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Pyrazole
Chemical compound

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. Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms. Pyrazole itself has few applications but many substituted pyrazoles are of commercial interest. Notable drugs containing a pyrazole ring are celecoxib (celebrex) and the anabolic steroid stanozolol.

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Properties

Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugate acid 2.49 at 25 °C).1 According to X-ray crystallography, the compound is planar. The two C-N distances are similar, both near 1.33 Å2

History

The term pyrazole was given to this class of compounds by German Chemist Ludwig Knorr in 1883.3 In a classical method developed by German chemist Hans von Pechmann in 1898, pyrazole was synthesized from acetylene and diazomethane.4

Preparation

Pyrazoles are synthesized by the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation:5

Substituted pyrazoles are prepared by condensation of 1,3-diketones with hydrazine (Knorr-type reactions).67 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:9

Occurrence and uses

In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.1011

In medicine, derivatives of pyrazole are widely used,12 including celecoxib and similar COX-2 inhibitors, zaleplon, betazole, and CDPPB.13 The pyrazole ring is found within a variety of pesticides as fungicides, insecticides and herbicides,14 including fenpyroximate, fipronil, tebufenpyrad and tolfenpyrad.15 Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDA16

3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is used in the manufacture of six commercial fungicides which are inhibitors of succinate dehydrogenase.1718

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.19

Conversion to scorpionates

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:

See also

Further reading

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.

References

  1. "Dissociation constants of organic acids and bases" (PDF). Archived (PDF) from the original on 12 July 2017. http://sites.chem.colostate.edu/diverdi/all_courses/CRC%20reference%20data/dissociation%20constants%20of%20organic%20acids%20and%20bases.pdf ↩

  2. 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. /wiki/Doi_(identifier) ↩

  3. Knorr, L. (1883). "Action of ethyl acetoacetate on phenylhydrazine. I". Chemische Berichte. 16: 2597–2599. doi:10.1002/cber.188301602194. /wiki/Ludwig_Knorr ↩

  4. 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. /wiki/Hans_von_Pechmann ↩

  5. 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. /wiki/Curr._Org._Chem. ↩

  6. Nozari, Mohammad; Addison, Anthony W.; Reeves, Gordan T.; Zeller, Matthias; Jasinski, Jerry P.; Kaur, Manpreet; Gilbert, Jayakumar G.; Hamilton, Clifton R.; Popovitch, Jonathan M.; Wolf, Lawrence M.; Crist, Lindsay E.; Bastida, Natalia (2018). "New Pyrazole- and Benzimidazole-derived Ligand Systems". Journal of Heterocyclic Chemistry. 55 (6): 1291–1307. doi:10.1002/jhet.3155. https://doi.org/10.1002/jhet.3155 ↩

  7. Eicher, T.; Hauptmann, S. (2003). The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications (2nd ed.). Wiley-VCH. ISBN 3-527-30720-6. 3-527-30720-6 ↩

  8. Johnson, William S.; Highet, Robert J. (1951). "3,5-Dimethylpyrazole". Organic Syntheses. 31: 43. doi:10.15227/orgsyn.031.0043. /wiki/Doi_(identifier) ↩

  9. Nozari, Mohammad; Addison, Anthony W.; Reeves, Gordan T.; Zeller, Matthias; Jasinski, Jerry P.; Kaur, Manpreet; Gilbert, Jayakumar G.; Hamilton, Clifton R.; Popovitch, Jonathan M.; Wolf, Lawrence M.; Crist, Lindsay E.; Bastida, Natalia (2018). "New Pyrazole- and Benzimidazole-derived Ligand Systems". Journal of Heterocyclic Chemistry. 55 (6): 1291–1307. doi:10.1002/jhet.3155. https://doi.org/10.1002/jhet.3155 ↩

  10. Fowden; Noe; Ridd; White (1959). Proc. Chem. Soc.: 131. {{cite journal}}: Missing or empty |title= (help) /wiki/Proc._Chem._Soc. ↩

  11. 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. https://doi.org/10.1038%2F184069a0 ↩

  12. 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. 978-981-16-8398-5 ↩

  13. 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. /wiki/Doi_(identifier) ↩

  14. 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. 978-981-16-8398-5 ↩

  15. FAO http://www.fao.org/docrep/019/i3518e/i3518e.pdf ↩

  16. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845. ↩

  17. 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. 9783527339471 ↩

  18. 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. 9783527347117 ↩

  19. 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 (196). doi:10.3791/65320. PMC 11164185. PMID 37427930. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164185 ↩