pyrazole

Pyrazole is a weak base, with pK_b 11.5 (pK_a of the conjugate acid 2.49 at 25 °C).{{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}} According to X-ray crystallography, the compound is planar. The two C-N distances are similar, both near 1.33 Å{{cite journal |doi=10.3891/acta.chem.scand.27-1845 |title=The Structure of Pyrazole, C3H4N2, at 295 K and 108 K as determined by X-Ray Diffraction |date=1973 |last1=La Cour |first1=Troels |last2=Rasmussen |first2=Svend Erik |last3=Hopf |first3=Henning |last4=Waisvisz |first4=Jacques M. |last5=Van Der Hoeven |first5=Marcel G. |last6=Swahn |first6=Carl-Gunnar |journal=Acta Chemica Scandinavica |volume=27 |pages=1845–1854 }}

The term pyrazole was given to this class of compounds by German Chemist Ludwig Knorr in 1883.{{Cite journal |author=Knorr, L. |date=1883 |title=Action of ethyl acetoacetate on phenylhydrazine. I |journal=Chemische Berichte |volume=16 |pages=2597–2599 |author-link=Ludwig Knorr |doi=10.1002/cber.188301602194 |url=https://zenodo.org/record/1425305}} In a classical method developed by German chemist Hans von Pechmann in 1898, pyrazole was synthesized from acetylene and diazomethane.{{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}}

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

:File:Pyrazoles synthesis.png

Substituted pyrazoles are prepared by condensation of 1,3-diketones with hydrazine (Knorr-type reactions).{{cite journal | url=https://doi.org/10.1002/jhet.3155 | doi=10.1002/jhet.3155 | title=New Pyrazole- and Benzimidazole-derived Ligand Systems | date=2018 | last1=Nozari | first1=Mohammad | last2=Addison | first2=Anthony W. | last3=Reeves | first3=Gordan T. | last4=Zeller | first4=Matthias | last5=Jasinski | first5=Jerry P. | last6=Kaur | first6=Manpreet | last7=Gilbert | first7=Jayakumar G. | last8=Hamilton | first8=Clifton R. | last9=Popovitch | first9=Jonathan M. | last10=Wolf | first10=Lawrence M. | last11=Crist | first11=Lindsay E. | last12=Bastida | first12=Natalia | journal=Journal of Heterocyclic Chemistry | volume=55 | issue=6 | pages=1291–1307 | url-access=subscription }}

{{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}} For example, acetylacetone and hydrazine gives 3,5-dimethylpyrazole:{{cite journal|journal=Organic Syntheses|first1 = William S.|last1 = Johnson|first2 = Robert J.|last2 = Highet|title = 3,5-Dimethylpyrazole|year=1951|volume=31|page=43|doi=10.15227/orgsyn.031.0043}}

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

A wide variety of pyrazoles can be made so:

:File:Aryl camphor-fused pyrazole synth.pngFile:Aryl-alicyclic quinol-pyrazole synth.pngFile:Aryl-fused quinol-pyrazole synth.png

File:Celecoxib structure.png, a pyrazole-derived analgesic]]

In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.{{cite journal |last1=Fowden |last2=Noe |last3=Ridd |last4=White |journal=Proc. Chem. Soc. |year=1959 |pages=131}}{{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 }}

In medicine, derivatives of pyrazole are widely used,{{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 }} including celecoxib and similar COX-2 inhibitors, zaleplon, betazole, and CDPPB.{{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}}

The pyrazole ring is found within a variety of pesticides as fungicides, insecticides and herbicides, including fenpyroximate, fipronil, tebufenpyrad and tolfenpyrad.[http://www.fao.org/docrep/019/i3518e/i3518e.pdf FAO] Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDATaylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.

:File:Pyrazole SDHI intermediate.svg

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

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.{{cite journal | pmid=37427930 | date=2023 | last1=Xiao | first1=T. | last2=Chen | first2=Y. | last3=Boisvert | first3=A. | last4=Cole | first4=M. | last5=Kimbrough | first5=A. | title=Chronic Intermittent Ethanol Vapor Exposure Paired with Two-Bottle Choice to Model Alcohol Use Disorder | journal=Journal of Visualized Experiments | issue=196 | doi=10.3791/65320 | pmc=11164185 }}

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:

:File:Potassium scorpionate.svg

• 3,5-dimethylpyrazole
• Pyrazolidine, fully saturated analogue
• imidazole, structural analogue of pyrazole with two non-adjacent nitrogen atoms.
• isoxazole, another analogue, the nitrogen atom in position 1 replaced by oxygen.

{{Reflist}}

{{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:Aromatic bases

Category:Simple aromatic rings

Category:Substances discovered in the 19th century