Benzopyrrole, ketole,
1-benzazole
Identifiers
3D model (
JSmol
)
3DMet
107693
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.004.019 Edit this at Wikidata
EC Number
  • 204-420-7
3477
KEGG
RTECS number
  • NL2450000
UNII
  • InChI=1S/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H checkY
    Key: SIKJAQJRHWYJAI-UHFFFAOYSA-N checkY
  • InChI=1/C8H7N/c1-2-4-8-7(3-1)5-6-9-8/h1-6,9H
    Key: SIKJAQJRHWYJAI-UHFFFAOYAI
  • C12=C(C=CN2)C=CC=C1
Properties
C8H7N
Molar mass 117.151 g·mol−1
Appearance White solid
Odor Feces or jasmine like
Density 1.1747 g/cm3, solid
Melting point 52 to 54 °C (126 to 129 °F; 325 to 327 K)
Boiling point 253 to 254 °C (487 to 489 °F; 526 to 527 K)
0.19 g/100 ml (20 °C)
Soluble in hot water
Acidity (pKa) 16.2
(21.0 in DMSO)
Basicity (pKb) 17.6
-85.0·10−6 cm3/mol
Structure
Pna21
Planar
2.11 D in benzene
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Skin sensitising
GHS labelling:
GHS06: ToxicGHS07: Exclamation mark
Danger
H302, H311
P264, P270, P280, P301+P312, P302+P352, P312, P322, P330, P361, P363, P405, P501
Flash point 121 °C (250 °F; 394 K)
Safety data sheet (SDS) [1]
Related compounds
Other cations
 Indolium
methylindole,
oxindole, pyrrole,
skatole, benzophosphole
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Indole is an

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 acid tryptophan and neurotransmitter serotonin.[2]

General properties and occurrence

Indole is a

perfumes. It also occurs in coal tar. It has been identified in cannabis.[4] It is the main volatile compound in Stinky tofu.[5]

When indole is a

systematic nomenclature
.

Indole undergoes

betablocker pindolol
.

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

Baeyer's original structure for indole, 1869

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]

Biosynthesis and function

Indole is biosynthesized in the shikimate pathway via anthranilate.[2] It is an intermediate in the biosynthesis of tryptophan, where it stays inside the tryptophan synthase molecule between the removal of 3-phospho-glyceraldehyde and the condensation with serine. When indole is needed in the cell, it is usually produced from tryptophan by tryptophanase.[10]

Indole is produced via anthranilate and reacts further to give the amino acid tryptophan.

As an

spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence.[11] A number of indole derivatives have important cellular functions, including neurotransmitters such as serotonin.[2]

Tryptophan metabolism by
human gastrointestinal microbiota (
)
Tryptophanase-
expressing
bacteria
AST-120
Intestinal
immune
cells
Mucosal homeostasis:
↓
TNF-α
↑Junction protein-
coding mRNAs
β-amyloid
fibril formation
Maintains mucosal reactivity:
↑IL-22 production
Associated with
calcification
Associated with
Uremic toxin
The image above contains clickable links
This diagram shows the biosynthesis of
activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[12]

As an

spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence.[11]

Detection methods

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]

Medical applications

Indoles and their derivatives are promising against

viruses.[20][21][22][23][24]

Synthetic routes

Indole and its derivatives can also be synthesized by a variety of methods.[25][26][27]

The main industrial routes start from

catalysts
:

Reaction of aniline 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

cyclizations.[28]


Leimgruber–Batcho indole synthesis

Main article: Leimgruber–Batcho indole synthesis
The Leimgruber–Batcho indole synthesis

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.

Fischer indole synthesis

Main article: Fischer indole synthesis
The Fischer indole synthesis
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 the

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]

Other indole-forming reactions

Chemical reactions of indole

Basicity

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

formylation of indole[34]
will take place at room temperature exclusively at C3.

The Vilsmeyer–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.[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.

Synthesis of gramine from indole

N–H acidity and organometallic indole anion complexes

The N–H center has a pKa of 21 in

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]

Formation and reactions of the indole anion

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.

2-position lithiation of indole

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).

Oxidation of indole by N-bromosuccinimide

Cycloadditions of indole

Only the C2–C3

dienophile
. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.

Example of a cycloaddition of indole

Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.

yield
of the desired product.

Hydrogenation

Indoles are susceptible to hydrogenation of the imine subunit.[45]

See also

References

  1. ISBN 978-0-85404-182-4
    .
  2. ^
    ISBN 0-7167-4339-6
    .
  3. ^ 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. Retrieved 20 October 2020.
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  6. PMID 31640239
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  7. doi:10.1002/jlac.18661400306
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  8. doi:10.1002/cber.186900201268
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    .
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    .
  11. ^
    PMID 20070374
    .
  12. ^
    PMID 27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
    Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
  13. PMID 19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes.
    IPA metabolism diagram
  14. ^ "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018.
  15. S2CID 6630247
    . [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.
  16. PMID 188858
    .
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    .
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  24. S2CID 219021072
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    .
  29. ^ "Indol NSP" (PDF).
  30. doi:10.1016/j.tetlet.2007.12.015
    .
  31. doi:10.1002/jlac.19345110114
    .
  32. doi:10.1021/ja01591a055
    .
  33. ISBN 9781118681961
    .
  34. doi:10.15227/orgsyn.039.0030
    .
  35. doi:10.1021/jo01339a013
    .
  36. doi:10.15227/orgsyn.054.0058
    .
  37. doi:10.1021/jo00034a058
    .
  38. doi:10.1021/jo00116a026
    .
  39. PMID 12489950
    .
  40. doi:10.1021/cr00038a004
    .
  41. PMID 10891200
    .
  42. hdl:2027/spo.5550190.0006.c09
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  44. PMID 12425597
    .
  45. ^ Zhu, G.; Zhang, X. Tetrahedron: Asymmetry 1998, 9, 2415.

General references

External links

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