View source for Chemistry:Pyrazole

{{Chembox
| Watchedfields = changed
| verifiedrevid = 464376682
| ImageFileL1 = Pyrazole 2D full aromatic.svg
| ImageAltL1 = Full structural formula
| ImageFileR1 = Pyrazole 2D numbered.svg
| ImageAltR1 = Skeletal formula with numbers
| ImageFileL2 = Pyrazole-3D-balls.png
| ImageAltL2 = Ball-and-stick model
| ImageFileR2 = Pyrazole-3D-spacefills.png
| ImageAltR2 = Space-filling model
| PIN = 1''H''-Pyrazole<ref name=iupac2013>{{cite book |title=Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) |publisher=[[Organization:Royal Society of Chemistry|The Royal Society of Chemistry]] |date=2014 |location=Cambridge |page=141 |doi=10.1039/9781849733069-FP001 |isbn=978-0-85404-182-4 |chapter=Front Matter}}</ref>
| SystematicName = 1,2-Diazacyclopenta-2,4-diene
| OtherNames = 1,2-Diazole
|Section1={{Chembox Identifiers
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C00481
| InChI = 1/C3H4N2/c1-2-4-5-3-1/h1-3H,(H,4,5)
| InChIKey = WTKZEGDFNFYCGP-UHFFFAOYAW
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 15967
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C3H4N2/c1-2-4-5-3-1/h1-3H,(H,4,5)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = WTKZEGDFNFYCGP-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo =288-13-1
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3QD5KJZ7ZJ
| PubChem = 1048
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 1019
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB02757
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 17241
| SMILES = c1cn[nH]c1
}}
|Section2={{Chembox Properties
| C=3 | H=4 | N=2
| Appearance =
| Density =
| MeltingPtC = 66 to 70
| MeltingPt_notes = 
| BoilingPtC = 186 to 188
| BoilingPt_notes = 
| Solubility =
| pKa = 
| pKb = 11.5
  }}
|Section3={{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt = 
  }}
|Section8={{Chembox Related
| OtherCompounds = 
 }}
}}

'''Pyrazole''' is an organic compound of [[Chemistry:Azole|azole]] group with the [[Chemistry:Chemical formula|formula]] C<sub>3</sub>H<sub>3</sub>N<sub>2</sub>H. It is a heterocycle characterized by a 5-membered ring of three [[Chemistry:Carbon|carbon]] atoms and two adjacent nitrogen atoms, which are in [[Chemistry:Arene substitution pattern|ortho-substitution]]. Pyrazole is a weak base, with p''K''<sub>b</sub> 11.5 (p''K''<sub>a</sub> of the conjugate acid 2.49 at 25&nbsp;°C).<ref>{{Cite web|title=Dissociation constants of organic acids and bases|url=http://sites.chem.colostate.edu/diverdi/all_courses/CRC%20reference%20data/dissociation%20constants%20of%20organic%20acids%20and%20bases.pdf|url-status=live|archive-url=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|archive-date=12 July 2017}}</ref> Pyrazoles are also a class of compounds that have the ring C<sub>3</sub>N<sub>2</sub> with adjacent nitrogen atoms.<ref name=Eicher>
{{cite book
|author1=Eicher, T. |author2=Hauptmann, S. | title = The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications
| publisher = Wiley-VCH
| year = 2003|edition=2nd
| location = 
| pages = 
| isbn = 3-527-30720-6}}</ref> Notable drugs containing a pyrazole ring are [[Biology:Celecoxib|celecoxib]] (celebrex) and the anabolic steroid [[Chemistry:Stanozolol|stanozolol]].

==Preparation and reactions==
Pyrazoles are synthesized by the reaction of α,β-unsaturated [[Chemistry:Aldehyde|aldehyde]]s with [[Chemistry:Hydrazine|hydrazine]] and subsequent [[Chemistry:Dehydrogenation|dehydrogenation]]:<ref>{{cite journal | last1 = Schmidt | first1 = Andreas | first2 = Andrij | last2 = Dreger | journal = Curr. Org. Chem. | year = 2011 | volume = 15 | pages = 1423–1463 | doi = 10.2174/138527211795378263 | title = Recent Advances in the Chemistry of Pyrazoles. Properties, Biological Activities, and Syntheses | issue = 9}}</ref>

:[[File:Pyrazoles synthesis.png|300px]]

