Prepare By: Ms.

Ashwini Dhruv
Assistant Professor
School of Pharmacy, RK University
Pharmaceutical Organic chemistry-III (BP401T)
 CONTENT TO BE COVERED:
Synthesis, reactions and medicinal uses of following
compounds/derivatives
Pyrazole, Imidazole, Oxazole and Thiazole. Pyridine, Quinoline,

Isoquinoline, Acridine and Indole.

Basicity of pyridine

Synthesis and medicinal uses of Pyrimidine, Purine, azepines and their

derivatives.
RING-I: PYRAZOLE
Pyrazole is an unsaturated five membered heterocyclic ring consists of two

nitrogen's as heteroatoms at 1st and 2nd positions.

Molecular Formula: C3H4N2

The IUPAC name of Pyrazole is 1,2 Daizole or 1,2-Diazacyclopenta-2,4-diene

1. Pyrazole is a colorless solid.

2. It possesses a pleasant smell.

3. Pyrazole is soluble in water.

4. Pyrazole exhibits Tautomerism.

5. Pyrazole has aromatic properties.

 SYNTHESIS OF PYRAZOLE:
1. From Pyrimidine:
Pyrimidine is susceptible to nucleophilic addition reaction. It reacts with hot

hydrazine solution to give pyrazole.

 SYNTHESIS OF PYRAZOLE:
2. From α,β-unsaturated carbonyl compounds:

In α,β-unsaturated carbonyl compound, if either of the double bonded carbon atom is

attached to a halogen atom, Pyrazole is directly obtained.

 SYNTHESIS OF PYRAZOLE:
3. From 1,3-di polar compounds-

Pyrazole derivatives can also be prepared by adding a diazo compound to an acetylenic

derivative.
 SYNTHESIS OF PYRAZOLE:
4. Knorr Pyrazole Synthesis (From β–diketones)

It is a condensation of acetyl acetone with hydrazine

 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
Pyrazole undergoes Electrophilic substitution reaction at 4th position.
1. ELECTROPHILIC SUBSTITUTION REACTIONS:
Pyrazole is an aromatic compound.

It readily undergoes electrophilic substitution at position 4 through the

intermediate formation of arsenium ion as the electrophilic attack at C-3

and C-5 generates highly unstable positively charged intermediate.
Electrophilic attack at C-4 competes with any such highly unstable

intermediate.
The electrophilic substitution is favored in neutral or basic medium but

not in acidic medium.

1. ELECTROPHILIC SUBSTITUTION REACTIONS:
 2. OXIDATION REACTION:
Pyrazole is resistant to oxidizing agents but the side chain may be oxidized

to carboxylic acid group in presence of potassium permanganate.

KMnO4
 3. REDUCTION REACTION:
Pyrazole ring system can be reduced with molecular hydrogen and metal

catalyst. “Pyrazolene and pyrazolidine are stronger bases than PYRAZOLE”

 4. RING OPENING REACTION
N-substituted pyrazole reacts with strong base (Sodamide) to cause ring

opening reaction in pyrazole

 SYNTHETIC/MEDICINAL USES:
1. Antipyrine- used as anti- pyretic drug

2. Analgin- analgesic and anti-pyretic drug

3. Phenylbutazone- used as anti-pyretic, analgesic and anti-inflammatory

drug (NSAID)
4. Oxyphenbutazone- used as anti-pyretic, analgesic and anti-inflammatory

drug (NSAID)
5. Phenazone- used as anti-pyretic, analgesic

6. Celecoxib- anti- inflammatory drug (NSAID)

SYNTHETIC/MEDICINAL USES:

PHENYLBUTAZONE
RING-II:
Imidazole is an important nucleus in heterocyclic chemistry.

Imidazole is an unsaturated five membered heterocyclic ring consists of two

nitrogen's as hetero atoms at 1st and 3rd positions.

It follows Huckel’s rule and hence it is Aromatic heterocyclic compound.

