Indole is an

aromatic In chemistry, aromaticity is a chemical property of cyclic (ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to sat ...

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon- hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...

with the formula C₈ H₇ N. It has a bicyclic structure, consisting of a six-membered

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen ato ...

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 Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

. As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including

spore In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plants, algae, ...

formation,

plasmid A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; howev ...

stability, resistance to drugs,

biofilm A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular ...

formation, and

virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...

. The

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromati ...

is an indole derivative and the precursor of the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...

serotonin.

General properties and occurrence

Indole is a

solid Solid is one of the four fundamental states of matter (the others being liquid, gas, and plasma). The molecules in a solid are closely packed together and contain the least amount of kinetic energy. A solid is characterized by structura ...

at room temperature. It occurs naturally in human

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...

and has an intense fecal

odor An odor (American English) or odour (Commonwealth English; see spelling differences) is caused by one or more volatilized chemical compounds that are generally found in low concentrations that humans and animals can perceive via their sense ...

. At very low concentrations, however, it has a flowery smell, and is a constituent of many perfumes. It also occurs in

coal tar Coal tar is a thick dark liquid which is a by-product of the production of coke and coal gas from coal. It is a type of creosote. It has both medical and industrial uses. Medicinally it is a topical medication applied to skin to treat psoria ...

. The corresponding

substituent A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and '' functional group'', as well as '' ...

is called indolyl. Indole undergoes

electrophilic substitution Electrophilic substitution reactions are chemical reactions in which an electrophile displaces a functional group in a compound, which is typically, but not always, aromatic. Aromatic substitution reactions are characteristic of aromatic compounds ...

, mainly at position 3 (see diagram in right margin).

Substituted A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...

indoles are structural elements of (and for some compounds, the synthetic precursors for) the tryptophan-derived

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole ─ a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the f ...

alkaloids, which includes the

serotonin and the

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrat ...

, as well as the naturally occurring psychedelic drugs

dimethyltryptamine ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as ...

and

psilocybin Psilocybin ( , ) is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus ''Psilocybe'', such as '' P. azurescens'', '' P. semilanceata'', and '' P.&n ...

. Other indolic compounds include the plant hormone auxin (indolyl-3-acetic acid, IAA), tryptophol, the anti-inflammatory drug

indomethacin Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of pros ...

, and the betablocker pindolol. The name ''indole'' is a

portmanteau A portmanteau word, or portmanteau (, ) is a blend of wordsindigo'' 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 is a deep color close to the color wheel blue (a primary color in the RGB color space), as well as to some variants of ultramarine, based on the ancient dye of the same name. The word "indigo" comes from the Latin word ''indicum'', ...

. Indigo can be converted to isatin and then to oxindole. Then, in 1866,

Adolf von Baeyer Johann Friedrich Wilhelm Adolf von Baeyer (; 31 October 1835 – 20 August 1917) was a German chemist who synthesised indigo and developed a nomenclature for cyclic compounds (that was subsequently extended and adopted as part of the IUPAC or ...

reduced oxindole to indole using

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic t ...

dust. In 1869, he proposed a formula for indole. 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

alkaloid Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...

s, known as indole alkaloids (e.g.,

and auxins), and it remains an active area of research today.

Biosynthesis and function

Indole is

biosynthesized Biosynthesis is a multi-step, enzyme- catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecu ...

in the shikimate pathway via anthranilate. It is an intermediate in the biosynthesis of

, where it stays inside the tryptophan synthase molecule between the removal of 3-phospho-glyceraldehyde and the condensation with

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

. When indole is needed in the cell, it is usually produced from tryptophan by tryptophanase. : Tryptophan biosynthesis (en)

As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including

formation,

stability, resistance to drugs,

formation, and

. A number of indole derivatives have important cellular functions, including

s such as serotonin.

Medical applications

Indoles and their derivatives are promising against

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in w ...

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or deat ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

, migraines,

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

, hypertension, bacterial infections of methicillin-resistant ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posit ...

'' ( MRSA) and even

viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room ...

Synthetic routes

Indole and its derivatives can also be synthesized by a variety of methods. The main industrial routes start from

aniline Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile start ...

via vapor-phase reaction with

ethylene glycol Ethylene glycol ( IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an od ...

in the presence of

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

s: :

Indole from aniline and ethylene glycol 2

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 The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, Vaccine, vaccinate them, or alleviate s ...

, where many pharmaceutical

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

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 Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ac ...

followed by

decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.

Other indole-forming reactions

* Bartoli indole synthesis *

Bischler–Möhlau indole synthesis The Bischler–Möhlau indole synthesis, also often referred to as "The Bischler Indole Synthesis," is a chemical reaction that forms a 2-aryl- indole from an α-bromo- acetophenone and excess aniline; it is named after August Bischler and . D ...

