INDOLE

    
EC / List no.: 204-420-7
CAS no.: 120-72-9
Mol. formula: C8H7N

Indole is an aromatic heterocyclic organic compound with formula C8H7N. 
Indole has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring.
Indole is widely distributed in the natural environment and can be produced by a variety of bacteria. 
As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence.
The amino acid tryptophan is an indole derivative and the precursor of the neurotransmitter serotonin.

General properties and occurrence
Indole is a solid at room temperature. 
Indole occurs naturally in human feces and has an intense fecal odor. 
At very low concentrations, however, it has a flowery smell, and is a constituent of many perfumes. 
Indole also occurs in coal tar.

The corresponding substituent is called indolyl.
Indole undergoes electrophilic substitution, mainly at position 3 (see diagram in right margin). 
Substituted indoles are structural elements of (and for some compounds, the synthetic precursors for) the tryptophan-derived tryptamine alkaloids, which includes the neurotransmitters serotonin and melatonin, as well as the naturally occurring psychedelic drugs dimethyltryptamine and psilocybin. 
Other indolic compounds include the plant hormone auxin (indolyl-3-acetic acid, IAA), tryptophol, the anti-inflammatory drug indomethacin, and the 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
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.
In 1869, he proposed a formula for indole (left).

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.

Biosynthesis and function
Indole is biosynthesized in the shikimate pathway via anthranilate.
Indole 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.

As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence.
A number of indole derivatives have important cellular functions, including neurotransmitters such as serotonin.

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.
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.
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
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.

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.
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–Haack formylation of indole 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.

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. 
Indole 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.

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, as did Katritzky.

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. 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.

Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.
One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes, which produces a mixture of diastereomers, leading to reduced yield of the desired product.

Hydrogenation
Indoles are susceptible to hydrogenation of the imine subunit.
    
Indole, also called Benzopyrrole, an aromatic heterocyclic organic compound occurring in some flower oils, such as jasmine and orange blossom, in coal tar, and in fecal matter. 
Indole has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. 
Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. 
Indole occurs naturally in human feces and has an intense fecal smell. 
This off flavour occurs in beer due to contaminant coliform bacteria during the primary fermentation stage of beer brewing. 
At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. 
Natural jasmine oil, used in the perfume industry, contains around 2.5% of indole. 
Indole also occurs in coal tar. 
The participation of the nitrogen lone electron pair in the aromatic ring means that indole is not a base, and it does not behave like a simple amine.
Indoles are important precursors for other substances made within the human body and are, therefore, researched and used in lifestyle and medical applications. 
The compound was officially discovered in 1866 by a scientist working with the properties of zinc dust who reduced oxindole from the zinc dust into an indole. 
After the discovery, indoles became important constituents of the textile industry, and as more research was conducted, the larger role that indoles played within the human body system was realized. 
The indolic nucleus in substances like tryptophan and auxin has led to a better understanding of their mechanism within the body.

Content analysis    
Press GT-10-4 gas chromatography method for the determination with polar column.
Using the polar column method in GT-10-4 gas chromatography to determine the content of indole.
Control of Bacterial Processes    
As an intercellular signal molecule in both gram-positive and gram-negative bacteria, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence. Indole has been shown to control a number of bacterial processes such as spore formation, plasmid stability, drug resistance, biofilm formation, and virulence. Indole may have anticarcinogenic activity.
Commonly synthesized from phenylhydrazine and pyruvic acid, although several other procedures have been discovered, indole also can be produced by bacteria as a degradation product of the amino acid tryptophan.

Chemical property    
Indole is the shiny flaky white crystals, and would turn into dark colors when it exposed to light. 
There would be a strong unpleasant odor with high concentration of indole, but the flavor would change into oranges and jasmine after highly diluted (concentration <0.1%). 
Indole has the melting point of 52~53 ℃ and the boiling point of 253~254 ℃. 
Indole is soluble in alcohol, ether, hot water, propylene glycol, petroleum ether and most of the non-volatile oil, insoluble in glycerin and mineral oil.
Natural indole are widely contained in neroli oil, orange oil, lemon oil, lime oil, citrus oil, peel oil, jasmine oil and other essential oil.

Uses    
(1) According to the GB 27 60-96 , indole can be used as flavouring agent and mainly used for preparing the essence of cheese, citrus, coffee, nuts, grape, strawberry, raspberry, chocolate, assorted fruit, jasmine and lily etc.
(2) Indole can be used as the reagent for the determination of nitrite, can also used in the manufacture of perfume and medicine.
(3) Indole can be used as the raw material of perfume, pharmaceuticals and plant growth hormone.
(4) Indole is the intermediate for the indole acetic acid and indole butyric acid. 
The indole acetic acid and indole butyric are plant growth regulator.
(5) Indole can be widely used in the manufacture of the essences of jasmine, lilac, orange blossom, gardenia, honeysuckle, lotus, narcissus, ylang, orchid and prynne etc. 
Indole is usually combined with the methyl indole to imitate the artificial civet. 
The extremely few of the indole can be used in chocolate, raspberry, strawberry, bitter orange, coffee, nuts, cheese, grapes and fruit and other fruity essential oil.
(6) Indole is mainly used as spices, dyes, amino acids and the raw materials of pesticide. 
Indole itself is a spice commonly used in producing the essences of jasmine, lilac, lotus flowers, orchids and other flower flavor. The usage is generally in a few thousandths.
(7) Indole can be used for verifying the gold, potassium and nitrite and manufacturing jasmine-type fragrance. 
Indole can also be used in pharmaceutical industry.

