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Heterocyclic Chemistry


N

OS Indoles and

Isoindoles

NH

NH


IntroductionIntroduction

As a result of the fusion between benzene ring and 5-memebered heterocyclic ring there are two possible aromatic structures differ in position of fusion:

(a) Indole and its analogs (b) Isoindole and its analogs

Xa

b

X=

NIndole

SBenzo[b]thiophene

OBenzo[b]furan

Xa

b

Isoindole

Benzo[c]thiophene

Benzo[c]furan

c


Resonance structures of indole Resonance structures of indole and its analogsand its analogs

It appears from these resonance structures It appears from these resonance structures that all C atomsthat all C atoms bear – ve. charge while the hetero bear – ve. charge while the hetero atom bears atom bears

+ ve. charge+ ve. charge

X X X X

X X X X

X

XXX

X X


Synthesis of IndoleSynthesis of Indole

NH

NH2

+

R1

R2O

H+

- NH3NH

R2

R11.1. Fischer SynthesisFischer Synthesis

2.2. Madelung SynthesisMadelung Synthesis

NH

NH

R

R

ONaNH2 or RONa

200 - 300 C°

NH

NH

R

R

O BuLi / THF

R'R'


Pyrroles, indoles and isoindoles have a Pyrroles, indoles and isoindoles have a partially positive nitrogen, and partially partially positive nitrogen, and partially negative carbons therefore these carbons negative carbons therefore these carbons react easily with electrophilic reagents, and react easily with electrophilic reagents, and resist substitution by nucleophilic reagents.resist substitution by nucleophilic reagents.

Indoles, like pyrroles are Indoles, like pyrroles are non basic due to if protonation on nitrogen occurs, the aromaticity would be lost. Similar to pyrrole protonation occurs at ring carbons

The main differences between indole and The main differences between indole and pyrrole include:pyrrole include:

1.1. The reactivity order in the electrophilic The reactivity order in the electrophilic substitutionsubstitution

2.2. the regioselectivity in electrophilic the regioselectivity in electrophilic substitutionsubstitution

Comparison with pyrroleComparison with pyrrole


1. 1. The reactivity order in the The reactivity order in the electrophilic substitutionelectrophilic substitution

Generally Generally indole and its analogsindole and its analogs are are less less reactive compared to the corresponding reactive compared to the corresponding single heterocyclicsingle heterocyclic rings therefore the rings therefore the electrophilic aromatic substitution is slower electrophilic aromatic substitution is slower with these compoundswith these compounds

This can be attributed to the fact that the This can be attributed to the fact that the share of each carbon atom of the –ve charge share of each carbon atom of the –ve charge in these compound is lesser due to in these compound is lesser due to delocalization of the charge on the benzene delocalization of the charge on the benzene (as appeared from the resonance structure (as appeared from the resonance structure of indoleof indole..

Reactivity order in electrophilic aromatic substitution:N

H

>O

>S

>NH


Fusion of the benzene ring with heterocyclic rings alter the regioselectivity from the α- position in the single heterocylic compounds (e.g. pyrrole) to β- position in indole

This This ββ preference in case of indole can be preference in case of indole can be attributed to the extra stability attributed to the extra stability experienced by the cations resulted from experienced by the cations resulted from ββ attack (cation I) over that resulted from attack (cation I) over that resulted from αα attack (cation II). Where the attack at the attack (cation II). Where the attack at the ββ position does not disturb the aromaticity of position does not disturb the aromaticity of the benzene ring thus the +ve. charge in the benzene ring thus the +ve. charge in the intermediate is delocalized round the the intermediate is delocalized round the benzene ring and gets more stabilizationbenzene ring and gets more stabilization..

2. The regioselectivity in E. 2. The regioselectivity in E. substitutionsubstitution


2. The regioselectivity in E. . The regioselectivity in E. substitutionsubstitution

XX

EH attackattack

X

E

H

More preferred the 6-membered ring is aroamtic

Cation ICation II


1- Protonation1- Protonation

Electrophilic substitution reactionsElectrophilic substitution reactions

NH

PhCOONO2

NH

NO2

2- Nitration2- Nitration

NH

H+

NH

HH


Electrophilic substitution Electrophilic substitution reactionsreactions

NH

Br2

Dioxan / 0°C NH

NH

BrI

I2

EtOH

3- Halogenations3- Halogenations

4- Sulphonation4- Sulphonation

NH

NHN

H

SO3HN

SO3-

SO3-

NH

SO3Me

H+

Pyridine / heat

CH2N2


I-Electrophilic substitution I-Electrophilic substitution reactionsreactions

Ac2O

NH

NN

Ac

AcOH /

O CH3

OCH3

Ac2O

Na Ac /

5- Acylation5- Acylation

6- Alkylation6- Alkylation

N

Me

NH

MeOH / 110°C

Me

Me

Me

I

1,2,3,3-Tetramethyl-3H-indolium iodide

Excess MI


II-Nucleophilic substitutionII-Nucleophilic substitution

NH

CH3MgI

N

MgI

Br

NH

/ H3O

N

Br

N

KOH

K


Nucleophilic substitutionNucleophilic substitution

N

CO2

N

SO2Ph

NH

BuLi

N

SO2Ph SO2Ph

LiCO2H

CO2H

H3O+


Oxidation of IndoleOxidation of Indole

NH

NBS

N

Br

H2O

NH

Br

OH

H

- HBr

NH

OH

NH

O

Oxindole

Reduction of IndoleReduction of Indole

NH

Zn / HClNi / HCl

NH

NH

IndolineOctahydroindole


Diels Alder Reaction

Indole and its analogs Indole and its analogs do not undergo do not undergo D.A.R.D.A.R. while while isoindole and its analogs doisoindole and its analogs do thus this reaction is used to differentiate thus this reaction is used to differentiate between these compoundsbetween these compounds..

X + O

O

O

O

O

O

X


Thanks for your attentionThanks for your attention