Heterocyclic Chemistry
N
S
O
Benzopyridines
Quinoline and
Isoquinoline:
Heterocyclic Chemistry
Introduction:
N
N
Quinoline
Benzo[b]pyridine
Isoquinoline
Benzo[c]pyridine
N
Quinolizinium ion
Benzo[a]pyridinium
Heterocyclic Chemistry
Introduction :
 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).
 Both quinoline and isoquinoline are planar 10πelectron aromatic systems in which all atoms are
sp2 hybridized and contribute one electron each in
orthogonal p-orbitals for delocalization over the
rings with resonance energies of 198 and 143
KJ/mol respectively
Heterocyclic Chemistry
Resonance structures of Quinoline and isoquinoline
Occurrence of quinoline
 Both
ring systems occur naturally and were
originally isolated from coal tar.
Heterocyclic Chemistry
Occurrence isoquinoline
Emetine is a drug used as both an
anti-protozoal and to induce vomiting
It is a toxic crystalline alkaloid
It inhibits protein synthesis and
may inhibit ascorbic acid
biosynthesis
it serves some interest in the study of
certain yeasts
Heterocyclic Chemistry
Basicity

Quinoline and isoquinoline are weak bases but
slightly more basic than pyridine (why?) 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.
Heterocyclic Chemistry
Preparation of Quinoline
1. Friedländer Synthesis
O
O
CH
+
H2O, NaOH, 50 ºC
H
N
NH2
2-Aminobenzenecarboxaldehyde
Enolizable
carbonyl
compound
85%
Paul Friedländer
(1857 - 1923)
Preparation of Quinoline
2- Skraup’s Synthesis
General Equation:
H
CH2
CH 2OH
CHOH
CH 2OH
Glycerol
O
CH 2
NH2
CH
-H2O
CH 2
C
H
N
H
O
Acroline
-H2O
C6H5NO2
Oxidation
N
N
H
Preparation of Isoquinoline
Bischler-Napieralski Synthesis
POCl3, P2O5, 100 ºC
NH
R
O
H
+
N
-H2O
Pd, 200 ºC,
- H2
R
N
R
Electrophilic
aromatic substitution
Isoquinoline
in
quinoline
and
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
Electrophilic aromatic substitution in quinoline
and isoquinoline
Electrophilic
aromatic substitution
Isoquinoline
in
quinoline
 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
and
Nucleophilic aromatic substitution in quinolines and
Isoquinolines
 Quinoline
and
isoquinoline
undergo
facile
nucleophilic
substitution as in pyridine.
 Quinoline undergoes Chichibabin reaction to give 2-aminoquinoline 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.
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
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
Oxidations
 Quinoline and isoquinoline undergo oxidative cleavage with
alkalian potassium permangnate to give pyridine-2,3dicarboxylic
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.
Thanks for your attention
Heterocyclic Chemistry