UNIT IV
AZOLES
Azoles are a class of five-membered heterocyclic compounds containing
a nitrogen atom and at least one other non-carbon atom
(i.e. nitrogen, sulfur, or oxygen) as part of the ring.
Their names originate from the Hantzsch–Widman nomenclature.
The parent compounds are aromatic and have two double bonds; there are
successively reduced analogs (azolines and azolidines) with fewer.
One, and only one, lone pair of electrons from each heteroatom in the ring
is part of the aromatic bonding in an azole. Names of azoles maintain the
prefix upon reduction (e.g., pyrazoline, pyrazolidine).
The numbering of ring atoms in azoles starts with the heteroatom that is
not part of a double bond, and then proceeds towards the other
heteroatom.
Imidazole and other five-membered aromatic heterocyclic systems with
two nitrogens are extremely common in nature and form the core of
many biomolecules, such as histidine.
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Nitrogen only
Imidazole Pyrazole 1,2,3-Triazole 1,2,4-Triazole Tetrazole Pentazole
N, O compounds
Oxazole Isoxazole 1,2,3-Oxadiazole 1,2,4-Oxadiazole 1,2,5-Oxadiazole 1,3,4-Oxadiazole
N, S compounds
Thiazole Isothiazole Thiadiazole 1,2,4-Thiadiazole 1,2,5-Thiadiazole 1,3,4-Thiadiazole
Use as anti-fungal agents.
Ketoconazole, the first azole-based oral treatment of systemic fungal
infections, in the early 1980s.
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Triazoles, fluconazole and itraconazole, with a broader spectrum of
antifungal activity and improved safety profile were developed.
Fluconazole Itraconazole
Second-generation triazoles, including voriconazole, posaconazole and
ravuconazole, are more potent and more active against resistant
pathogens.
Voriconazole Posaconazole
Ravuconazole
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PYRAZOLE
Preferred IUPAC name: 1H-Pyrazole
Systematic IUPAC name: 1,2-Diazacyclopenta-2,4-diene
Other names: 1,2-Diazole
Pyrazoles are the important members of heterocyclic compounds with two
adjacent nitrogens in a five-membered ring system. Among the two
nitrogen atoms; one is basic and the other is neutral in nature.
Notable drugs containing a pyrazole ring are celecoxib (Celebrex) and the
anabolic steroid stanozolol.
Celecoxib Stanozolol
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STRUCTURE & AROMATICITY:
All atoms in the pyrrole ring are sp2 hybridised, so the pyrrole contains a
planar ring structure.
The sp2 hybrid orbitals overlap with each other and with "s" atomic orbital
of the four hydrogens forming C-C, C-N, C-H, and N-H sigma bonds.
All these sigma bonds lie in one plane.
Pyrazole also has unhybridized p orbitals and these are perpendicular to
the plane of the ring.
Each p orbital on carbon atom contains one electron and the p orbital on
nitrogen contains lone pair of electrons (two electrons).
The p orbital overlap to form delocalized pi molecular orbital.
Pyrazole shows aromaticity because the resulting pi molecular orbital
which contain 6 electrons (carbon having 3 electrons, one nitrogen one
electron, one nitrogen having 2 electrons) satisfies the Huckel's rule.
Resonance structures:
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Tautomerism:
Hydrogen atom migrates rapidly from one nitrogen to other nitrogen. Pyrazole
is a tautomeric substance, therefore, positions 3 and 5 are equivalent.
SYNTHESIS:
1. From Acetylene:
2. From Diazo Compound: Addition of diazo compound to acetylenic
derivatives gives pyrazole.
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3. Knorr Pyrazole Synthesis: 1,3-dicarbonyl compound reacts with
hydrazine or its derivatives in the presence of acid catalyst gives 3,5-
substituted pyrazole derivatives.
Mechanism:
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4. From Pyramidine: Pyramidine reacts with hot hydrazine solution gives
pyrazole.
Mechanism:
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5. By the condensation reaction: 1, 1, 3, 3 -tetraethoxypropane
(malonoaldehyde diethyl acetal) with hydrazine dihydrochloride.
6. From Pyrazole Derivatives:
7. From α, β- Ethylene Carbonyl Compounds:
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PHYSICAL PROPERTIES:
Colour: colorless
State: solid
Boiling point: 186 - 188oC
Melting point: 66 - 70oC, this high value is due to intermolecular hydrogen
bonding which results in a dimer.
Solubility: soluble in hot water, soluble in organic solvents.
CHEMICAL PROPERTIES:
1. Basicity:
2. Electrophilic Substitution Reaction:
Electrophilic attack at C-3 and C-5 gives unstable intermediates,
electrophilic attack at C-4 gives the stable product.
Electrophilic reactions are readily taking place in neutral and basic
media. In acidic media, pyrazole is protonated and resistant to further
electrophilic reactions.
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i. Nitration: Pyrazole reacts with nitrating mixture gives 4-nitro Pyrazole.
ii. Sulphonation: Pyrazole reacts with sulphuric acid in oleum gives
pyrazole-4-sulphonic acid.
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iii. Halogenation: Pyrazole reacts with halogens in presence of Lewis acids
gives 4-halo Pyrazole.
3. N-Alkylation: Pyrazole reacts with alkyl halides give N-alkyl pyrazole.
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4. N-Acylation and Benzoylation: Pyrazole reacts with acetyl chloride gives
N-acetylpyrazole and N-benzoylpyrazole.
5. Oxidation: Pyrazole ring is stable towards oxidation reaction, but
substitutes present on ring gets oxidized.
6. Reduction: Pyrazole reduced under lower temperature to give 4,5-
Dihydro-pyrazole, under higher temperature to give pyrazolidine.
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MEDICINAL USES:
1. Antipyrine: Used as Analgesic (relieve pain) And Antipyretic (decrease
body temperature).
2. Analgin: Used as Analgesic and Antipyretic.
3. Phenylbutazone: Used as an Analgesic, Antipyretic and Anti-
inflammatory agent.
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4. Oxybutazone: Used as an Analgesic, Antipyretic and Anti-inflammatory
agent.
5. Celecoxib: Used as an Analgesic, Antipyretic and Anti-inflammatory
agent.
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