INDOLE

Mrs. Hemalatha Y R
Asst. Professor
Dept. of Pharmaceutical Chemistry
NCOPS
Hemalatha Y R, NCOPS
Contents

• Synthesis,
• reactions and
• medicinal uses of Indole

Hemalatha Y R, NCOPS
INDOLE

• Indole consists of a benzene ring fused to the α,β-position of a pyrrole ring.

• It derives its name from the fact that it is first obtained by distilling oxindole,
a degradation product of Indigo with Zinc dust.
• It occurs in a coal tar and oils of Jasmine and Orange blossoms.

Hemalatha Y R, NCOPS
Synthetic Methods

• By Lipp synthesis: In this method, O- amino-ω- chlorostyrene is heated with

sodium ethoxide at 160-170°C to yield Indole.

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Synthetic Methods Contd…

• By Fischer Indole Synthesis: In this method, Pyruvic acid is first treated

with Phenyl hydrazine to form corresponding Phenyl hydrazone. Then
Phenyl hydrazone is heated with anhydrous zinc chloride or Phosphoric acid
to give Indole 2-carboxylic acid which on decarboxylation yields Indole.

Hemalatha Y R, NCOPS
Synthetic Methods Contd…

• By Reissert Synthesis: In this method, o-Nitro toluene is condensed with

diethyl oxalate in presence of a base to form a 2- keto ester. This is then
reduced with zinc and glacial acetic acid to give Indole 2-carboxylic acid
which on decarboxylation yields Indole.

Hemalatha Y R, NCOPS
Synthetic Methods Contd…

• From o-Toluidine: This involves treatment of o- toluidine with formic acid

to form N-formyl o-Toluidine. This undergoes dehydration on heating with
Potassium t-butoxide to yield Indole.

Hemalatha Y R, NCOPS
Synthetic Methods Contd…

• From o-Nitrophenyl acetaldehyde: This involves reduction of o- Nitro

phenyl acetaldehyde with iron powder and Sodium bi sulphite to form o-
amino phenyl acetaldehyde which cyclizes spontaneously to yield Indole.

Hemalatha Y R, NCOPS
Structure of Indole
• Like Pyrrole, Indole is a planar molecule with SP2
hybridized atoms. All ring atoms in Indole (the
nitrogen atom and 8 carbon atoms) are SP2
hybridized.
• SP2 hybrid orbitals overlap with each other and
with S atomic orbitals Hydrogen atom forming C-
C, C-N, C-H and N-H σ bonds. All these σ bonds
lie in one planar.
• Also each carbon atom and Nitrogen atom possess
an unhybridized P atomic Orbital and these are
perpendicular to plane of σ bonds. The P orbital
on carbon atom contain one electron each and P Formation of σ bonds in Indole.
orbital on nitrogen atom contain two electron.

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Hybridization
• The lateral overlap of these P orbitals produce a
π molecular orbital containing ten electrons, an
arrangement.
• The unhybridized P orbital in indole overlap with
each other to form a delocalized π molecular
P-P orbital orbital above and below the plane containing σ
overlap bonds.
• Indole satisfies Huckle’s rule i.e, (4n+2) π
electrons.
• So Indole is an aromatic compound, it will
undergo resonance.

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Resonance structures or Canonical forms
• According to resonance theory, Indole is considered to be hybrid of
following resonance structures.
• The result of donation of electrons by nitrogen atom, carbon atoms of Indole ring
have gained electron density. Thus carbon atom of ring bears negative charge and
Nitrogen atom positive charge.

Hemalatha Y R, NCOPS
Physical Properties of Indole

• State- Colorless solid

• Melting point - 52°C
• Odour- Pleasant
• Solubility- Sparingly soluble in cold water, Soluble in hot water and freely
soluble in organic solvents.

Hemalatha Y R, NCOPS
Chemical Properties of Indole

• It is very reactive behaves both as an acid and base.

• Basic Character: Like Pyrrole, Indole is a weak base and weak acid. It is
polymerized with dilute HCl to give a crystalline hydrochloride.

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Chemical Properties of Indole

• Acidic Character: Indole is not only a weak base and also acts as a weak
acid. It reacts with solid potassium hydroxide (KOH) and Grignard reagents.

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Chemical Reaction

• Electrophilic aromatic substitution: Unlike Pyrrole, indole undergoes

Electrophilic aromatic substitution at C-3.

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Chemical Reaction • Electrophilic aromatic
substitution:
• Unlike Pyrrole, indole undergoes
Electrophilic aromatic
substitution at C-3.
• The attack of electrophile to
aromatic ring, which takes place
to yield the most stable
intermediate carbocation.
• Attack at C3 position yields a
carbocation that hybrid structure
of I and II.
• Attack at C2 position yields a
carbocation hybrid structure of
III.

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Chemical Reaction Contd..
• Nitration: Indole undergoes nitration at low temperature with ethyl nitrate in
presence of sodium ethoxide to give 3-Nitroindole.

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Chemical Reaction Contd..
• Sulphonation: Indole is sulphonated with sulphurtrioxide in presence of
Pyridine at 110°C to yields Indole 3- sulphonic acid.

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Chemical Reaction Contd..
• Bromination: It is carried out with Bromine in dioxane at 0°C to give 3-
bromo indole.

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Chemical Reaction Contd..
• Friedel Craft’s acylation reaction: Indole is acetylated with acetyl chloride
in presence of Tin chloride at 250°C to give 3-acetyl Indole.

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Chemical Reaction Contd..
• Friedel Craft’s alkylation reaction: Indole reacts with Methyl iodide in
presence of Dimethyl sulfoxide at 80°C to give 3-methy Indole.

• Reimer Tiemann Reaction(Formylation): Indole reacts with chloroform in

presence of alkali to yield Indole 3- aldehyde and 3- Chloro quinoline.

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Chemical Reaction Contd..
• Diazo Coupling reaction: Indole couples with benzene diazonium chloride
in a weakly acidic solution to give 3-Phenyl diazo Indole.

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Chemical Reaction Contd..

• Oxidation reaction: It is oxidized with ozone in presence of formamide to

give 2- formamido benzaldehyde.

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Chemical Reaction Contd..

• Reduction reaction: Mild reduction of Indole with Zinc or tin and HCl to
give 2,3- Dihydro indole (Indoline). Catalytic reduction with hydrogen in
presence of Nickel at 250°C to yield octahydro indole.

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Medicinal Compounds:

• Indomethacin:
• Uses: It is a Non steroidal Anti Inflammatory drug. It is
used to relieve moderate to severe pain, tenderness,
swelling, and stiffness caused by osteoarthritis, rheumatoid
arthritis and spondylitis.
• Sumatriptan:
• Uses: It is used to treat migraine. To relieve head ache,
pain.

Hemalatha Y R, NCOPS