PYRAZOLE

Contents

• Synthesis,
• reactions and
• medicinal uses of Pyrazole
PYRAZOLE

• Pyrazole is a heterocyclic compound with three carbon atoms and two

heteroatoms i.e, Nitrogen atoms.
• Pyrazole was first described by Buchner in 1889 , who discovered it during
the decomposition of Pyrazole 3,4,5-tricarboxylic acid.
• It does not occur naturally.
Synthetic Methods
• By passing acetylene gas into a cold ethereal solution of diazomethane, Pyrazole is obtained.
Synthetic Methods
• α,β- unsaturated aldehyde reacts with Hydrazine in presence of bromine to
yield Pyrazole.
Synthetic Methods
• Hydrazine reacts with 1,3-Propane dial in presence of acid to yield Pyrazole.
Structure of Pyrazole
• In Pyrazole, the two nitrogen atom and 3 carbon atoms are
SP2 hybridized.
• SP2 hybrid orbitals overlap with each other and with S
atomic orbitals of 5 Hydrogen atom forming C-C, C-N, N-
N and N-H σ bonds. All these σ bonds lie in one planar.
• Also each carbon atom and Nitrogen atom possess an
unhybridized P atomic Orbital and these are perpendicular
to plane of σ bonds. The P orbital on carbon atom contain
one electron each and P orbital on nitrogen atom contain
two electron.
 • The lateral overlap of these P orbitals produce a π
molecular orbital containing six electrons, an arrangement
i.e, frequently referred to as an aromatic sextet.
• The unhybridized P orbital in pyrazole overlap with each
other to form a delocalized π molecular orbital above and
below the plane containing σ bonds.
• N1 atom contains a pyrrole like nitrogen where lone pair
P-P orbital of electron takes part in formation of π molecular orbital
overlap where as N3 atom contains a pyridine like nitrogen have a
lone pair of electrons does not take part in delocalization
to form π molecular orbital.
• Pyrazole satisfies Huckle’s rule i.e, (4n+2) π electrons.
• So Pyrazole is an aromatic compound, it will undergo
resonance.
 Resonance structures or Canonical forms
• According to resonance theory, pyrazole is considered to be hybrid of following
resonance structures.
• The result of donation of
electrons by nitrogen atom,
carbon atoms of pyrazole
ring have gained electron
density. Thus carbon atom of
ring bears negative charge
and Nitrogen atom positive
charge.
Physical Properties of Pyrazole

• State- Solid
• Color- colorless
• Boiling point - 70°C
• Odour- Pleasant smell
• Solubility- Soluble in water.
Chemical Properties of Pyrazole

• Pyrazole with free N-H groups are amphoteric though more basic than acidic.
• Basic Character: It is weak basic in nature. The nitrogen atom at position 1
is not basic at position 2 is weakly basic.
Chemical Reaction- Electrophilic aromatic Substitution
• Electrophilic aromatic substitution:
The attack of electrophile to aromatic
ring, which takes place to yield the
most stable intermediate carbocation.
• Attack at C3 position yields a
carbocation that hybrid structure of I
and II.
• Attack at C4 position yields a
carbocation hybrid structure of III and
IV.
• Attack at C5 position yields a
carbocation hybrid structure of V, VI
and VII.
• Attack at C4 position, is more
preferable than at other position, since
more stable carbocations are formed.
Chemical Reaction Contd..
• Nitration: Pyrazole undergoes nitration with nitric acid in presence of sulphuric acid to give
4-NitroPyrazole.

• Sulphonation: Pyrazole is sulphonated with sulphuric acid to yield Pyrazole 4- sulphonic

acid.
Chemical Reaction Contd..
• Halogenation:
• Chlorination: It is carried out with chlorine to give 4- chloro Pyrazole.

• Bromination: Pyrazole is heated with Bromine to give 4- bromo Pyrazole.

Chemical Reaction Contd..

• Reduction reaction: Pyrazole undergoes catalytic reduction with Hydrogen in presence of

palladium at 20°C to give 4-Pyrazoline. 4-Pyrazoline undergo further catalytic reduction
with Hydrogen in presence of palladium at 80°C to give Pyrazolidine.
Medicinal Compounds:

• Phenyl Butazone:
• Uses: ( Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) and
cyclooxygenase inhibitor.)
• It is a potent pain reliever, antipyretic, and anti-inflammatory.
• Oxyphenbutazone:
• Uses: It is used in the treatment of osteoarthritis, rheumatoid arthritis,
muscle pain and gout.
IMIDAZOLE

• Imidazole is an unsaturated heterocyclic 5 membered ring which contains

three carbon atoms and two heteroatoms i.e, Nitrogen atoms, which are
present at 1,3 position.
• Imidazole is an aza pyrrole where Nitrogen atoms are separated by one
carbon atom.
• This compound was earlier also called as Glyoxaline, where it was prepared
in 1858 from glyoxal and Ammonia.
• Imidazole nucleus is found in certain natural products viz histidine (an α-
amino acid), purines and also as a riboside.
Synthetic Methods
• Rediszweski or Debus synthesis: It involves reaction between glyoxal with
formaldehyde in presence of ammonia to yield Imidazole.
Synthetic Methods Contd…

