Heterocyclic Chemistry

Heterocyclic Chemistry

N

OS Benzopyridines

Quinoline and Isoquinoline:

Heterocyclic Chemistry

Introduction:Introduction:

N

N

QuinolineBenzo[b]pyridine

IsoquinolineBenzo[c]pyridine

N

Quinolizinium ionBenzo[a]pyridinium

Heterocyclic Chemistry

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 10π-electron 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

Introduction :Introduction :

Resonance structures of Quinoline and Resonance structures of Quinoline and isoquinolineisoquinoline

Heterocyclic Chemistry

Both ring systems occur naturally and were originally isolated from coal tar.

Occurrence of quinolineOccurrence of quinoline

Heterocyclic Chemistry

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 biosynthesisit serves some interest in the study of certain yeasts

Occurrence isoquinolineOccurrence isoquinoline

BasicityBasicity

Heterocyclic Chemistry

Quinoline and isoquinoline are Quinoline and isoquinoline are weak bases weak bases but slightlybut slightly more basic than pyridine (why?) more basic than pyridine (why?) but but less basic than anilinesless basic than anilines since the since the nitrogen in quinoline and isoquinoline is nitrogen in quinoline and isoquinoline is more electronegative being spmore electronegative being sp22 hybridized hybridized compared to spcompared to sp33 hybridized nitrogen of hybridized nitrogen of anilines. anilines.

Preparation of QuinolinePreparation of Quinoline

1. Friedländer Synthesis

2-Aminobenzene-2-Aminobenzene-carboxaldehydecarboxaldehyde

Enolizable Enolizable carbonyl carbonyl

compoundcompound

85%85%

HH22O, NaOH, 50O, NaOH, 50 ºC ºC

Paul Friedländer (1857 - 1923)

CH

O

NH2

+

H

O

N

2- Skraup’s Synthesis2- Skraup’s Synthesis

CH2OH

CHOH

CH2OH

CH2

CH

C

OH

Glycerol Acroline

NH2

NH

CH2

CH2

H

O

-H2O

NH

C6H5NO2

Oxidation

-H2O

N

General Equation:General Equation:

Preparation of QuinolinePreparation of Quinoline

Bischler-Napieralski SynthesisBischler-Napieralski Synthesis

POCl3, P2O5, 100 ºC

Pd, 200 ºC,- H2

-H-H22OONH

O

R

H+

N

R

N

R

Preparation of IsoquinolinePreparation of Isoquinoline

Heterocyclic Chemistry

The nitrogen of the quinoline and isoquinoline has The nitrogen of the quinoline and isoquinoline has deactivating effect on the ring towards electrophilic deactivating effect on the ring towards electrophilic substitutionsubstitution as in case of pyridine. However as in case of pyridine. However electrophilic substitution of quinoline and isoquinoline electrophilic substitution of quinoline and isoquinoline requires less vigorous conditions than pyridine.requires less vigorous conditions than pyridine.Consequently Consequently electrophilic aromatic substitution electrophilic aromatic substitution occurs at the benzene ring at positions 5 and 8.occurs at the benzene ring at positions 5 and 8.

Electrophilic aromatic substitution in quinoline and Isoquinoline

Electrophilic aromatic substitution in quinoline and isoquinoline

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

Heterocyclic Chemistry

Quinoline and isoquinoline undergo facile Quinoline and isoquinoline undergo facile

nucleophilic substitution as in pyridine. nucleophilic substitution as in pyridine.

Quinoline undergoes Quinoline undergoes Chichibabin reaction Chichibabin reaction to give 2-to give 2-

amino- quinoline while isoquinoline undergoes amino- quinoline while isoquinoline undergoes

Chichibabin reaction to give 1-amino isoquinoline . Chichibabin reaction to give 1-amino isoquinoline .

Isoquinoline undergoes substitution faster than Isoquinoline undergoes substitution faster than

quinoline. The reaction proceeds in a manner quinoline. The reaction proceeds in a manner

analogues to pyridine.analogues to pyridine.

Nucleophilic aromatic substitution in quinolines and Isoquinolines

Reduction of quinolineReduction of quinoline

Heterocyclic Chemistry

The pyridine ring is more easily reducedThe pyridine ring is more easily reduced Quinoline can be selectively reduced at 1,2-bond by Quinoline can be selectively reduced at 1,2-bond by

reaction with lithium aluminium hydride but the 1,2-reaction with lithium aluminium hydride but the 1,2-dihydro quinolines are unstable and disproportionate dihydro quinolines are unstable and disproportionate easily to give quinoline and 1,2,3,4-easily to give quinoline and 1,2,3,4-tetrahydroquinoline.tetrahydroquinoline.

Quinoline can be converted to 1,2,3,4-Quinoline can be converted to 1,2,3,4-tetrahydroquinoline by catalytic hydrogenation or with tetrahydroquinoline by catalytic hydrogenation or with tin and hydrochloric acidtin and hydrochloric acid

The pyridine ring is more easily reducedThe pyridine ring is more easily reduced Isoquinoline can also be converted to 1,2-dihydro Isoquinoline can also be converted to 1,2-dihydro

or 1,2,3,4-tetrahydroisoquinoline with diethyl or 1,2,3,4-tetrahydroisoquinoline with diethyl aluminium hydride and sodium-ethanol, aluminium hydride and sodium-ethanol, respectivelyrespectively

Reduction of Reduction of isoquinolineisoquinoline

Quinoline and isoquinoline Quinoline and isoquinoline undergo oxidative undergo oxidative cleavagecleavage with alkalian potassium permangnate to with alkalian potassium permangnate to give pyridine-2,3-dicarboxylic acid and pyridine-3,4-give pyridine-2,3-dicarboxylic acid and pyridine-3,4-dicarboxylic acid respectively.dicarboxylic acid respectively.

However, pyridine-2,3-dicarboxylic acid is not However, pyridine-2,3-dicarboxylic acid is not stable and undergoes decarboxylation to give stable and undergoes decarboxylation to give nicotinic acid. Quinoline and isoquinoline both form nicotinic acid. Quinoline and isoquinoline both form N-oxides when treated with hydrogen peroxide in N-oxides when treated with hydrogen peroxide in acetic acid or with organic peracids.acetic acid or with organic peracids.

Oxidations

Heterocyclic Chemistry

Thanks for your attentionThanks for your attention