Imidazole has 3C and 4N atoms and all are sp2 hybridized

Molecular formula: C3N2H4

1. DEBUS RADISZEWSKI SYNTHESIS:

 It consists of condensing a dicarbonyl compound (e.g.: glyoxal, α-keto aldehydes) or

diketones with an aldehyde in the presence of ammonia.

 Example: Benzil with benzaldehyde and two molecules of ammonia reacts to yield 2,4,5-

triphenylimidazole
2. DEHYDROGENATION OF IMIDAZOLINES:
 Imidazole's prepared by dehydrogenation of imidazolines in presence of milder
reagent, barium managanate.
 Imidazolines obtained from alkyl nitriles and 1,2- ethane diamine on reaction with
BaMnO4 yields 2- substituted imidazole's.
3. FROM α-Halo Ketones:

 This reaction involves an interaction between an amidine and an α-halo ketone.

 Example: Phenacyl bromide and benzamidine affords 2,4- diphenylimidazole

 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
 Imidazole is more susceptible to electrophilic attack than Pyrazole, Thiazole, furan
or Thiophene.
 Electrophilic attack takes place at 4th or 5th position in imidazole.
 Electrophilic attack at C-2 involves a canonical form (resonance structure) with a
highly unfavoured positive nitrogen at position 3
 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
i. Nitration: Imidazole on nitration with fuming HNO3 & H2SO4 afford 4(5)-nitro
imidazole.

ii. Sulphonation: Imidazole on Sulphonation with sulphuric acid afford imidazole-

4(5)-sulphonic acid
 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
iii. Bromination: Brominated with bromine in chloroform

iv. Iodination: Imidazole is iodinated with iodine in alkaline condition

 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
v. Diazo Coupling reaction: Coupling of Imidazole with Diaz onium salts takes place in
the 2-position.

v. Alkylation: The imino hydrogen atom of Imidazole can be replaced by alkyl groups on
reaction with alkyl halide. N-alkylimidazoles isomerise on passing through red- hot
tube to 2-alkylimidazole.
 2. OXIDATION REACTION:
 Imidazole ring is resistant to oxidation but it is degraded by hydrogen peroxide

and per benzoic acid.

 3. RING OPENING REACTION:
 Benzoyl chloride in the presence of sodium hydroxide opens the Imidazole
ring.
 SYNTHETIC/MEDICINAL USES:
1. Metronidazole: Anti-amoebic agent for the treatment of amoebic dysentery.
2. Methimazole and Carbimazole: Antithyroid drugs, used to control hyperthyroidism.
3. Cimetidine: H2 Antagonist- antiulcer drug used for the treatment of gastric and
duodenal ulcers.
4. Ketoconazole, Miconazole, Clotrimazole: Antifungal drug used to treat fungal
infections
Cimetidine
RING III:
Oxazole is the parent compound for a vast class of heterocyclic aromatic

organic compounds. These are azoles with an oxygen and a nitrogen

separated by one carbon.
Oxazole are aromatic compounds but less than that of Thiazole.

Oxazole is a weak base

Aromaticity- Oxazole follow Huckel's rule (4n+2πe) because it have 6πe

Show sp2 hybridization and cyclic planer structure

1. ROBINSON–GABRIEL SYNTHESIS:

It is an organic reaction in which a 2-acylamino-ketone reacts intramolecularly

followed by a dehydration to give an Oxazole. A cyclodehydrating agent is needed to

catalyze the reaction
2. From α-hydroxy carbonyl carbon:
α- hydroxy ketones react with amide to form Oxazole after undergoing

dehydrogenation.
EXAMPLE…
3. FROM ISOCYANIDES:
 Reaction of isocyanides with acid chlorides or anhydride yields substituted

Oxazole
 1. ELECTROPHILIC SUBSTITUTION REACTION:
1. It is less reactive due to oxygen is present in heteroskeletal
2. Reaction is only present at 5th position if ring is activated by EDG group
3. Nitration and Sulphonation are more difficult.
E.g.: Bromination of 2-phenylpyrazole