• Imidazoleis prepared by action of ammonia with a mixture of

formaldehyde and tartaric acid nitrate and decarboxylating the
product.
Structure of Imidazole
• In Imidazole, the two nitrogen atom and 3
carbon atoms are SP2 hybridized.
• SP2 hybrid orbitals overlap with each other and
with S atomic orbitals of 5 Hydrogen atom
forming C-C, C-N, C-H and N-H σ bonds. All
these σ bonds lie in one planar.
• Also each carbon atom and Nitrogen atom
possess an unhybridized P atomic Orbital and
these are perpendicular to plane of σ bonds. The
P orbital on carbon atom contain one electron
each and P orbital on nitrogen atom contain two
electron.
 • The lateral overlap of these P orbitals produce a π
molecular orbital containing six electrons, an arrangement
i.e, frequently referred to as an aromatic sextet.
• The unhybridized P orbital in Imidazole overlap with each
other to form a delocalized π molecular orbital above and
below the plane containing σ bonds.
P-P orbital • N1 atom contains a pyrrole like nitrogen where lone pair
overlap of electron takes part in formation of π molecular orbital
where as N3 atom contains a pyridine like nitrogen have a
lone pair of electrons does not take part in delocalization
to form π molecular orbital.
• Imidazole satisfies Huckle’s rule i.e, (4n+2) π electrons.
• So, Imidazole is an aromatic compound, it will undergo
resonance.
Resonance structures or Canonical forms
• According to resonance theory, Imidazole is considered to be hybrid of
following resonance structures.
• The result of donation of electrons by
nitrogen atom, carbon atoms of
pyrazole ring have gained electron
density. Thus carbon atom of ring
bears negative charge and Nitrogen
atom positive charge.
Physical Properties of Imidazole

• State- Liquid
• Color- colorless to pale yellow
• Boiling point - 256°C
• Odour- Alcohol odour
• Solubility- Soluble in water.
Chemical Properties of Imidazole

• Imidazole is amphoteric in nature i.e, it behaves as base and acid.

• Basic Character: Imidazole is amphoteric in nature, it function both as an
acid and a base. The nitrogen present at 3rd position will undergo protonation
when treated with mineral acid i.e, HCl to form Imidazolium cation.
• Imidazole > Pyrazole> Pyridine> Pyrrole
• Imidazole is more basic than Pyrazole, Pyridine and Pyrrole. Imidazole and
Pyrazole are more stable in acidic medium.
Chemical Reaction- Electrophilic aromatic Substitution
• Electrophilic aromatic substitution:
The attack of electrophile to aromatic
ring, which takes place to yield the
most stable intermediate carbocation.
• Attack at C3 position yields a
carbocation that hybrid structure of I, II
and III.
• Attack at C4 position yields a
carbocation hybrid structure of IV and
V.
• Attack at C5 position yields a
carbocation hybrid structure of V, VI
and VIII.
• Attack at C5 position, is more
preferable than the other position, since
more stable carbocations are formed
here.
Chemical Reaction Contd..
• Nitration: Imidazole undergoes nitration with nitric acid in presence of
Sulphuric acid to give 5-NitroImidazole.

• Sulphonation: Imidazole is sulphonated with sulphuric acid at 160°C to

yields Imidazole 5- sulphonic acid. Thiazoles are much less reactive than
imidazoles at high temperature and Mercuric sulfate as a catalyst.
Chemical Reaction Contd..
• Halogenation:
• Bromination: It is carried out with Bromine in presence of Chloroform at
-10°C to give 2,4,5- Tribromo Imidazole.

• Chlorination: It is carried out with Chlorine in presence of Ferric chloride and

acetic acid to give 5- chloro imidazole.
Medicinal Compounds:

• Metronidazole:
• Uses: Antiprotozoal agent, It's used in the treatment of conditions such as bacterial
vaginosis and pelvic inflammatory disease. It's also used to treat infected insect bites, skin
ulcers, bed sores and wounds, and to treat and prevent bacterial and parasitic infections.

• Methimazole: Carbimazole:
• Uses: hyperthyroidism Uses: hyperthyroidism
OXAZOLE

• Oxazole is an unsaturated heterocyclic 5 membered ring which contains

three carbon atoms and two heteroatoms i.e, Nitrogen atom and oxygen
atom, which are present at 1,3 position.
• This compound was first introduced by Hantzsch in 1887 but it was not
synthesized until 1947.
• Oxazole nucleus does not occur in nature.
Synthetic Methods

• From Ethyl α- hydroxy keto succinate: It involves a reaction between ethyl α

- hydroxy keto succinate and formamide to give oxazole 4,5- diethyl
carboxylate which is subsequently hydrolysed and decarboxylated to yield
Oxazole.
Synthetic Methods Contd…

