Heterocyclic Chemistry
Heterocyclic Chemistry
N
OS Indoles and
Isoindoles
NH
NH
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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'
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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
Heterocyclic Chemistry
1- Protonation1- Protonation
Electrophilic substitution reactionsElectrophilic substitution reactions
NH
PhCOONO2
NH
NO2
2- Nitration2- Nitration
NH
H+
NH
HH
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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
Heterocyclic Chemistry
II-Nucleophilic substitutionII-Nucleophilic substitution
NH
CH3MgI
N
MgI
Br
NH
/ H3O
N
Br
N
KOH
K
Heterocyclic Chemistry
Nucleophilic substitutionNucleophilic substitution
N
CO2
N
SO2Ph
NH
BuLi
N
SO2Ph SO2Ph
LiCO2H
CO2H
H3O+
Heterocyclic Chemistry
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
Heterocyclic Chemistry
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
Heterocyclic Chemistry
Thanks for your attentionThanks for your attention