N-Bromo succianmide
 2. DIELS ALDER REACTION:
1. O atom is highly electronegative so conjugated double bonds are readily
available as diene in Diel’s Alder reaction.
2. Oxazoles readily undergo Diels Alder type of cycloaddition reaction at 2,5
positions.
Example-1: Synthesis of FURAN
 2. DIELS ALDER REACTION:
Example-1: Synthesis of PYRIDINE

Oxazole Dienophile Substituted Pyridine

 MEDICINAL/SYNTHETIC USES:
1. BENGAZOLES: It is used as an anti-fungal agent

2. OXAPROZIN: It is used as Non-Steroidal anti-inflammatory drug and in the

treatment of Rheumatoid Arthritis

Oxaprozin
Bengazoles
RING IV:
Thiazole or 1,3-thiazole, is a 5-membered heterocyclic compound that contains

both sulfur and nitrogen.

The term 'thiazole' also refers to a large family of derivatives.

Thiazole itself is a pale yellow liquid with a pyridine-like odor

Molecular formula C3H3NS.

1. ROBINSON–GABRIEL SYNTHESIS:

 Condensation of acylamino carbonyl compound in presence of phosphorous

pentasulphide
2. From α-hydroxy carbonyl carbon/ Hantzsch Thiazole Synthesis
Condensation of α- halo ketones and thioamide react to form Thiazole
after undergoing dehydration.

thioamide
3. FROM AN THIOCYANATE SALTS:

Reaction of thiocyanate with chloroacetone yields substituted Thiazole.

 1. ELECTROPHILIC SUBSTITUTION REACTION:
Electrophilic substitution is favored at position 4 and 5 of Thiazole ring, Thereby

Electron releasing group is favored at position-2 of Thiazole.

A. NITRATION REACTION:
Dinitrogen Tetra oxide
 1. ELECTROPHILIC SUBSTITUTION REACTION:
B. SULPHONATION:

C. CHLORINATION:
 1. ELECTROPHILIC SUBSTITUTION REACTION:
D. BROMINATION:
1. H2 receptor blocker:
Famotidine and Nizatidine are sued in Peptic Ulcer
Clormethiazole
2. Clormethiazole is used as Sedative or Hypnotic

3. Vitamin (B1)- Thiamine:

It is used in thiamine deficiency
RING V:
Pyridine also called as Azabenzene or Azine.
Pyridine is an unsaturated six numbered heterocyclic ring consists of nitrogen
as hetero atom.
It possess planar conjugated ring structure consists of six delocalized π-
electrons.
Molecular formula: C5H5N1
Thus pyridine behaves as a tertiary base.
 BASICITY OF PYRIDINE:
Pyridine behaves as a base (pKb = 8.77)

It reacts with acid to form fairly stable salts.

The reason for the basic character of pyridine is that the nitrogen lone pair of

electrons being in sp2 hybrid orbital is not involved in the formation of the
delocalized π molecular orbital.
It is readily available for the formation of a new N-H bond with proton
 BASICITY OF PYRIDINE:
I. PYRIDINE IS MORE BASIC THAN PYRROLE
Pyridine is a stronger base than pyrrole (or aniline) in which the basicity is

reduced by delocalization of the nitrogen lone pair.

Pyridine ➔ N does not involve in the resonance and those lone pair of electrons

are readily available for reactions.

Pyrrole ➔ N involved in the resonance (delocalization) and those lone pair of

electrons are not readily available for reactions

 BASICITY OF PYRIDINE:
II. PYRIDINE IS LESS BASIC THAN ALIPHATIC AMINES
 Pyridine is a considerably weaker base than trimethyl amine (aliphatic
tertiary amine).
 This is probably due to the difference in the nature of hybrid orbitals
containing the nitrogen lone pair in the two molecules.
 Pyridine ➔ sp2 orbital (smaller) ➔ more s character ➔ more electronegative
✓ Trimethylamine ➔ sp3 orbital ➔ less s character ➔ less electronegative
 BASICITY OF PYRIDINE:
II. PYRIDINE IS LESS BASIC THAN ALIPHATIC AMINES
This means that the lone pair of electrons on nitrogen in pyridine is more closely

associated with the nitrogen nucleus.