Description    
Indole has an almost floral odor when highly purified. 
Otherwise, it exhibits the characteristic odor of feces. 
Indole is not very stable on exposure to light (turns red). 
Indole may be obtained from the 220 - 260°C boiling fraction of coal tar or by heating sodium phenylglycine-o-carboxylate with NaOH, saturating the aqueous solution of the melt with C 02, and finally reducing with sodium amalgam; can be prepared also by the reduction of indoxyl, indoxyl carboxylic acid, or indigo.

Chemical Properties    
Indole has an unpleasant odor at high concentration, odor becomes floral at higher dilutions
white crystals with an unpleasant odour

Colorless to yellow scales with an unpleasant odor. 
Turns red on exposure to light and air. Odor threshold of 0.14 ppm was reported by Buttery et al. (1988).

Occurrence
Reported occurring in several natural products as a complex compound that decomposes during enfleurage or steam distillation yielding free indole; reported found in the essential oil from flower of Jasminum grandiflorum, in neroli oil and in the oil extracted from flowers of bitter orange; also reported in the flowers of several plants: lemon, coffee, Hevea brasiliensis and Randia formosa in the oil extracted from flowers of Jasminum odoratissinium L. and in the oil of Narcissus jonquilla. 
Also reported found in apricot, mandarin orange peel oil, grapes, kohlrabi, French fried potato, crispbread, cheeses, butter, milk, milk powder, boiled egg, fish oil, chicken, beef, pork, beer, rum, Finnish whiskey, red and white wine, coffee, tea, soybean, mushrooms, cauliflower, figs, rice, licorice, buckwheat, malt, wort, elder flower, clary sage, shrimp, okra, crab, clam, squid and green maté

Uses:
Indole occurs in coal tar. 
Indole is used, underhigh dilution, in perfumery, and as an intermediatein organic synthesis.
Can be used in perfumes and in the synthesis of tryptophan.
In highly dil solutions the odor is pleasant, hence indole has been used in perfumery.
Indole is a flavoring agent that is a white, flaky crystalline product. 
Indole has an unpleasant odor when concentrated and a flowery odor when diluted. 
Indole is soluble in most fixed oils and propylene glycol and insoluble in glycerin and mineral oil. 
Indole is obtained from decomposi- tion of a protein.

Definition    indole: 
A yellow solid, C8H7N, m.p.52°C. 
Its molecules consist of a benzenering fused to a nitrogen-containingfive-membered ring. 
Indole occurs insome plants and in coal tar, and isproduced in faeces by bacterial action.
Indole is used in making perfumes.
Indole has the nitrogen atom positionednext to the fused benzenering. 
An isomer with the nitrogentwo atoms away from the fused ringis called isoindole.

Preparation    
Obtained from the 220 to 260°C boiling fraction of coal tar or by heating sodium phenyl-glycine-o-carboxylate with NaOH, saturating the aqueous solution of the melt with CO2 and finally reducing with sodium amalgam; can be prepared also by the reduction of indoxyl, indoxyl carboxylic acid or indigo.

Aroma threshold values    
Detection: 140 ppb

Indole is classified under the volatile flavor compounds (VFCs). 
Indole is known to play significant role in various biological functions such as anti-inflammatory, anticonvulsant, cardiovascular and antibacterial activities.

1H-indole is an indole and a polycyclic heteroarene. 
Indole has a role as an Escherichia coli metabolite. 
Indole is a tautomer of a 3H-indole.

Indole is a natural product found in Hordeum vulgare, Daphne papyracea, and other organisms with data available.

indole, also called Benzopyrrole, a heterocyclic organic compound occurring in some flower oils, such as jasmine and orange blossom, in coal tar, and in fecal matter. 
Indole is used in perfumery and in making tryptophan, an essential amino acid, and indoleacetic acid (heteroauxin), a hormone that promotes the development of roots in plant cuttings.

Indole, first isolated in 1866, has the molecular formula C8H7N, and it is commonly synthesized from phenylhydrazine and pyruvic acid, although several other procedures have been discovered.

In addition to tryptophan, indigo, and indoleacetic acid, numerous compounds obtainable from plant or animal sources contain the indole molecular structure. 
The best-known group of these compounds is the indole alkaloids, members of which have been isolated from plants representing more than 30 families. 
Psilocin, psilocybin, reserpine, and strychnine belong to this group.

Indole is a colourless solid having a pleasant fragrance in highly dilute solutions. 
Indole melts at 52.5° C (126.5° F).

