Pechmann_pyrazole_synthesis

Pyrazole

Pyrazole

Chemical compound

Quick Facts Names, Identifiers ...

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).[3] Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms.[4] 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:[5]

Substituted pyrazoles are prepared by condensation of 1,3-diketones with hydrazine (Knorr-type reactions).[6] For example, acetylacetone and hydrazine gives 3,5-dimethylpyrazole:[7]

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

History

The term pyrazole was given to this class of compounds by German Chemist Ludwig Knorr in 1883.[8] In a classical method developed by German chemist Hans von Pechmann in 1898, pyrazole was synthesized from acetylene and diazomethane.[9]

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[10] or sodium persulfate,[11] or by using a hydrazone in which case an azine is produced as a by-product.[12]

Occurrence and uses

Celecoxib, a pyrazole derivative used as an analgesic

In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.[13][14]

In medicine, derivatives of pyrazole are widely used,[15] including celecoxib and similar COX-2 inhibitors, zaleplon, betazole, and CDPPB.[16]

The pyrazole ring is found within a variety of pesticides as fungicides, insecticides and herbicides,[15] including fenpyroximate, fipronil, tebufenpyrad and tolfenpyrad.[17] Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDA[18]

3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is used in the manufacture of six commercial fungicides which are inhibitors of succinate dehydrogenase.[19][20]

See also

References

  1. [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 (inactive 12 April 2024). ISBN 978-0-85404-182-4.{{cite book}}: CS1 maint: DOI inactive as of April 2024 (link)
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    "Pyrazole". pubchem.ncbi.nlm.nih.gov. Retrieved 17 February 2024.
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    "Dissociation constants of organic acids and bases" (PDF). Archived (PDF) from the original on 12 July 2017.
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    Eicher, T.; Hauptmann, S. (2003). The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications (2nd ed.). Wiley-VCH. ISBN 3-527-30720-6.
  5. [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.
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    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.
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    Johnson, William S.; Highet, Robert J. (1963). "3,5-Dimethylpyrazole". Organic Syntheses; Collected Volumes, vol. 4, p. 351.
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    Knorr, L. (1883). "Action of ethyl acetoacetate on phenylhydrazine. I". Chemische Berichte. 16: 2597–2599. doi:10.1002/cber.188301602194.
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    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.
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    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.
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    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 (inactive 17 February 2024).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
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    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.
  13. [13]
    Fowden; Noe; Ridd; White (1959). Proc. Chem. Soc.: 131. {{cite journal}}: Missing or empty |title= (help)
  14. [14]
    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.
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    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.
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    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.
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    FAO
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    Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.
  19. [19]
    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.
  20. [20]
    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.

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.
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