INDOLES
Group - 4
Presented By
Presented To
1024032702
1024032701 Dr. Md. Nurnobi Rashed
1024032711 Assistant Professor
1024032706 Department of
1024032710 Chemistry,BUET
Department of Chemistry
Bangladesh University of Engineering and
Technology(BUET)
INTRODUCTION
Indole is a heterocyclic aromatic organic compound.
Indole is a benzo[b]pyrrole formed by the fusion of benzene ring to the 2,3 positions of pyrrole
nucleus.
Molecular formula: C₈H₇N
Structure: Benzene ring fused to a pyrrole ring.
Found in nature (e.g., tryptophan, plant hormones).
Commercially indole is produced from coal tar .
Indole
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PROPERTIES
Physical Properties: Chemical Properties:
• Appearance: Colorless to pale
• Aromatic character
yellow solid • Electron-rich nitrogen makes it
• Melting point: ~52°C
reactive in electrophilic substitution
• Boiling point: ~254°C
• Slightly soluble in
water, soluble in organic
solvents
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SYNTHESIS
Fischer Indole Synthesis:
This reaction was discovered in 1983 by Emil Fischer and so far remained the most extensively used method of preparation
of indoles.
The synthesis involves cyclization of arylhydrazones under heating conditions in presence of protic acid or Lewis acids such
as ZnCl2, PCl3, FeCl3, TsOH, HCl, H2SO4, PPA etc.
The starting material arylhydrazones can be obtained from aldehydes, ketones, keto acids, keto esters and diketones etc.
Reaction produces 2,3-disubtituted products. Unsymmetrical ketones can give a mixture of indoles.
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Fischer Indole Synthesis Mechanism
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SYNTHESIS
Bischler Indole Synthesis:
Reaction involves acidic treatment of 2-arylamino-ketones (produced from a 2–halo-ketone and an arylamine) to bring
about electrophilic cyclisation onto the aromatic ring .Often result in mixtures of products via rearrangements.
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REACTIONS OF INDOLE
Electrophilic Substitution Reactions:
Indole is a π-excessive (electron rich) heterocycle, so their chemistry is mostly dominated by electrophilic substitution
reactions. The pyrrole ring in indole is very electron rich, in comparison to the benzene ring, therefore, electrophile’s attack
always takes place in the five-membered ring, except in special circumstances.
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The preferred site of electrophilic substitution is C-3, because the cation formed by the C-3 attack of electrophile is more
stable than that of the C-2 attack. In case of C-3 attack, transition intermediate formed has positive charge adjacent to N
atom that can be stabilized by the delocalization of lone pair of electrons of nitrogen. Whereas, the positive charge of
transition intermediate formed by the C-2 attack, cannot be stabilized without disturbing aromaticity of benzene ring. If C-3
position is occupied, then electrophilic substitution takes place at C-2 and if both of them are occupied then electrophile
attacks at C-6 position.
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ELECTROPHILIC REACTIONS OF INDOLE
Nitration: Nitration of indole is carried out using non-acidic nitrating agent such as benzoyl nitrate and ethyl nitrate.
Common nitrating reagent, mixture of acids (H2SO4 + HNO3) does not used in the nitration of indole .Because in the
presence of common nitrating agent (H2SO4 + HNO3), acid-catalysed polymerisation of indole occur.
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Nitration of 2-Methylindole under acidic conditions using nitric/sulfuric acids gives C-5 –NO2
substituted product.
The absence of attack on the heterocyclic ring can be explained: 2-methylindole undergoes protonation at C-3 under
strongly acidic condition and this leads to deactivation of pyrrole ring for further electrophilic attack. The regioselectivity
of attack, para to the nitrogen, may mean that the actual moiety attacked is a hydrogen sulfate adduct of the initial 3H-
indolium cation.
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Sulphonation:
Sulfonation of indole, at C-3, is performed using the pyridine–sulfur trioxide complex in hot pyridine.
Halogenation: 3-Halo- and 2-halo-indoles are unstable therefore, must be utilised immediately after their
preparation.
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Alkylation:
Indoles do not react with alkyl halides at room temperature. Indole itself begins to react with methyliodide in
dimethylformamide at about 80°C, to give main product 3-methyl indole(Skatole). As the temperature is
increased, further methylation takes place resulting in 1,2,3,3- tetramethyl-3H-indolium iodide.
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SPECIAL REACTION OF INDOLE
Mannich reaction (reaction with iminium ions):
Indole reacts with a mixture of formaldehyde and dimethylamine at 0°C in neutral conditions to give N-substituted
dimethylaminomethyl indole. Under neutral conditions at higher temperature or in acidic medium acetic acid, N-substituted
dimethylaminomethyl indole gets transformed into thermodynamically more stable 3(dimethylaminomethyl)indole,
gramine. Gramine can be directly prepared in high yield, by reaction of indole with formaldehyde and dimethylamine in
acetic acid.
The Mannich reaction is useful because the product gramine can be used as intermediates to access various 3-
substituted indoles.
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SYNTHESIS OF DRUG FROM INDOLE
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QUESTION
1. Complete the following reactions :
i. +
ii.
2. Outline a synthetic route for preparing indole starting from benzene.
3. Why common Nitrating agent (H2SO4 + HNO3) does not used in the nitration of indole ?
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4.
Route-1
Route-2
2-nitroindole
Predict the most probable route for the preparation of nitro derivative of indole with
proper evidence.
5.
Give the possible reason for the formation of (C-5 –NO2) substituted product.
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6. Prepare Gramine from Indole with possible reaction mechanism.
7. Complete the following reactions :
?
i.
?
ii.
iii. Skatole from Indole.
8. Write down the steps involve in the synthesis process of ondansetron drug.
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