It is therefore, less available for the formation of a bond with proton (chemical

reactions) and consequently the relative basicity is reduced.

1. HANTZSCH SYNTHESIS : It involves condensation of an aldehyde with two moles of a

dicarbonyl compound or β-keto esters and ammonia.

2. GUARESCHI SYNTHESIS: It involves treating a cyanoacetamide with a diketone
(acetoacetic ester) yield pyridone which converted into pyridine.
3. FROM FURANS: By heating tetrahydrofurfuryl alcohol with ammonia in
the presence of aluminum oxide at 500°C
4. FROM ALDEHYDES/KETONES and AMMONIA: Aldehydes or ketones on reaction

with ammonia under suitable conditions such as high temperature and pressure
gives pyridine.
5. FROM PIPERIDINE : By dehydrogenation of Piperidine with
concentrated sulphuric acid at 300°C or nitrobenzene at 260°C gives
pyridine
 1. ELECTROPHILIC SUBSTITUTION REACTION:
Pyridine is considerably less reactive than benzene towards electrophilic

substitution.
Because:

i. The nitrogen atom in pyridine, because of its electronegativity lowers the

electron density around the ring carbons.
ii. The usual electrophiles can coordinate with the lone pair of electrons on
nitrogen to form resonance stabilized pyridinium salts.
 1. ELECTROPHILIC SUBSTITUTION REACTION:
Nitrogen is electronegative, so +ve charge on N destabilize the structure

Attack at C2 and C4 generates N+ intermediates → less favorable

C3 position do not generate intermediates → favorable

 1. ELECTROPHILIC SUBSTITUTION REACTION:
1. Nitration: Pyridine undergoes nitration with potassium nitrate in the presence of

sulphuric acid at 300 °C to yield 3-nitro pyridine

2. Sulphonation: It undergoes Sulphonation with fuming sulphuric acid in the

presence of mercuric sulphate to give pyridine-3-sulphonic acid.

 1. ELECTROPHILIC SUBSTITUTION REACTION:
3. Halogenation:

3-bromopyridine is produced in good yield by action of bromine in oleum

3-Cloropyridine can be produced by action of chlorination in presence of aluminum

chloride
 2. NUCLEOPHILIC SUBSTITUTION REACTION:
Substitution occurs almost exclusively at C-2 or C-4 position if C-2 is blocked.

Attack on C-2 position gives more stable intermediate containing –ve charge on N

CHICHIBABIN REACTION

Pyridine reacts with sodamide in liquid ammonia at about 100°C to form 2-

aminopyridine.
 3. OXIDATION REACTION:
Pyridine is quite stable towards mild oxidizing agents.

It does not react with chromic acid or nitric acid.

However, it may be oxidized by per acetic acid to give pyridine-N-oxide

 4. REDUCTION REACTION:
Pyridine undergoes reduction with lithium aluminum hydride (LiAlH4) or

hydrogen in the presence of nickel catalyst to form Piperidine

 MEDICINAL/SYNTHETIC USES:
1. Isoniazid and Ethionamide: They are used to treat tuberculosis (TB) infections
2. Pyridostigmine: Anticholinesterase inhibitor used to treat the symptoms of Myasthenia
gravis (neuromuscular disorder that causes weakness in the skeletal muscles.
3. Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole: They are proton pump
inhibitors used to prevent and treat ulcer conditions.
4. Sulphapyridine, Sulphasalazine: It is used to treat bacterial infections

Omeprazole

Isoniazid
RING VI:
Indole is an aromatic heterocyclic organic compound with formula C8H7N.

It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five

membered nitrogen-containing pyrrole ring.

