Chemistry of Indole

Session Objectives

By the end of this
session, students will be able to:

• Discuss the chemistry, reactivity, properties and method
of synthesis of Indole

Chemistry
of Indole

• Indole was first prepared by Baeyer in 1866 by zinc dust
distillation of oxindole

• Found in coal tar and in essential oils (jasmine oil,
orange oil) of many plants

• Also occurs in amino acids (tryptophan), plant growth
hormone (indole-3-acetic acid), alkaloids (brucine, psilecene) and dye stuff
(indigo)

• Ring comprises of benzene ring fused to 2- and 3-
positions of a pyrrole nucleus

• IUPAC name is 1H-benzo[b]pyrrole

• Positions 2- and 3- can be designated as α and β, 3a and 7a are bridgehead carbons

• Tautomeric forms of indole, known as indolenines

Physical properties of Indole:

• Colorless crystalline solids with melting point 52 ⁰C
and boiling point 254 ⁰C

• Soluble in most organic solvents

• Pure indole has a very pleasant smell and used as perfume
base

• Impure indole and skatole (2-methylindole) have unpleasant
odor

• Many indoles are quite stable in air

• With exception of simple alkyl group at 2-position,
oxidizes readily even when stored in a dark brown bottle

• Responds to Ehrlich test and gives blue colour

• Planar molecule with a conjugated system of 10π-electrons, two from nitrogen and
8 from carbon atoms- π
excessive molecule

Synthetic methods of Indole:

1) Fischer-Indole synthesis:

• Most widely investigated method

• Involves acid catalyzed rearrangement of a phenylhydrazone
of an aldehyde or ketone with the elimination of molecule of ammonia

• Conventional catalysts employed are zinc chloride,
polyphosphoric acid

2) Madelung synthesis:

• Involves cyclic dehydration of acyl o-toluidine in the
presence of strong base and at high temperature

3) Microwave irradiation:

• Phenylhydrazine and acetone on treatment with clay under
microwave irradiation gives an excellent yield (86%) of 2-methylindole

Chemical properties of Indole:

1) Reaction of Indole with acids:

• Indole is very weak base

• In dilute acid, β-protonated 3H-indolium (1) cation is formed

• In strong acid solutions, proton can be added to 1- and 2-
positions

2) Electrophilic substitution of Indole:

• Indole is a π-excessive
molecule and electron density on its carbon atoms is greater than in benzene
molecule

• Reacts easily with electrophile and attack takes place in
heterocyclic ring

• Highly regiospecific for position-3  

3) Halogenation of Indole:

• Mild reagents are used for halogenation

• For chlorination, sulfuryl chloride, chlorine,
N,N-dichlorocarbonate, phosphorus pentachloride and tert. Butyl hypochloride
have been used

• For bromination, Br₂/dioxane/0 ⁰C or
Br₂/CH₃COOH or NBS

• If 3^rd position is occupied by
electron-withdrawing groups then attack occurs in benzene ring