![5. Condensation of hydrazine with α,β-unsaturated carbonyl compounds.
Condensation of hydrazine with acrolein gives Pyrazoline which can be oxidised to
pyrazole.
In α,β-unsaturated carbonyl compound, if either of the doubly bonded carbon atom is
attached to a halogen atom, pyrazole is directly obtained.
CHO
H2C
Acrolein
+
NH2-NH2
Hydrazine
N
CH2
NH2
Acraldehyde
hydrazone
N
N
H
Pyrazoline
Br (or) HgO
[O]
N
N
H
Pyrazole
C6H5-CH=C-CO-C 6H5
Br
2 -Bromo chalcone
+ C6H5NH.NH 2
Phenylhydrazine
N
N
C6H5
H5C6
C6H5
1, 3, 5 -triphenylpyrazole
+ HBr + H2O](https://image.slidesharecdn.com/heterocycliccompounds-pyrazole-synthesisofpyrazole-characteristicreactionsofpyrazole-medicinalusesof-210820155511/75/Pyrazole-Synthesis-of-Pyrazole-Characteristic-Reactions-of-Pyrazole-Medicinal-uses-of-Pyrazole-5-2048.jpg)
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Pyrazole - Synthesis of Pyrazole - Characteristic Reactions of Pyrazole - Medicinal uses of Pyrazole
- 1.
- 2. Synthesis of Pyrazole 1.Decarboxylation of various pyrazolecarboxylic acids, on heating, gives pyrazole. 2. Condensation of hydrazine with β-diketones. Condensation of acetylacetone with hydrazine N N H COOH HOOC HOOC Pyrazole- 3, 4, 5-tricarboxylic acid 300 °C N N H Pyrazole H3C O CH3 O + H2N - NH 2 Hydrazine N N H CH3 H3C 3, 5 -dimethyl pyrazole Acetyl acetone - 2H2O
- 3. Condensation of benzoylacetonewith phenylhydrazine H5C6 O CH3 O Benzoylacetone + C6H5NH.NH 2 Phenylhydrazine - H2O H5C6 O CH3 N NHC 6H5 N N CH3 HO C6H5 H5C6 - H2O N N CH3 H5C6 C6H5 3 -methyl- 1, 5 -diphenylpyrazole
- 4. 3. Condensation ofhydrazine with β-ketoesters Condensation between acetoacetic ester and phenylhydrazine 4. Condensation of hydrazine with malondialdehyde diethyl acetal H5C2O O CH3 O + C6H5NH.NH 2 Acetoacetic ester Phenylhydrazine N N CH3 O C6H5 1 -phenyl- 3 -methyl- 5 -pyrazolone OC2H5 O H5C2O H5C2O C2H5 Malondialdehyde diethyl acetal + NH2-NH2 Hydrazine N N H Pyrazole
- 5. 5. Condensation ofhydrazine with α,β-unsaturated carbonyl compounds. Condensation of hydrazine with acrolein gives Pyrazoline which can be oxidised to pyrazole. In α,β-unsaturated carbonyl compound, if either of the doubly bonded carbon atom is attached to a halogen atom, pyrazole is directly obtained. CHO H2C Acrolein + NH2-NH2 Hydrazine N CH2 NH2 Acraldehyde hydrazone N N H Pyrazoline Br (or) HgO [O] N N H Pyrazole C6H5-CH=C-CO-C 6H5 Br 2 -Bromo chalcone + C6H5NH.NH 2 Phenylhydrazine N N C6H5 H5C6 C6H5 1, 3, 5 -triphenylpyrazole + HBr + H2O
- 6. Characteristic Reactions ofPyrazole N 2 3 N H 1 5 4
- 7. 1. Reaction withinorganic acids: Pyrazole is weakly basic compound and forms salts with inorganic acids. 2. Acylation: The imino hydrogen atom of the pyrazole replaced by an acyl group. 3. Benzoylation: The imino hydrogen atom of the pyrazole replaced by benzoyl group N N H + HCl N N H .HCl Pyrazole Pyrazole hydrochloride N N H + (CH3CO) 2O Acetic anhydride N N COCH 3 N-acetylpyrazole N N H + C6H5COCl N N COC 6H5 Benzoyl chloride 1- benzoylpyrazole
- 8. 4. Oxidation: C-alkylatedpyrazole readily oxidised to the corresponding carboxylic acid. When pyrazole polycarboxylic acids are heated, corresponding monocarboxylic acids are obtained in which carboxyl group in the α-position to nitrogen is the first to be removed. Repeating decarboxylation at higher temperature, the monocarboxylic acids are converted into parent compounds. N N H3C C6H5 5- methyl- 1-phenylpyrazole KMnO4 N N HOOC C6H5 1- Phenylpyrazole- 5 -carboxylic acid N N H COOH HOOC HOOC Pyrazole- 3, 4, 5- tricarboxylic acid 200 °C - 2CO2 N N H HOOC Pyrazole- 3 - carboxylic acid 300 °C - CO2 N N H Pyrazole