Indole-3-carbinol is formed from a substance called glucobrassicin found in vegetables such as broccoli, Brussels sprouts, cabbage, collards, cauliflower, kale, mustard greens, turnips, and rutabagas. 
Indole-3-carbinol is formed when these vegetables are cut, chewed or cooked. 
Indole can also be produced in the laboratory.

People use indole-3-carbinol for cancer prevention, to treat systemic lupus erythematosus (SLE), and for many other conditions, but there is no good scientific evidence to support these uses.

About Indole
Helpful information
Indole is registered under the REACH Regulation and is manufactured in and / or imported to the European Economic Area, at ≥ 10 to < 100 tonnes per annum.

Indole is used by consumers, in articles, by professional workers (widespread uses), in formulation or re-packing and at industrial sites.

Consumer Uses
Indole is used in the following products: air care products, biocides (e.g. disinfectants, pest control products), polishes and waxes, washing & cleaning products and cosmetics and personal care products.
Other release to the environment of Indole is likely to occur from: indoor use as processing aid and outdoor use as processing aid.
Article service life
Release to the environment of Indole can occur from industrial use: industrial abrasion processing with low release rate (e.g. cutting of textile, cutting, machining or grinding of metal).
Other release to the environment of Indole is likely to occur from: outdoor use in long-life materials with high release rate (e.g. tyres, treated wooden products, treated textile and fabric, brake pads in trucks or cars, sanding of buildings (bridges, facades) or vehicles (ships)).
Indole can be found in products with material based on: fabrics, textiles and apparel (e.g. clothing, mattress, curtains or carpets, textile toys).
Widespread uses by professional workers
Indole is used in the following products: polishes and waxes and washing & cleaning products.
ECHA has no public registered data on the types of manufacture using Indole. Other release to the environment of Indole is likely to occur from: indoor use as processing aid.

Formulation or re-packing
Indole is used in the following products: perfumes and fragrances.
Release to the environment of Indole can occur from industrial use: formulation of mixtures.
Uses at industrial sites
Indole is used in the following products: washing & cleaning products.
Indole is used for the manufacture of: chemicals.
Release to the environment of Indole can occur from industrial use: in processing aids at industrial sites and as an intermediate step in further manufacturing of another substance (use of intermediates).
Manufacture
ECHA has no public registered data on the routes by which Indole is most likely to be released to the environment.

IUPAC NAMES:
1,3-benzopyrrole
1H-Benzo[b]pyrrole
1H-INDOLE
1H-Indole
1H-indole
2,3-BENZOPYROLE
Indol
indol
INDOLE
Indole
indole
Indole, 1-Azaindene, 1-Benzazole, 1H-Indole, 2,3-Benzopyrrole, Benzo[b]pyrrole, ketole

SYNONYMS:
FEMA 2593
INDOLE
BENZO(B)PYRROLE
1-Azaindene
IndoleGr
2,3-Benzopyrrole,OrBenzazole,Indole
INDOLE CRYSTALLINE GR
Indole-15N
Indole-UL-13C8, 15N
indole,2,3-benzopyrrole,1-benzazole
indole solution
INDOLE,REAGENT
INDOLE(RG)
1-BENZAZOLE
1-BENZO(B)PYRROLE
2,3-BENZOPYRROLE
1H-BENZO[B]PYRROLE
1H-INDOLE
benzo[d]pyrrole
INDOLE crystalline extrapure AR
ETHYL 4,6-DIAMINO-1H-INDOLE-2-CARBOXYLATE
ETHYL 4,6-DINITRO-1H-INDOLE-2-CARBOXYLATE
ETHYL 4-AMINO-7-HYDROXY-1H-INDOLE-2-CARBOXYLATE
ETHYL 6-AMINO-4-NITRO-1H-INDOLE-2-CARBOXYLATE
ETHYL 6-NITRO-4-AMINO-1H-INDOLE-2-CARBOXYLATE
ETHYL 7-HYDROXY-4-NITRO-1H-INDOLE-2-CARBOXYLATE
INDOL-3-YLACETICACID
3-BROMO-5-METHYL-1H-INDOLE
Indole, standard for GC,>99.5%(GC)
1H-indole analogue
Indole, 98+%
1H-Indol
Benzaole
Benzopyrrole
Indol
Ketole
INDOLE, 1000MG, NEAT
INDOLE, 99+%
INDOLE 99+% FCC
INDOLE, 1X1ML, MEOH, 2000UG/ML
INDOLE GC STANDARD
Benzazole
INDOLE (I)
Indole perfume
Indole industrial
Molten indole
Indole, (1-Benzazole)
Indole, 99+% 100GR
Indole, 99+% 25GR
Indole GR for analysis
1H-Indole, 1-Azaindene
NSC 1964
INDOLE GR FOR ANALYSIS 10 G
INDOLE GR FOR ANALYSIS 100 G
Indole@50 μg/mL in Toluene
Indole>
INDOLE FOR SYNTHESIS 100 G
INDOLE FOR SYNTHESIS 25 G