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Pyrazole

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Pyrazole is an organic compound with the formula (CH)3N2H. It is a heterocycle characterized as an azole with a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole itself has few applications but many substituted pyrazoles are of commercial interest.

Pyrazole
Full structural formula
Skeletal formula with numbers
Ball-and-stick model
Space-filling model
Names
Preferred IUPAC name
1H-Pyrazole[1]
Systematic IUPAC name
1,2-Diazacyclopenta-2,4-diene
Other names
1,2-Diazole
Identifiers
3D model (JSmol)
103775
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.005.471 Edit this at Wikidata
EC Number
  • 206-017-1
1360
KEGG
UNII
  • InChI=1S/C3H4N2/c1-2-4-5-3-1/h1-3H,(H,4,5) checkY
    Key: WTKZEGDFNFYCGP-UHFFFAOYSA-N checkY
  • InChI=1/C3H4N2/c1-2-4-5-3-1/h1-3H,(H,4,5)
    Key: WTKZEGDFNFYCGP-UHFFFAOYAW
  • c1cn[nH]c1
Properties
C3H4N2
Molar mass 68.079 g·mol−1
Melting point 66 to 70 °C (151 to 158 °F; 339 to 343 K)
Boiling point 186 to 188 °C (367 to 370 °F; 459 to 461 K)
Basicity (pKb) 11.5
Hazards
GHS labelling:[2]
GHS05: CorrosiveGHS06: ToxicGHS07: Exclamation markGHS08: Health hazard
Danger
H302, H311, H315, H318, H319, H335, H372, H412
P260, P261, P262, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P305+P354+P338, P316, P317, P319, P321, P330, P332+P317, P337+P317, P361+P364, P362+P364, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Properties

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Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugate acid 2.49 at 25 °C).[3] According to X-ray crystallography, the compound is planar. The two C-N distances are similar, both near 1.33 Å[4]

Substituted pyrazoles

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Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms.[5] Notable drugs containing a pyrazole ring are celecoxib (celebrex) and the anabolic steroid stanozolol.

Preparation and reactions

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Pyrazoles are synthesized by the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation:[6]

 

Substituted pyrazoles are prepared by condensation of 1,3-diketones with hydrazine (Knorr-type reactions).[7] For example, acetylacetone and hydrazine gives 3,5-dimethylpyrazole:[8]

CH3C(O)CH2C(O)CH3   +   N2H4   →   (CH3)2C3HN2H   +   2 H2O

A wide variety of pyrazoles can be made so:[7]

   

History

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The term pyrazole was given to this class of compounds by German Chemist Ludwig Knorr in 1883.[9] In a classical method developed by German chemist Hans von Pechmann in 1898, pyrazole was synthesized from acetylene and diazomethane.[10]

Conversion to scorpionates

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Pyrazoles react with potassium borohydride to form a class of ligands known as scorpionate. Pyrazole itself reacts with potassium borohydride at high temperatures (~200 °C) to form a tridentate ligand known as Tp ligand:

 

3,5-Diphenyl-1H-pyrazole

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3,5-Diphenyl-1H-pyrazole is produced when (E)-1,3-diphenylprop-2-en-1-one is reacted with hydrazine hydrate in the presence of elemental sulfur[11] or sodium persulfate,[12] or by using a hydrazone in which case an azine is produced as a by-product.[13]

 

Occurrence and uses

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Celecoxib, a pyrazole-derived analgesic

In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.[14][15]

In medicine, derivatives of pyrazole are widely used,[16] including celecoxib and similar COX-2 inhibitors, zaleplon, betazole, and CDPPB.[17] The pyrazole ring is found within a variety of pesticides as fungicides, insecticides and herbicides,[16] including fenpyroximate, fipronil, tebufenpyrad and tolfenpyrad.[18] Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDA[19]

 

3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is used in the manufacture of six commercial fungicides which are inhibitors of succinate dehydrogenase.[20][21]

Pyrazole is an inhibitor of the alcohol dehydrogenase enzyme, and, as such, is used as an adjuvant with ethanol, to induce alcohol dependency in experimental laboratory mice.[22]