- 9. 5. Reduction: Pyrazoleitself is resistant to reduction by sodium-ethanol, its N- phenyl derivative may be reduced by sodium-ethanol to the corresponding pyrazoline. Pyrazole itself catalytically reduced to pyrazoline and pyrazolidine. N N C6H5 1- phenylpyrazole Na C2H5OH N N C6H5 1- phenyl-4, 5-dihydropyrazole ( 1- phenyl pyrazoline) N N H H2 Catalyst N N H Pyrazoline H2 Catalyst NH N H Pyrazolidine
- 10. 6. Nitration: Pyrazolecan be nitrated with concentrated nitric acid in sulphuric acid. 7. Sulphonation: Sulphonated with fuming sulphuric acid. N N H N N H O2N 4- nitropyrazole HNO3 H2SO4 N N H N N H HO3S Pyrazole-4 -sulphonic acid H2SO4
- 11. 8. Halogenation: Takesplace at position-4 to form 4-halopyrazole. Chlorination: Chlorinated with sulfuryl chloride or chlorine. Bromination: Brominated with bromine in dioxan. N N H SO2Cl2 (or) Cl2 N N H Cl 4- chloropyrazole N N H N N H Br 4- bromoyrazole Br2 Dioxane
- 12. 9. Chloromethylation: Pyrazoleshaving free imino group cannot be chloromethylated – it can give carbinols. N-phenylpyrazole can readily be chloromethylated. N N H CH3 H3C CH2O HCl N N CH3 H3C CH2OH + N N H CH3 H3C HOH 2C + N N CH3 H3C HOH 2C CH2OH 3, -5-dimethylpyrazole N N C6H5 N- phenylpyrazole + CH2O HCl - H2O N N ClH 2C C6H5 4- Chloromethyl- N-phenylpyrazole
- 13. 10. Formylation: Directformylation of N-phenylpyrazole with dimethyl formamide and phosphoryl chloride gives N-phenylpyrazole-4-aldehyde. 11. Mercuration: N-phenylpyrazole is mercurated at 4-position using mercuric chloride in sodium acetate. N N C6H5 N- phenylpyrazole + (CH3)2NCHO DMF POCl3 N N OHC C6H5 N- phenylpyrazole- 4- aldehyde N N C6H5 N- phenylpyrazole HgCl2 CH3COONa N N ClHg C6H5 N- phenylpyrazole- 4- mercury chloride
- 14. 12. Reaction withalkyl halide: N-phenylpyrazole when treated with methyl iodide forms quaternary pyrazole which on boiling with concentrated aqueous potassium hydroxide decomposes to substituted hydrazine. 13. Effect of heating: Esters of pyrazole carboxylic acids are decomposed on heating to form cyclopropane derivative with the evolution of nitrogen. N N C6H5 N- phenylpyrazole + CH3I N N CH3I C6H5 + KOH C6H5NH.NH.CH 3 + HCOOH 1- methyl- 2 -phenylhydrazine N N H COOC 2H5 R R Cu powder R R COOC2H5 + N2
- 15. Medicinal Uses ofPyrazole N N H
- 16. Antipyrine/phenazone Antipyrine is anantipyretic agent used for the symptomatic treatment of acute otitis media, most commonly in combination with benzocaine. N N O H3C CH3 Antipyrine (P henazone)
- 17. Aminophenazone/aminopyrine Aminophenazone is ananalgesic drug used to treat acute migraine attacks in combination with ergotamine and caffeine. N N O H3C (H3C)2N CH3 Aminophenazone (Aminopyrine)
- 18. Celecoxib Celecoxib is usedto relieve pain, tenderness, swelling and stiffness caused by osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. N N CF 3 H3C SO2NH2 Celecoxib
- 19. Sulfaphenazole Sulfaphenazole is usedfor the treatment bacterial infections N N O2S-HN H2N Sulfaphenazole
- 20. Fomepizole Fomepizole is indicatedas an antidote for ethylene glycol or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis. N N H H3C Fomepizole
- 21. Metamizole Metamizole is anantipyretic and analgesic drug used to relieve severe and persistent fever and pain. N N CH3 CH3 HO-O 2S-N O CH3 Metamizole
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