INTERNATIONAL INSTITUTE OF TECHNOLOGY, CULTURE AND

HEALTH SCIENCES (II-TECH), GUJRANWALA

HETEROCYCLIC
COMPUNDS
(Quinoline)

Dr. SAMAR FATIMA HASHMI

Pharm-D (UVAS)
MPhil Pharmaceutical Chemistry (UVAS)
Lecturer IITECH
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HEALTH SCIENCES (II-TECH), GUJRANWALA

QUINOLINE

Quinoline is a heteroaromatic compound composed of a benzene ring fused with a

pyridine ring, forming a bicyclic system. Quinoline consists of a benzene ring
fused to the Alpha and Beta positions of a pyridine ring. The fusion occurs
between the 2- and 3-positions of pyridine and the 5- and 6-positions of benzene,
resulting in a planar aromatic system.

Quinoline is also known as 1-azanaphthalene or benzopyridine, reflecting its

structural analogy to naphthalene with one carbon replaced by nitrogen. It naturally
occurs in coal tar and is synthetically significant in the preparation of dyes,
agrochemicals, and pharmaceuticals. It serves as a foundational source for many
antimalarial, antibacterial, antitumor, and anti-inflammatory drugs.

MOLECULAR ORBITAL STRUCTURE OF QUINOLINE

Quinoline possesses an extended π-conjugated system resulting from the fusion of

two aromatic rings. The pyridine ring contributes 6 π-electrons (with nitrogen's
lone pair in a sp² orbital not involved in aromaticity), and the benzene ring also
contributes 6 π-electrons, maintaining aromaticity in both rings. The planar
geometry facilitates orbital overlap and π-delocalization across the fused ring
system, though the electron density is not distributed equally due to the presence of
nitrogen at position 1.
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The nitrogen atom withdraws electron density through both inductive and
resonance effects, rendering the pyridine ring more electron-deficient compared to
the benzene ring. This affects quinoline’s reactivity, especially in electrophilic and
nucleophilic aromatic substitution reactions. The π-electron cloud is extended but
more localized around the benzene ring, making the benzene ring more reactive
towards electrophiles.

PHYSICAL PROPERTIES OF QUINOLINE

 Quinoline is a colorless to pale yellow oily liquid that possesses a pungent,

irritating odor reminiscent of pyridine.
 It has the molecular formula C₉H₇N and a molar mass of 129.16 g/mol. The
compound exhibits a melting point of approximately -15 °C and a boiling point
around 237 °C, indicating its relatively high thermal stability among
heteroaromatic compounds.
 Its density is about 1.09 g/cm³, and it displays a refractive index of 1.626, which
is characteristic of aromatic systems.
 Quinoline is only slightly soluble in water, but it is freely soluble in organic
solvents such as ethanol, diethyl ether, and benzene, making it suitable for use
in organic synthesis.
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 Due to its physical characteristics and volatility, quinoline must be handled in

well-ventilated environments to avoid inhalation of its sharp vapors.

METHODS OF PREPARATION OF QUINOLINE

1. By Skraup Synthesis: (Commercial method)

In this reaction, a mixture of aniline and glycerol is heated in the presence of

sulphuric acid and a mild oxidizing agent, usually nitrobenzene or arsenic
pentoxide. The reaction is exothermic and tends to become very violent. Ferrous
sulphate or boric acid is generally added to make the reaction less violent.

Mechanism:
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2. By the Friedlander Synthesis:

This involves the condensation of o-aminobenzaldehyde with acetaldehyde in the

presence of an alkali.

Mechanism:

3. Doebner–Von Miller Synthesis

Aniline reacts with α,β-unsaturated aldehydes (e.g., cinnamaldehyde) in the

presence of acid to yield substituted quinolines. In the presence of HCl, two moles
of aniline and two moles of acetaldehyde form Schiff's base. This Schiff's base is a
quinoline derivative formed by combining two molecules.
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4. Conrad – Limpach – Knorr synthesis

The reaction between anilines and β-keto esters (e.g., ethyl acetoacetate) occurs at
a lower temperature and gives a β-amino acrylate, which after cyclization gives a
4-quinolone. At high temperatures, 2-quinolones are formed by cyclizing β-
ketoester anilides.

5. Pfitzinger synthesis

The conversion of isatin to isotonic acid in the presence of a base results in

quinoline-4-carboxylic acid being synthesized by combining a ketone with the
isotonic acid. Pyrolysis with calcium oxide can be used to remove the carboxylic
acid group and yield substituted quinolines.
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6. Combes synthesis

The condensation of 1,3-dicarbonyl compounds with arylamines gives a cyclized

β-amino enone, which is then cyclized with heat to afford quinoline.

