Chemistry, Properties and Synthesis of Quinoline and Isoquinoline

Chemistry of Quinoline &
Isoquinoline

Session Objectives

By the end of this
session, students will be able to:

• Discuss various methods of synthesis of Quinoline and
Isoquinoline

• Discuss the chemistry, reactivity, properties of Quinoline
and Isoquinoline

Chemistry
of Quinoline

• Quinoline structure obtained by ortho-condensation of
benzene ring with pyridine

• Also called as azanaphthalene or benzopyridine

• First isolated by Runge in 1834, from coal tar bases

• In 1842 by Gerhardt from the alkaline pyrolysis of
cinchonine, an alkaloid related to quinoline

• Numbering starts from nitrogen atom, which is assigned
postion-1

• Dehydrogenation of quinolone yields 1,2-dihydroquinoline
(1), 1,2,3,4-tetrahydroquinoline (2) and decahydroquinoline (3)

Physical properties of Quinoline:

• Quinoline is a colorless hygroscopic liquid with boiling
point 2370C

• Has a characteristic smell resembling that of pyridine

• On exposure to air it develops a yellow color

• Miscible with organic solvents and soluble in water to
extent of 0.7%

• Highly aromatic

• Weakly basic with pKa of 4.94

• Presence of electron-donating groups at 2nd and
4th position increase the basicity, 2-methylquinoline pKa 5.83

Synthetic methods of Quinoline:

1) The Skraup
synthesis
:

• Most important method of preparation

• Involves an aniline derivative is heated with glycerol,
conc. Sulfuric acid and an oxidizing agent (nitrobenzene).

2) The
Friedlander synthesis
:

• Most useful method

• o-aminobenzaldehyde or o-aminoacetophenone is condensed
with aldehyde or ketone when  refluxed in
presence of alcoholic sodium hydroxide solution to quinoline

• First step is the formation of Schiffs base followed by
ring closure to quinoline by a Knoevenagel condensation.

Chemical properties of Quinoline:

• Because of fusion of benzene ring, properties of both
benzenoid and pyridinoid compounds frequently manifest themselves

1) Reaction
with acids
: quinoline is a weak base and gets protonated on ring nitrogen
with mineral acids to form water soluble salts

2) Electrophilic
substitution
: electron rich nitrogen atom is main center for attack of
electrophiles

• Also heteroatom has considerable deactivating effect on
ring towards electrophilic attack

• It requires severe conditions though less than pyridine

• C-5 and C-8 positions are preferred for electrophilic
attack

Halogenation:
depends on the nature of reagent employed

Chlorination
(SO2Cl2) yields 3-chloroquinoline

Bromination (Br2,
CCl4) yields 3-bromoquinoline

• In the presence of strong acids (Br2, Ag2SO4)
give a mixture of 5- and 8-bromoquinolines

Reaction with
nucleophiles:
attack by nucleophile occurs on pyridine ring of quinoline
and position-2 is preferred

• If position-2 is occupied the attack may takes place at
4-position

• Chichibabin reaction is example of normal attack at C-2

Chemistry
of Isoquinolines

• Obtained by the fusion of pyridine with a benzene ring

• First isolated by Hoogewerff and Dorp from the quinoline
fraction of coal tar in 1885

• Isoquinoline doesn’t occur free in nature but abundantly
in several alkaloids

• It is called as 2-azanaphthalene or benzo [c] pyridine

• Numbering same as quinoline, but the nitrogen atom is
assigned postion-2

• Because of similar in structure, both show close
relationship in physical and chemical properties

Physical properties of Isoquinolines:

• Colorless solid with melting point 243 0C

• Smell resembling that of benzaldehyde

• Steam volatile and sparingly soluble in water but soluble
in most organic solvents

• Isoquinoline turns yellow on keeping

• Isoquinoline is highly aromatic

• Weak base with pKa 5.14

• Electrophilic attack is preferred at C-5 and C-8 positions

Synthetic methods of Isoquinoline:

The Bischler-Napieralski synthesis:

• Involves a cyclodehydration of an acyl derivative of β-phenylethylamine to give
3,4-dihydroisoquinoline in the presence of polyphosphoric acid, zinc chloride
or phosphorus pentoxide

• Then its dehydrogenated to isoquinoline

Chemical properties of Isoquinoline:

Electrophilic substitution: takes place under rather
drastic conditions than pyridine

• 5- and 8- positions are mostly preferred

Halogenation:

• Chlorination (Cl2, AlCl3) gives
5-chloroisoquinoline in a low yield

• Bromination (Br2, AlCl3) takes place
at 5-position

Reaction with nucleophiles: attack of nucleophile
takes place at position-1

• If its occupied then attack occurs at 3-position

• Chichibabin reaction is an example of normal attack at C-1

Summary

• Quinoline structure obtained by ortho-condensation of
benzene ring with pyridine

• Highly aromatic

• Pyridine ring in quinolone is π-electron deficient,
therefore nucleophilic attack takes place at 2- and 4- position

• Chichibabin reaction is an example of normal attack at C-2

• Electrophilic attack preferably takes place at 5- and 8-
positions

• Isoquinoline is obtained by the fusion of pyridine with a
benzene ring

• Electrophilic attack is preferred at C-5 and C-8 positions

• Chichibabin reaction is an example of normal attack at C-1

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