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 2^nd and 4^th 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