Substituted pyrazoles are prepared by condensation of 1,3-[[Chemistry:Diketone|diketone]]s with hydrazine ([[Chemistry:Knorr pyrrole synthesis|Knorr]]-type reactions).<ref>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.</ref> For example, [[Chemistry:Acetylacetone|acetylacetone]] and [[Chemistry:Hydrazine|hydrazine]] gives 3,5-dimethylpyrazole:<ref>{{OrgSynth|first1 = William S.|last1 = Johnson|first2 = Robert J.|last2 = Highet|year = 1963|title = 3,5-Dimethylpyrazole|collvol = 4|collvolpages = 351|prep = CV4P0351}}</ref>
:CH<sub>3</sub>C(O)CH<sub>2</sub>C(O)CH<sub>3</sub> &nbsp; + &nbsp; N<sub>2</sub>H<sub>4</sub> &nbsp; → &nbsp; (CH<sub>3</sub>)<sub>2</sub>C<sub>3</sub>HN<sub>2</sub>H &nbsp; + &nbsp; 2&nbsp;H<sub>2</sub>O
[[File:Novel pyrazole ligands.tif|thumb|Novel pyrazole ligands]]

===History===
The term pyrazole was given to this class of compounds by German Chemist Ludwig Knorr in 1883.<ref>{{Cite journal |author=Knorr, L. |date=1883 |title=Action of ethyl acetoacetate on phenylhydrazine. I |journal=Chemische Berichte |volume=16 |pages=2597–2599 |doi=10.1002/cber.188301602194 |url=https://zenodo.org/record/1425305}}</ref> In a classical method developed by German chemist Hans von Pechmann in 1898, pyrazole was synthesized from [[Chemistry:Acetylene|acetylene]] and [[Chemistry:Diazomethane|diazomethane]].<ref>{{cite journal |title=Pyrazol aus Acetylen und Diazomethan |first=Hans | last=von Pechmann |author-link=Hans von Pechmann |journal=Berichte der deutschen chemischen Gesellschaft |volume=31 |issue=3 |pages=2950–2951 |date=1898 |doi=10.1002/cber.18980310363 |language=German |url=https://zenodo.org/record/1425922}}</ref>

===Conversion to scorpionates===
Pyrazoles react with potassium borohydride to form a class of ligands known as [[Chemistry:Scorpionate ligand|scorpionate]]. Pyrazole itself reacts with potassium borohydride at high temperatures (~200&nbsp;°C) to form a [[Chemistry:Tridentate ligand|tridentate ligand]] known as [[Chemistry:Trispyrazolylborate|Tp ligand]]:

:[[File:Potassium scorpionate.svg|400px]]

===3,5-Diphenyl-1''H''-pyrazole===
3,5-Diphenyl-1''H''-pyrazole is produced when [[Chemistry:Chalcone|(''E'')-1,3-diphenylprop-2-en-1-one]] is reacted with hydrazine hydrate in the presence of elemental [[Chemistry:Sulfur|sulfur]]<ref>{{cite journal |title=New one step synthesis of 3,5-disubstituted pyrazoles under microwave irradiation and classical heating |year=2008 |journal=[[Chemistry:Journal of Heterocyclic Chemistry|Journal of Heterocyclic Chemistry]] |volume=45 |issue=2 |pages=503–505 |doi=10.1002/jhet.5570450231 |first1=Moha |last1=Outirite |first2=Mounim |last2=Lebrini |first3=Michel |last3=Lagrenée |first4=Fouad |last4=Bentiss}}</ref> or [[Chemistry:Sodium persulfate|sodium persulfate]],<ref>{{cite journal |title=One-pot synthesis of 3,5-diphenyl-1''H''-pyrazoles from chalcones and hydrazine under mechanochemical ball milling |year=2014 |journal=Heterocycles |volume=89 |issue=1| pages=103–112 |doi=10.3987/COM-13-12867 |first1=Ze |last1=Zhang |first2=Ya-Jun |last2=Tan |first3=Chun-Shan |last3=Wang |first4=Hao-Hao |last4=Wu}}</ref> or by using a [[Chemistry:Hydrazone|hydrazone]] in which case an [[Chemistry:Azine|azine]] is produced as a by-product.<ref>{{cite journal|title = Metal-free and FeCl<sub>3</sub>-catalyzed synthesis of azines and 3,5-diphenyl-1''H''-pyrazole from hydrazones and/or ketones monitored by high resolution ESI<sup>+</sup>-MS |year=2018 |journal=Indian Journal of Chemistry, Section B |volume=57B |issue=3 |pages=362–373 |url=http://nopr.niscair.res.in/handle/123456789/43824 |first1=Jamal |last1=Lasri |first2=Ali I. |last2=Ismail}}</ref>

:[[File:Lasri condensation reaction.svg|700px]]