Satisfies Huckel’s rule (sp2 hybrid orbital, planar molecule)

It is a very weak base

IUPAC Name:
1-H Indole
Other Names:
2,3 Benzo pyrrole
1-H benzo [b] pyrrole
1. FISCHER INDOLE SYNTHESIS:

Acid-catalyzed rearrangement of an arylhydrazone to an indole with the elimination

of ammonia. Reaction can be carried out by heating together the aldehyde or ketone
and aryl hydrazine. Formation of arylhydrazone and its subsequent rearrangement
take place to give Indole
2. THE BISCHLER’S SYNTHESIS:

Synthesis of 2-aryl indole from an α-bromo acetophenone and excess of

aniline
3. MADELUNG SYNTHESIS:

Intramolecular cyclization of N-phenyl amide using strong base at high

temperature.
1. ELECTROPHILIC SUBSTITUTION REACTIONS:
Unlike pyrrole, electrophilic substitution in Indole takes place preferentially at C3
 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
The intermediate of the attack at C3 is stabilized by delocalization of the positive

charge. However, no delocalization is possible in the intermediate derived from attack

at C2 position without disrupting the aromaticity of the six membered rings. The
common electrophilic substitution reactions of Indole are discussed as follow.
1. Bromination: Indole undergoes Bromination at very low temperature (0°C) in

dioxane.
 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
2. Nitration: Indole undergoes nitration in presence of ethyl nitrate at low temperature

(0–5 °C).

3. Sulphonation: Sulphonation of Indole is carried out only under milder conditions

using pyridine-sulphur trioxide complex in order to minimize the acidity of the

reagent.
 1. ELECTROPHILIC SUBSTITUTION REACTIONS:
4. Friedel crafts alkylation: Indole undergoes alkylation with alkyl iodide in (DMF) or

(DMSO) as solvent

5. Diazo coupling or Diazotization reaction: Indole reacts with benzene Diazonium

chloride to give 3-phenylazoindole, a diazotized coupled product.

 2. REDUCTION REACTION:
Lithium/liquid ammonia reduces the benzene ring; 4-7 dihydroindole is

the main product.

 3. OXIDATION REACTION:
In presence of peroxy acid or ozone, Indole is oxidized to form 2-

formamidobenzaldehyde by opening the heterocyclic ring

4. NUCLEOPHILIC SUBSTITUTION REACTION:
1. INDOLE ALKALOIDS:

A. Reserpine: Used as anti-hypertensive agent, treats agitated psychotic conditions.

B. Vinca alkaloids:

A. Vincristine, Vinblastine: Used as anticancer agent

C. Ergot alkaloids:

A. Ergometrine: Prevents bleeding after child birth (Smooth muscle constriction)

B. Ergotamine: Used in Migraine attack.

2. PINDOLOL:

Non selective β-blockers, used in treatment of hypertension and angina pectoris.

 Pindolol
Reserpine
RING VII:
INTRODUCTION:
Acridine is an organic compound and a nitrogen heterocycle with the formula C13H9N.

Acridine are substituted derivatives of the parent ring.

It is a planar molecule that is structurally related to anthracene with one of the

central C-H groups replaced by nitrogen.

SYNTHESIS OF ACRIDINE:
1. ULLMANN SYNTHESIS

The condensation of primary amine with aromatic aldehyde/aromatic carboxylic

acid in the presence of strong mineral acids (H2SO4/HCl), followed by

dehydrogenation, yield Acridine.
SYNTHESIS OF ACRIDINE:
2. BERNTHSEN ACRIDINE SYNTHESIS

Bernthsen synthesis involves the reaction of diphenylamine with carboxylic acid in

the presence of zinc chloride, resulting in the formation of Acridine.

