Indole

Key takeaways

Indole belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Indole to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Indole from memory before moving on to harder problems.

Reference excerpt

Indole is an organic compound with the formula C6H4CCNH3. 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 Indoles are derivatives of indole where one or more of the hydrogen atoms have been replaced by substituent groups.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.. In plants, IAA is a common plant hormone which is a derivative of Indole.

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, and is a constituent of many perfumes. It also occurs in coal tar. It has been identified in cannabis. It is the main volatile compound in stinky tofu. 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). Substituted 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 melatonin, as well as the naturally occurring psychedelic drugs dimethyltryptamine and psilocybin. Other indolic compounds include the plant hormone auxin (indole-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. In 1866, Adolf von Baeyer reduced oxindole to indole using zinc 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 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. 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.

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.

Detection methods Common classical methods applied for the detection of extracellular and environmental indoles, are Salkowski, Kovács, Ehrlich's reagent assays and HPLC. For intracellular indole detection and measurement genetically encoded indole-responsive biosensor is applicable.

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. According to a 2011 review, all known syntheses fall into 9 categories. The main industrial routes start from aniline via vapor-phase reaction with ethylene glycol in the presence of catalysts:

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.

Other indole-forming reactions Bartoli indole synthesis Bischler–Möhlau indole synthesis Cadogan-Sundberg indole synthesis Fukuyama indole synthesis Gassman indole synthesis Hemetsberger indole synthesis Larock indole synthesis Madelung synthesis Nenitzescu indole synthesis Reissert indole synthesis Baeyer–Emmerling indole synthesis In the Diels–Reese reaction dimethyl acetylenedicarboxylate reacts with 1,2-diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2,3-dicarboxylate and aniline. With other solvents, other products are formed: with glacial acetic acid a pyrazolone, and with pyridine a quinoline.

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. 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.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Indole

Start with the simplest possible case. Write down what Indole claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Indole before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Indole ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Indole

In research: Indole appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Indole in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Indole is common in secondary-school and first-year university syllabi. It links to neighbouring topics 5-HT3 receptor positive allosteric modulators, Foul-smelling chemicals, Heterocyclic compounds with 2 rings, so understanding it makes those chapters shorter.
In everyday life: Look for Indole outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Indole in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Indole means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Indole out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Indole in simple terms?

Indole is an organic compound with the formula C6H4CCNH3. Indole is classified as an aromatic heterocycle.

Why does Indole matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Indole?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Indole.