==Occurrence and uses==
[[File:Celecoxib structure.png|thumb|right|[[Biology:Celecoxib|Celecoxib]], a pyrazole derivative used as an analgesic]]
In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.<ref>{{cite journal |last1=Fowden |last2=Noe |last3=Ridd |last4=White |journal=Proc. Chem. Soc. |year=1959 |pages=131}}</ref><ref>{{cite journal |volume=184 |issue=4688 |pages=69–70 |last1=Noe |first1=F. F. |last2=Fowden |first2=L. |title=alpha-Amino-beta-(pyrazolyl-N) propionic acid: a new amino-acid from ''Citrullus vulgaris'' (water melon) |journal=Nature |year=1959 |doi=10.1038/184069a0 |bibcode=1959Natur.184...69B |last3=Richmond |first3=P. T. |pmid=13804343 |s2cid=37499048|doi-access=free }}</ref>

In medicine, derivatives of pyrazole are widely used,<ref name=Kabi>{{cite book |doi=10.1007/978-981-16-8399-2_7 |chapter=Overview on Biological Activities of Pyrazole Derivatives |title=Nanostructured Biomaterials |series=Materials Horizons: From Nature to Nanomaterials |year=2022 |last1=Kabi |first1=Arup K. |last2=Sravani |first2=Sattu |last3=Gujjarappa |first3=Raghuram |last4=Garg |first4=Aakriti |last5=Vodnala |first5=Nagaraju |last6=Tyagi |first6=Ujjawal |last7=Kaldhi |first7=Dhananjaya |last8=Singh |first8=Virender |last9=Gupta |first9=Sreya |last10=Malakar |first10=Chandi C. |pages=229–306 |isbn=978-981-16-8398-5 |display-authors=3 }}</ref> including [[Biology:Celecoxib|celecoxib]] and similar COX-2 inhibitors, [[Chemistry:Zaleplon|zaleplon]], [[Chemistry:Betazole|betazole]], and [[Chemistry:CDPPB|CDPPB]].<ref name=":0">{{Cite journal |last1=Faria |first1=Jéssica Venância |last2=Vegi |first2=Percilene Fazolin |last3=Miguita |first3=Ana Gabriella Carvalho |last4=dos Santos |first4=Maurício Silva |last5=Boechat |first5=Nubia |last6=Bernardino |first6=Alice Maria Rolim |date=1 November 2017 |title=Recently reported biological activities of pyrazole compounds |journal=Bioorganic & Medicinal Chemistry |volume=25 |issue=21 |pages=5891–5903 |doi=10.1016/j.bmc.2017.09.035 |pmid=28988624 |issn=0968-0896}}</ref>

The pyrazole ring is found within a variety of pesticides as fungicides, insecticides and herbicides,<ref name=Kabi/> including fenpyroximate, [[Chemistry:Fipronil|fipronil]], [[Chemistry:Tebufenpyrad|tebufenpyrad]] and tolfenpyrad.<ref>[http://www.fao.org/docrep/019/i3518e/i3518e.pdf FAO]</ref> Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDA<ref>Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.</ref>
:[[File:Pyrazole SDHI intermediate.svg|100px]]
[[Chemistry:3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid|3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid]] is used in the manufacture of six commercial fungicides which are inhibitors of [[Biology:Succinate dehydrogenase|succinate dehydrogenase]].<ref name=Walter>{{cite book |doi=10.1002/9783527693931.ch31 |chapter=Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides |title=Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals |year=2016 |last1=Walter |first1=Harald |editor-last1=Lamberth |editor-first1=Clemens |editor-first2=Jürgen |editor-last2= Dinges |publisher=Wiley |pages=405–425 |isbn=9783527339471 }}</ref><ref>{{cite book |doi=10.1002/9783527825158.ch11  |chapter=Current Trends in the Design of Fluorine‐Containing Agrochemicals |title=Organofluorine Chemistry |year=2021 |last1=Jeschke |first1=Peter |pages=363–395 |editor-first1=Kálmán |editor-last1=Szabó |editor-first2=Nicklas |editor-last2=Selander |publisher=Wiley |isbn=9783527347117 |s2cid=234149806 }}</ref>

==See also==
*[[Chemistry:3,5-Dimethylpyrazole|3,5-dimethylpyrazole]]
*[[Chemistry:Pyrazolidine|Pyrazolidine]], fully saturated analogue 
*[[Chemistry:Imidazole|imidazole]], structural analogue of pyrazole with two ''non''-adjacent nitrogen atoms.
*[[Chemistry:Isoxazole|isoxazole]], another analogue, the nitrogen atom in position 1 replaced by oxygen.

==References==
{{Reflist}}

==Further reading==
{{Cite journal |author1=A. Schmidt |author2=A. Dreger |journal=Curr. Org. Chem. |date=2011 |volume=15 |issue=16 |pages=2897–2970 |title=Recent Advances in the Chemistry of Pyrazoles. Part 2. Reactions and N-Heterocyclic Carbenes of Pyrazole |doi=10.2174/138527211796378497}}

[[Category:Pyrazoles| ]]
[[Category:Simple aromatic rings]]

{{Sourceattribution|Pyrazole}}