SYNTHESIS OF ACRIDINE:
3. FRIEDLANDER SYNTHESIS

In this synthesis the salt of anthranilic acid is treated with cyclohex-2-enone at 120°C

to obtain 9-methylacridine
 1. ELECTROPHILIC SUBSTITUTION REACTION:
Electrophilic substitutions of Acridine often results in di-substitution at the 2-

and 7-positions.
1. NITRATION:

2. BROMINATION:
 2. NUCLEOPHILIC SUBSTITUTION REACTION:
CHICHIBABIN REACTION:

Acridine readily reacts with Nucleophiles. The Chichibabin amination of

sodamide in Liquid ammonia leads to formation of 9-amino Acridine

 3. OXIDATION REACTION:
Acridine is oxidized by dichromate in acetic acid giving acridone whereas it get

degraded by permanganate in alkaline medium forming Quinoline 2,3-

dicarboxylic acid.
 4. REDUCTION REACTION:
Reduction of Acridine with Zn/HCl leads to form 9,10-dihydroacridine,

whereas reduction with Pt/HCl results to form octahydroacridine.

1. TACRINE: It is a reversible cholinesterase inhibitor used in the treatment of
Alzheimer disease
2. 9-AMINOACRIDINE: It is highly a fluorescent dye, used as antiseptic and
Disinfectant

Tacrine

9-Amino Acridine
RING VIII:
Quinoline is a heterocyclic aromatic organic compound with the chemical

formula C9H7N.
Each atom is sp2 hybridized, planar molecule

Obeys Huckel’s rule

Weakly basic in nature

1. SKRAUP SYNTHESIS

Aniline is heated with sulfuric acid, glycerol, and an oxidizing agent such as

nitrobenzene to yield Quinoline.

2. THE DOEBNER–MILLER REACTION
 It is the organic reaction of an aniline with α,β-unsaturated carbonyl
compounds to form quinolones.
3. THE FRIEDLANDER SYNTHESIS
It is a chemical reaction of 2-amino benzaldehydes with ketones to form

Quinoline derivatives.
 1. ELECTROPHILIC SUBSTITUTION REACTION:
Electrophilic substitution reactions occur in positions 5 and 8 of Quinoline.

Nucleophilic substitution proceeds faster in Quinoline than in pyridine.

2. Reduction Reaction:

3. Oxidation Reaction:
4. NUCLEOPHILIC SUBSTITUTION REACTION:
CHICHIBABIN REACTION:

The reaction of Quinoline with sodamide in presence of liquid ammonia

reacts to form 2-aminoquinoline

1. ANTI-MALERIAL: Following drugs are used to treat Malaria:
Cinchona Alkaloid : Quinine, Quinidine

4-Aminoquinolines; Chloroquine, Amodiaquine

8-Aminoquinolines: Primaquine

2. 8-hydroxyquinoline is used as TOPICAL ANTISEPTIC

8-hydroxyquinoline
RING IX:
Isoquinoline is a heterocyclic aromatic organic compound. It is a structural

isomer of Quinoline.
Each atom is sp2 hybridized, planar molecule

Obeys Huckel’s rule

Weakly basic in nature

1. BISCHLER NAPIERALSKI ISOQUINOLINE SYNTHESIS:
2-arylethanamine reacts with acyl chloride or anhydride to form an

amide
2. PICTET GAMS SYNTHESIS:
Modification of Bischler-Napieralski forms Isoquinoline from 2-

substituted reagent.
3. POMERANZ-FRITSCH SYNTHESIS:
Acid promoted synthesis of Isoquinoline from benzaldehyde and 2,2-

dialkoxyethylamine
1. ELECTROPHILIC SUBSTITUTION REACTION:
Electrophilic aromatic substitution occurs on benzene ring at position 5 and 8
 2. REDUCTION REACTION:
Isoquinoline is converted into 1,2-dihydro and 1,2,3,4 –tetra hydro when treated with

diethyl aluminum hydride and sodium-ethanol respectively

 3. OXIDATION REACTION:
Reaction of Isoquinoline in presence of strong oxidizing agent yields phthalic

acid.
 4. NUCLEOPHILIC SUBSTITUTION REACTION:
CHICHIBABIN REACTION:

Reaction of Isoquinoline with sodamide at high temperature.

 MEDICINAL/SYNTHETIC USES:
1. Neuromuscular Blocking agents: Curare alkaloids, Atracurium,
Doxacurium etc.
2. Papaverine: Anti-spasmodic agent
3. Noscapine: Used as Anti-tussive agent