• Robinson Gabriel Synthesis: This method involves α-acyl amino ketone which undergoes
cyclization and dehydration in presence of Phosphorous Penta Oxide and Sulphuric acid.
Structure of Oxazole

• In Oxazole, the Oxygen, nitrogen atom and 3 carbon

atoms are SP2 hybridized.
• SP2 hybrid orbitals overlap with each other and with S
atomic orbitals of 5 Hydrogen atom forming C-C, C-N, C-
H and C-O σ bonds. All these σ bonds lie in one planar.
• Also each carbon atom, Oxygen and Nitrogen atom
possess an unhybridized P atomic Orbital and these are
perpendicular to plane of σ bonds. The P orbital on carbon
atom contain one electron each and P orbital on nitrogen
atom contain two electron.
 • The lateral overlap of these P orbitals produce a π
molecular orbital containing six electrons, an
arrangement i.e, frequently referred to as an aromatic
sextet.
• The unhybridized P orbital in Imidazole overlap with
each other to form a delocalized π molecular orbital
above and below the plane containing σ bonds.
P-P orbital • Oxygen atom contains a lone pair of electron which
overlap
takes part in formation of π molecular orbital where as
N3 atom contains a pyridine like nitrogen have a lone
pair of electrons does not take part in delocalization
to form π molecular orbital.
• Oxazole satisfies Huckle’s rule i.e, (4n+2) π electrons.
• So, Oxazole is an aromatic compound, it will undergo
resonance.
Resonance structures or Canonical forms
• According to resonance theory, Oxazole is considered to be hybrid of following
resonance structures.
• The result of donation of electrons by
Oxygen atom, carbon atoms of
oxazole ring have gained electron
density. Thus carbon, Nitrogen atom
of ring bears negative charge and
Oxygen atom bears positive charge.
Physical Properties of Oxazole

• State- Liquid
• Color- colorless
• Boiling point - 69°C
• Odour- Resembles that of Pyridine odour
• Solubility- Soluble in water and Organic solvents
Chemical Reaction- Electrophilic aromatic Substitution
• Electrophilic aromatic substitution: The
attack of electrophile to aromatic ring,
which takes place to yield the most stable
intermediate carbocation.
• Attack at C2 position yields a carbocation
that hybrid structure of I, II and III.
• Attack at C4 position yields a carbocation
hybrid structure of IV and V.
• Attack at C5 position yields a carbocation
hybrid structure of VI, VII and VIII.
• Attack at C5 position, is more preferable
than the other position, since more stable
carbocations are formed here.
Chemical Reaction Contd..

• Note: Nitration and sulfonation of oxazole itself are difficult because of

presence of Pyridine type nitrogen.
• Halogenation:
• Bromination: It is carried out with Bromine in at -15°C to give 5-Bromo 2-
Phenyloxazole.
Chemical Reaction Contd..

• Diel’s alder reaction: Oxazoles behaves similarly to furan in Diel’s alder reaction. 4-Phenyl
oxazole with Anthranilic acid and isoamyl nitrate refluxing with dioxane leads to Bis
benzyne adduct.
• Reduction: 2,5-Diphenyl oxazole undergoes reduction with Lithium
aluminium hydride in presence of Tetra hydrofuran to yield 2-Benzylamino
1-Phenyl ethanol.
• Oxidation: oxazole is not stable to the oxidative conditions by using
Potassium Permanganate. However the oxidation is stable with Hydrogen
peroxide. 4-(2-oxazolyl) Pyridine reacts with Hydrogen peroxide in presence
of acetic acid gives Pyridine N-oxide.
Medicinal Compounds:

• Trimethadione:
• Uses: It is used to treat absence seizures (also called "petit mal" seizures) in adults and
children. It is an anti-epileptic drug.
• Sulfamoxole:
• Uses: used as an Antibacterial agent. It is used to treat a wide variety of bacterial infections
(such as middle ear, urine, respiratory, and intestinal infections). It is also used to prevent
and treat a certain type of pneumonia.
Questions:

1. What are heterocyclic compounds? Write a note on classification, nature, numbering and
nomenclature of heterocyclic compounds?
2. Outline two methods of synthesis of thiophene. Discuss its aromatic behaviour; compare
its aromaticity with furan and pyrrole?
3. Outline the synthesis, reactions and medicinal use of imidazole and its derivatives?
4. Outline the synthesis, reactions and medicinal use of Pyrazole and its derivatives?
5. Outline the synthesis, reactions and medicinal use of oxazole and its derivatives?
6. Explain the synthesis of Quinoline by Skraup’s method? (5 marks)
7. Account for the Aromatic properties of pyridine ring?
8. Outline the synthesis of Furan and Thiophene?
Questions:

9. Compare aromaticity of the following with Benzene, Pyrrole, Furan, and Thiophene?
10. Write the structure and medicinal uses for the following drugs: i) nicotinic acid ii)
carbimazole iii) sulphadiazine iv) piperazine v) metronidazole.