7. In the presence of tetra-alkyl ammonium salts, Indole and chloroform

react together to produce chloroquinoline.

CHEMICAL PROPERTIES OF QUINOLINE

The chemical reactivity of quinoline is determined by the fused aromatic nature of

its benzene and pyridine rings, with the nitrogen atom at position 1 exerting both
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inductive electron withdrawal and resonance effects that make the pyridine portion
electron-deficient compared to the benzene ring. Quinoline retains aromaticity in
both rings, with each satisfying Hückel’s rule, and the nitrogen’s lone pair residing
in an sp² orbital orthogonal to the π-system, making it available for protonation and
coordination while not participating in aromatic delocalization.

In electrophilic aromatic substitution, the benzene ring is more reactive than the
pyridine ring, and electrophiles preferentially attack at the 5- and 8-positions, while
substitutions at the 6- and 7-positions are less common and the pyridine ring
undergoes electrophilic attack only under forcing conditions.

Nucleophilic aromatic substitution is favored at the electron-deficient C-2 and C-4

positions of the pyridine ring, especially when an electron-withdrawing substituent
or a halogen is present, allowing displacement by nucleophiles such as alkoxides,
amines, and thiolates.

Quinoline can be reduced catalytically to yield partially hydrogenated products

such as 1,2,3,4-tetrahydroquinoline, and oxidized at the nitrogen atom to form
quinoline N-oxides, which serve as versatile intermediates in functionalization
reactions.

This dual aromatic and heteroatomic nature gives quinoline a rich and selective
reactivity profile, making it an important platform for both synthetic
transformations and drug development.

1. Basic Character:

Quinoline is slightly weaker base than pyridine. It reacts with acids to yield salts
which are sparingly soluble in water.
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2. Addition to Nitrogen

An extra bond can be formed using the N-atom's lone pair of electrons. Quinoline
reacts with acidic solutions or metallic ions to form quaternary salts.

3. Electrophilic substitution reaction

Benzene ring is more electron rich than pyridine ring. Undergo electrophilic
substitution in benzene ring and not in the more resistent pyridine ring. The
elctrophile attacks position 8 and 5.
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 Nitration

 Sulphonation

 Halogenation

4. Nucleophilic Substitution Reaction

Quinoline readily gives nucleophilic substitution reaction shown by pyridine ring.

It reacts with Sodium Amide (NaNH2) to give 2-Aminoquinoline. If any
substitution present at C-2 position then reaction occur at C-4 position.
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5. Reaction with KOH

6. Reaction with n-butyl lithium

7. Reaction with per acetic acid

8. Oxidation Reaction with KMnO4

Quinoline undergo oxidative cleavage with alkaline potassium permangnate to give

pyridine-2,3-dicarboxylic acid. However, pyridine-2,3-dicarboxylic acid is not
stable and undergoes decarboxylation to give nicotinic acid.
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9. Reduction

[Link] with alkyl halides

PHARMACEUTICAL USES OF QUINOLINE

 Quinoline ring has been found to possess antimalarial, anti-bacterial,

antifungal, anthelmintic (a group of antiparasitic drugs that expelinternal
parasites from the body), cardiotonic (drugs that increase the contracting
mechanism within the heart), anticonvulsant (drugs used in the treatment of
epileptic seizures), anti-inflammatory, and analgesic activity.
 Quinoline family compounds are widely used as a parent compound to make
drugs (especially anti-malarial medicines such as Chloroquine and
hydroxychloroquine), fungicides and biocides.
 Quinine is an anti-malarial natural product isolated from the bark of the
Cinchona tree.
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 Chloroquine is a completely synthetic anti-malarialdrug that has the

quinoline system found in quinine.

 They have antiseptic, antipyretic (substances that reduce fever), and

antiperiodic (Preventing regular recurrence of the symptoms of a disease, as
in malaria) properties.
 Quinaldine, 2-methylquinoline, is used as an anti-malarial and preparing
other anti- malarial drugs.

 Quinazoline, diazanaphthalene at 1,3 positions, is used as a chemical

intermediate for making medicines and other organic compounds. It is a
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fundamental structure in some antihypertensive agents such as prazosin and

doxazosin which are peripheral vasodilator.
 Quinoxaline, diazanaphthalene at 1,4 positions, is used as a chemical
intermediate for making fungicides and other organic compounds.