* Cadogan-Sundberg indole synthesis *

Fukuyama indole synthesis The Fukuyama indole synthesis is a versatile tin mediated chemical reaction that results in the formation of 2,3-disubstituted indoles. A practical one-pot reaction that can be useful for the creation of disubstituted indoles. Most commonly tribu ...

* Gassman indole synthesis * Hemetsberger indole synthesis *

Larock indole synthesis The Larock indole synthesis is a heteroannulation reaction that uses palladium as a catalyst to synthesize indoles from an ortho-iodoaniline and a disubstituted alkyne. It is also known as Larock heteroannulation. The reaction is extremely versati ...

* Madelung synthesis * Nenitzescu indole synthesis * Reissert indole synthesis * Baeyer–Emmerling indole synthesis * In the Diels–Reese reaction dimethyl acetylenedicarboxylate reacts with

1,2-diphenylhydrazine Hydrazobenzene (1,2-diphenylhydrazine) is an aromatic organic compound consisting of two aniline groups joined via their nitrogen atoms. It is an important industrial chemical used in the manufacture of dyes, pharmaceuticals, and hydrogen peroxid ...

to an adduct, which in

xylene In organic chemistry, xylene or xylol (; IUPAC name: dimethylbenzene) are any of three organic compounds with the formula . They are derived from the substitution of two hydrogen atoms with methyl groups in a benzene ring; which hydrogens are sub ...

gives dimethyl indole-2,3-dicarboxylate and

. With other solvents, other products are formed: with

glacial acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...

a pyrazolone, and with

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakl ...

quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only ...

Chemical reactions of indole

Basicity

Unlike most

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...

s, indole is not

basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...

: just like pyrrole, the aromatic character of the ring means that the

lone pair In chemistry, a lone pair refers to a pair of valence electrons that are not shared with another atom in a covalent bondIUPAC '' Gold Book'' definition''lone (electron) pair''/ref> and is sometimes called an unshared pair or non-bonding pair. L ...

of electrons on the nitrogen atom is not available for protonation. Strong acids such as

hydrochloric acid Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid. It is a component of the gastric acid in the dig ...

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

ring. The protonated form has a p''K''_a of −3.6. The sensitivity of many indolic compounds (e.g.,

s) under acidic conditions is caused by this protonation.

Electrophilic substitution

The most reactive position on indole for

electrophilic aromatic substitution Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic ni ...

is C3, which is 10¹³ times more reactive than

. 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. : Indole Vilsmeyer-Haack Formylation

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 Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...

. It is the precursor to indole-3-acetic acid and synthetic tryptophan. : Gramine From Indole Scheme

N–H acidity and organometallic indole anion complexes

The N–H center has a p''K''_a of 21 in DMSO, so that very strong bases such as

sodium hydride Sodium hydride is the chemical compound with the empirical formula Na H. This alkali metal hydride is primarily used as a strong yet combustible base in organic synthesis. NaH is a saline (salt-like) hydride, composed of Na+ and H− ions, in ...

or ''n''-butyl lithium and water-free conditions are required for complete

deprotonation Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...

. The resulting organometalic derivatives can react in two ways. The more ionic salts such as the

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosp ...

compounds tend to react with

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that ca ...

s at nitrogen-1, whereas the more

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

magnesium compounds (''indole

Grignard reagents A Grignard reagent or Grignard compound is a chemical compound with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromide ...

'') and (especially)

complexes tend to react at carbon 3 (see figure below). In analogous fashion, polar aprotic

solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...

s such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as

toluene Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) ...

favour C3 attack. : Indole anion reactions

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 Indole Lithiation

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). : Indole NBS Oxidation

Cycloadditions of indole

Only the C2–C3

pi bond In chemistry, pi bonds (π bonds) are covalent chemical bonds, in each of which two lobes of an orbital on one atom overlap with two lobes of an orbital on another atom, and in which this overlap occurs laterally. Each of these atomic orbita ...

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 Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the ey ...

intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular +3and +2cycloadditions. : Indole Cycloaddition Padwa

Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented. One example is the Pictet-Spengler reaction between

derivatives and

aldehydes In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

, which produces a mixture of diastereomers, leading to reduced yield of the desired product.

Hydrogenation

Indoles are susceptible to hydrogenation of the imine subunit.Zhu, G.; Zhang, X. ''Tetrahedron: Asymmetry'' 1998, ''9'', 2415. ImineScope3

References

General references

* * * * *

External links

Synthesis of indoles (overview of recent methods)

at chemsynthesis.com {{Authority control Foul-smelling chemicals Simple aromatic rings Perfume ingredients Heterocyclic compounds with 2 rings Nitrogen heterocycles