See also

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References

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  1. ^ "Front Matter". Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 141. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4.
  2. ^ "Pyrazole". pubchem.ncbi.nlm.nih.gov. Retrieved 17 February 2024.
  3. ^ "Dissociation constants of organic acids and bases" (PDF). Archived (PDF) from the original on 12 July 2017.
  4. ^ La Cour, Troels; Rasmussen, Svend Erik; Hopf, Henning; Waisvisz, Jacques M.; Van Der Hoeven, Marcel G.; Swahn, Carl-Gunnar (1973). "The Structure of Pyrazole, C3H4N2, at 295 K and 108 K as determined by X-Ray Diffraction". Acta Chemica Scandinavica. 27: 1845–1854. doi:10.3891/acta.chem.scand.27-1845.
  5. ^ Eicher, T.; Hauptmann, S. (2003). The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications (2nd ed.). Wiley-VCH. ISBN 3-527-30720-6.
  6. ^ Schmidt, Andreas; Dreger, Andrij (2011). "Recent Advances in the Chemistry of Pyrazoles. Properties, Biological Activities, and Syntheses". Curr. Org. Chem. 15 (9): 1423–1463. doi:10.2174/138527211795378263.
  7. ^ a b Nozari, M., Addison, A., Reeves, G.T, Zeller, M., Jasinski, J.P., Kaur, M., Gilbert, J. G., Hamilton, C. R., Popovitch, J. M., Wolf, L. M., Crist, L. E., Bastida, N., (2018) Journal of heterocyclic Chemistry 55, 6, 1291-1307. https://doi.org/10.1002/jhet.3155.
  8. ^ Johnson, William S.; Highet, Robert J. (1951). "3,5-Dimethylpyrazole". Organic Syntheses. 31: 43. doi:10.15227/orgsyn.031.0043.
  9. ^ Knorr, L. (1883). "Action of ethyl acetoacetate on phenylhydrazine. I". Chemische Berichte. 16: 2597–2599. doi:10.1002/cber.188301602194.
  10. ^ von Pechmann, Hans (1898). "Pyrazol aus Acetylen und Diazomethan". Berichte der deutschen chemischen Gesellschaft (in German). 31 (3): 2950–2951. doi:10.1002/cber.18980310363.
  11. ^ Outirite, Moha; Lebrini, Mounim; Lagrenée, Michel; Bentiss, Fouad (2008). "New one step synthesis of 3,5-disubstituted pyrazoles under microwave irradiation and classical heating". Journal of Heterocyclic Chemistry. 45 (2): 503–505. doi:10.1002/jhet.5570450231.
  12. ^ Zhang, Ze; Tan, Ya-Jun; Wang, Chun-Shan; Wu, Hao-Hao (2014). "One-pot synthesis of 3,5-diphenyl-1H-pyrazoles from chalcones and hydrazine under mechanochemical ball milling". Heterocycles. 89 (1): 103–112. doi:10.3987/COM-13-12867.
  13. ^ Lasri, Jamal; Ismail, Ali I. (2018). "Metal-free and FeCl3-catalyzed synthesis of azines and 3,5-diphenyl-1H-pyrazole from hydrazones and/or ketones monitored by high resolution ESI+-MS". Indian Journal of Chemistry, Section B. 57B (3): 362–373.
  14. ^ Fowden; Noe; Ridd; White (1959). Proc. Chem. Soc.: 131. {{cite journal}}: Missing or empty |title= (help)
  15. ^ Noe, F. F.; Fowden, L.; Richmond, P. T. (1959). "alpha-Amino-beta-(pyrazolyl-N) propionic acid: a new amino-acid from Citrullus vulgaris (water melon)". Nature. 184 (4688): 69–70. Bibcode:1959Natur.184...69B. doi:10.1038/184069a0. PMID 13804343. S2CID 37499048.
  16. ^ a b Kabi, Arup K.; Sravani, Sattu; Gujjarappa, Raghuram; et al. (2022). "Overview on Biological Activities of Pyrazole Derivatives". Nanostructured Biomaterials. Materials Horizons: From Nature to Nanomaterials. pp. 229–306. doi:10.1007/978-981-16-8399-2_7. ISBN 978-981-16-8398-5.
  17. ^ Faria, Jéssica Venância; Vegi, Percilene Fazolin; Miguita, Ana Gabriella Carvalho; dos Santos, Maurício Silva; Boechat, Nubia; Bernardino, Alice Maria Rolim (1 November 2017). "Recently reported biological activities of pyrazole compounds". Bioorganic & Medicinal Chemistry. 25 (21): 5891–5903. doi:10.1016/j.bmc.2017.09.035. ISSN 0968-0896. PMID 28988624.
  18. ^ FAO
  19. ^ Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.
  20. ^ Walter, Harald (2016). "Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides". In Lamberth, Clemens; Dinges, Jürgen (eds.). Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals. Wiley. pp. 405–425. doi:10.1002/9783527693931.ch31. ISBN 9783527339471.
  21. ^ Jeschke, Peter (2021). "Current Trends in the Design of Fluorine-Containing Agrochemicals". In Szabó, Kálmán; Selander, Nicklas (eds.). Organofluorine Chemistry. Wiley. pp. 363–395. doi:10.1002/9783527825158.ch11. ISBN 9783527347117. S2CID 234149806.
  22. ^ Xiao, T.; Chen, Y.; Boisvert, A.; Cole, M.; Kimbrough, A. (2023). "Chronic Intermittent Ethanol Vapor Exposure Paired with Two-Bottle Choice to Model Alcohol Use Disorder". Journal of Visualized Experiments : Jove (196). doi:10.3791/65320. PMC 11164185. PMID 37427930.

Further reading

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A. Schmidt; A. Dreger (2011). "Recent Advances in the Chemistry of Pyrazoles. Part 2. Reactions and N-Heterocyclic Carbenes of Pyrazole". Curr. Org. Chem. 15 (16): 2897–2970. doi:10.2174/138527211796378497.

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