Heterocyclic Chemistry

N
S Benzopyridines
O Quinoline and
Isoquinoline:

1
Heterocyclic Chemistry
 Introduction :

N
N

Quinoline Isoquinoline
Benzo[b]pyridine Benzo[c]pyridine

 Quninoline and isoquinoline are two fused

heterocycles derived by fusion of pyridine ring
with a benzene ring.
 Quinoline is high boiling liquid (b.p. 237°C) and
smells like pyridine while isoquinoline is a low
melting solid (m.p. 26.5°C, b.p. 243°C).

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Heterocyclic Chemistry
 Occurrence of quinolone and isoquinoline

Quinoline alkaloids

R=OMe: Quinine (Cinchonidine epimer at C-9)

H
HO N
R

3
Emetine is a drug used asan anti-protozoal Heterocyclic Chemistry
 Basicity

 Quinoline and isoquinoline are weak bases but

slightly more basic than pyridine but less basic
than anilines since the nitrogen in quinoline and
isoquinoline is more electronegative being sp2
hybridized compared to sp3 hybridized nitrogen of
anilines.

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Heterocyclic Chemistry
 Preparation of Quinoline

1. Friedländer Synthesis
O

CH O H2O, NaOH, 50 ºC
+
H
N
NH2

Enolizable 85%
2-Aminobenzene- carbonyl
carboxaldehyde compound

Paul Friedländer
(1857 - 1923) 5
Heterocyclic Chemistry
 Preparation of Quinoline

2- Skraup’s Synthesis
General Equation:

CH2
CH 2OH O
NH2 CH 2
CH
CHOH
-H2O CH 2
C
CH 2OH N
H O H

Glycerol Acroline
-H2O

C6H5NO2

Oxidation
N N 6
Heterocyclic Chemistry H
 Preparation of Isoquinoline

Bischler-Napieralski Synthesis

POCl3, P2O5, 100 ºC

NH N
R -H2O

O
+ Pd, 200 ºC, R
H - H2

R
 Electrophilic aromatic substitution in quinoline and
Isoquinoline

The nitrogen of the quinoline and isoquinoline has deactivating

effect on the ring towards electrophilic substitution as in case
of pyridine. However electrophilic substitution of quinoline and
isoquinoline requires less vigorous conditions than pyridine.
Consequently electrophilic aromatic substitution occurs at the
benzene ring at positions 5 and 8. Heterocyclic Chemistry 8
Electrophilic aromatic substitution in quinoline
and isoquinoline

9
Heterocyclic Chemistry
 Electrophilic aromatic substitution in quinoline and
Isoquinoline

 However, nitration can take place at pyridine ring using

nitric acid and acetic anhydride at position 3 in case of
quinoline and at position 4 in case of isoquinoline

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Heterocyclic Chemistry
 Nucleophilic aromatic substitution in quinolines and
Isoquinolines
 Quinoline and isoquinoline undergo facile nucleophilic
substitution as in pyridine.
 Quinoline undergoes Chichibabin reaction to give 2-amino-
quinoline while isoquinoline undergoes Chichibabin reaction to
give 1-amino isoquinoline . Isoquinoline undergoes substitution
faster than quinoline. The reaction proceeds in a manner
analogues to pyridine.

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Heterocyclic Chemistry
 Reduction of quinoline
 The pyridine ring is more easily reduced
 Quinoline can be selectively reduced at 1,2-bond by reaction
with lithium aluminium hydride but the 1,2-dihydro quinolines
are unstable and disproportionate easily to give quinoline and
1,2,3,4-tetrahydroquinoline.
 Quinoline can be converted to 1,2,3,4-tetrahydroquinoline
by catalytic hydrogenation or with tin and hydrochloric acid

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Heterocyclic Chemistry
 Reduction of isoquinoline
 The pyridine ring is more easily reduced
 Isoquinoline can also be converted to 1,2-dihydro
or 1,2,3,4-tetrahydroisoquinoline with diethyl
aluminium hydride and sodium-ethanol,
respectively

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Heterocyclic Chemistry
 Oxidations
 Quinoline and isoquinoline undergo oxidative cleavage with
alkalian potassium permangnate to give pyridine-2,3-
dicarboxylic acid and pyridine-3,4-dicarboxylic acid
respectively.
 However, pyridine-2,3-dicarboxylic acid is not stable and
undergoes decarboxylation to give nicotinic acid. Quinoline
and isoquinoline both form N-oxides when treated with
hydrogen peroxide in acetic acid or with organic peracids.

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Heterocyclic Chemistry