Pyrazole Explained

Pyrazole is an organic compound of azole group with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugate acid 2.49 at 25 °C).[1] Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms.[2] Notable drugs containing a pyrazole ring are celecoxib (celebrex) and the anabolic steroid stanozolol.

Preparation and reactions

Pyrazoles are synthesized by the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation:[3]

Substituted pyrazoles are prepared by condensation of 1,3-diketones with hydrazine (Knorr-type reactions).[4] For example, acetylacetone and hydrazine gives 3,5-dimethylpyrazole:

CH3C(O)CH2C(O)CH3   +   N2H4   →   (CH3)2C3HN2H   +   2 H2OA wide variety of pyrazoles can be made so:

History

The term pyrazole was given to this class of compounds by German Chemist Ludwig Knorr in 1883.[5] In a classical method developed by German chemist Hans von Pechmann in 1898, pyrazole was synthesized from acetylene and diazomethane.[6]

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:

3,5-Diphenyl-1H-pyrazole

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[7] or sodium persulfate,[8] or by using a hydrazone in which case an azine is produced as a by-product.[9]

Occurrence and uses

In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.[10] [11]

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,[12] including fenpyroximate, fipronil, tebufenpyrad and tolfenpyrad.[14] Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDA[15]

3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is used in the manufacture of six commercial fungicides which are inhibitors of succinate dehydrogenase.[16] [17]

See also

Further reading

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

Notes and References

  1. Web site: Dissociation constants of organic acids and bases. live. https://web.archive.org/web/20170712202558/http://sites.chem.colostate.edu/diverdi/all_courses/CRC%20reference%20data/dissociation%20constants%20of%20organic%20acids%20and%20bases.pdf. 12 July 2017.
  2. Book: Eicher, T. . Hauptmann, S. . The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications. Wiley-VCH. 2003. 2nd. 3-527-30720-6.
  3. Schmidt . Andreas . Andrij . Dreger . . 2011 . 15 . 1423–1463 . 10.2174/138527211795378263 . Recent Advances in the Chemistry of Pyrazoles. Properties, Biological Activities, and Syntheses . 9.
  4. 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.
  5. Knorr, L. . 1883 . Action of ethyl acetoacetate on phenylhydrazine. I . Chemische Berichte . 16 . 2597–2599 . Ludwig Knorr . 10.1002/cber.188301602194 .
  6. Pyrazol aus Acetylen und Diazomethan . Hans . von Pechmann . Hans von Pechmann . . 31 . 3 . 2950–2951 . 1898 . 10.1002/cber.18980310363 . German .
  7. New one step synthesis of 3,5-disubstituted pyrazoles under microwave irradiation and classical heating . 2008 . . 45 . 2 . 503–505 . 10.1002/jhet.5570450231 . Moha . Outirite . Mounim . Lebrini . Michel . Lagrenée . Fouad . Bentiss.
  8. One-pot synthesis of 3,5-diphenyl-1H-pyrazoles from chalcones and hydrazine under mechanochemical ball milling . 2014 . . 89 . 1. 103–112 . 10.3987/COM-13-12867 . Ze . Zhang . Ya-Jun . Tan . Chun-Shan . Wang . Hao-Hao . Wu. 17 February 2024 . free .
  9. 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 . 2018 . Indian Journal of Chemistry, Section B . 57B . 3 . 362–373 . Jamal . Lasri . Ali I. . Ismail.
  10. Fowden . Noe . Ridd . White . . 1959 . 131.
  11. 184 . 4688 . 69–70 . Noe . F. F. . Fowden . L. . alpha-Amino-beta-(pyrazolyl-N) propionic acid: a new amino-acid from Citrullus vulgaris (water melon) . . 1959 . 10.1038/184069a0 . 1959Natur.184...69B . Richmond . P. T. . 13804343 . 37499048. free .
  12. Book: 10.1007/978-981-16-8399-2_7 . Overview on Biological Activities of Pyrazole Derivatives . Nanostructured Biomaterials . Materials Horizons: From Nature to Nanomaterials . 2022 . Kabi . Arup K. . Sravani . Sattu . Gujjarappa . Raghuram . Garg . Aakriti . Vodnala . Nagaraju . Tyagi . Ujjawal . Kaldhi . Dhananjaya . Singh . Virender . Gupta . Sreya . Malakar . Chandi C. . 229–306 . 978-981-16-8398-5 . 3 .
  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 . 10.1016/j.bmc.2017.09.035 . 28988624 . 0968-0896.
  14. http://www.fao.org/docrep/019/i3518e/i3518e.pdf FAO
  15. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.
  16. Book: 10.1002/9783527693931.ch31 . Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides . Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals . 2016 . Walter . Harald . Lamberth . Clemens . Jürgen . Dinges . Wiley . 405–425 . 9783527339471 .
  17. Book: 10.1002/9783527825158.ch11 . Current Trends in the Design of Fluorine-Containing Agrochemicals . Organofluorine Chemistry . 2021 . Jeschke . Peter . 363–395 . Kálmán . Szabó . Nicklas . Selander . Wiley . 9783527347117 . 234149806 .

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