Indole

Chemical reactions of indole

Nitrogen basicity

Although the indole N-1 nitrogen atom has a lone pair of electrons, indole is not basic like amines and anilines because the lone pair is delocalised and contributes to the aromatic system. The protonated form has an pKa of -3.6 so that very strong acids like hydrochloric acid are needed to protonate a substantial amount of indole. The sensitivity of many indolic compounds (e.g. tryptamines) under acidic conditions is caused by this protonation.

Related Topics:
Lone pair - Electron - Basic - Amine - Aniline - PK_a - Hydrochloric acid - Protonate - Tryptamine

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Electrophilic substitution

The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive than benzene. For example, Vilsmeier-Haack formylation of indole{{Ref|2}} will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, nucleophilic substitution of the carbocylic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.

Related Topics:
Electrophilic aromatic substitution - Benzene - Vilsmeier-Haack - Formylation

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

Related Topics:
Gramine - Mannich reaction - Dimethylamine - Formaldehyde

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Nitrogen-H acidity and organometallic indole anion complexes

The N-H proton has a pKa of 21 in DMSO so that very strong bases like sodium hydride or butyl lithium and water-free conditions are needed for complete deprotonation. Salts of the resulting indole anion can react in two ways. Highly 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). For the same reason polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C-3 attack.{{Ref|3}}

Related Topics:
DMSO - Strong base - Sodium hydride - Butyl lithium - Deprotonation - Salt - Ionic - Sodium - Potassium - Electrophile - Covalent - Grignard reagents - Zinc - Polar - Solvent - DMF - DMSO - Toluene

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Carbon acidity and C-2 lithiation

After the N-H proton, the hydrogen at C-2 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 C-2 position. This strong nucleophile can then be used as such with other electrophiles.

Related Topics:
Butyl lithium - Lithium diisopropylamide

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Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole.{{Ref|4}}

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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).

Related Topics:
Oxidized - N-bromosuccinimide - Oxindole

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Cycloadditions of indole

Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intermolecular cycloadditions are not favorable, while intramolecular variants are often high yielding. For example, Padwa et al.{{Ref|5}} have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, while the indole is the dienophile.

Related Topics:
Cycloaddition reaction - Diels-Alder reaction - Strychnine - Diene - Dienophile

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Indoles also undergo intramolecular and cycloadditions.

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Upcoming:

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Color reactions

1H-Indole vs 3H-indole

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