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Pyrazole
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<h2 id="properties">Properties</h2> <p>Pyrazole is a weak base, with p<i>K</i>b 11.5 (p<i>K</i>a of the conjugate acid 2.49 at 25 °C).<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a> According to <a href="/facts/X-ray_crystallography/WtI0F5DN">X-ray crystallography</a>, the compound is planar. The two C-N distances are similar, both near 1.33 Å<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> </p> <h2 id="history">History</h2> <p>The term pyrazole was given to this class of compounds by German Chemist <a href="/facts/Ludwig_Knorr/hkSCcbQ6">Ludwig Knorr</a> in 1883.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> In a classical method developed by German chemist <a href="/facts/Hans_von_Pechmann/o2Ehtu2X">Hans von Pechmann</a> in 1898, pyrazole was synthesized from <a href="/facts/Acetylene/yaDh6cmJ">acetylene</a> and <a href="/facts/Diazomethane/KyBPQTGb">diazomethane</a>.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p> <h2 id="preparation">Preparation</h2> <p>Pyrazoles are synthesized by the reaction of α,β-unsaturated <a href="/facts/Aldehyde/xSIRkW03">aldehydes</a> with <a href="/facts/Hydrazine/G7P5ITzU">hydrazine</a> and subsequent <a href="/facts/Dehydrogenation/vwFAAqzp">dehydrogenation</a>:<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p> <p>Substituted pyrazoles are prepared by condensation of 1,3-<a href="/facts/Diketone/JbdbaftY">diketones</a> with hydrazine (<a href="/facts/Knorr_pyrrole_synthesis/mL0bm7pJ">Knorr</a>-type reactions).<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> For example, <a href="/facts/Acetylacetone/Ku1k97xz">acetylacetone</a> and <a href="/facts/Hydrazine/G7P5ITzU">hydrazine</a> gives 3,5-dimethylpyrazole:<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> CH3C(O)CH2C(O)CH3 + N2H4 → (CH3)2C3HN2H + 2 H2O <p>A wide variety of pyrazoles can be made so:<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="occurrence-and-uses">Occurrence and uses</h2> <p>In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of <a href="/facts/Watermelons/Tvtd0dDa">watermelons</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>In medicine, derivatives of pyrazole are widely used,<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> including <a href="/facts/Celecoxib/DqbVQYSs">celecoxib</a> and similar <a href="/facts/COX-2_inhibitors/UpxLSTyN">COX-2 inhibitors</a>, <a href="/facts/Zaleplon/NS8RvlIM">zaleplon</a>, <a href="/facts/Betazole/X5j5JA72">betazole</a>, and <a href="/facts/CDPPB/hbjkHTnj">CDPPB</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> The pyrazole ring is found within a variety of pesticides as fungicides, insecticides and herbicides,<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> including fenpyroximate, <a href="/facts/Fipronil/wf1Lu7ev">fipronil</a>, <a href="/facts/Tebufenpyrad/M2m0FN3W">tebufenpyrad</a> and tolfenpyrad.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Pyrazole moieties are listed among the highly used ring systems for small molecule drugs by the US FDA<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <p><a href="/facts/3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic_acid/xSd55RRc">3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</a> is used in the manufacture of six commercial fungicides which are inhibitors of <a href="/facts/Succinate_dehydrogenase/AswKYLm3">succinate dehydrogenase</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>Pyrazole is an inhibitor of the <a href="/facts/Alcohol_dehydrogenase/XWwHgyad">alcohol dehydrogenase</a> enzyme, and, as such, is used as an adjuvant with ethanol, to induce alcohol dependency in experimental laboratory mice.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h3>Conversion to scorpionates</h3> <p>Pyrazoles react with <a href="/facts/Potassium_borohydride/5zFNIPw7">potassium borohydride</a> to form a class of ligands known as <a href="/facts/Scorpionate_ligand/l9mFlmK3">scorpionate</a>. Pyrazole itself reacts with <a href="/facts/Potassium_borohydride/5zFNIPw7">potassium borohydride</a> at high temperatures (~200 °C) to form a <a href="/facts/Tridentate_ligand/xdrkcRGB">tridentate ligand</a> known as <a href="/facts/Trispyrazolylborate/CYfYo0f6">Tp ligand</a>: </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/3%2c5-Dimethylpyrazole/vvIDgQI2">3,5-dimethylpyrazole</a></li> <li><a href="/facts/Pyrazolidine/9fMmsTPw">Pyrazolidine</a>, fully saturated analogue</li> <li><a href="/facts/Imidazole/5MybM6Hh">imidazole</a>, structural analogue of pyrazole with two <i>non</i>-adjacent nitrogen atoms.</li> <li><a href="/facts/Isoxazole/uxqUPMdP">isoxazole</a>, another analogue, the nitrogen atom in position 1 replaced by oxygen.</li></ul> <h2 id="further-reading">Further reading</h2> <p>A. Schmidt; A. Dreger (2011). "Recent Advances in the Chemistry of Pyrazoles. Part 2. Reactions and N-Heterocyclic Carbenes of Pyrazole". <i>Curr. Org. Chem</i>. 15 (16): 2897–2970. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.2174%2F138527211796378497">10.2174/138527211796378497</a>. </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Dissociation constants of organic acids and bases" (PDF). Archived (PDF) from the original on 12 July 2017. <a href="http://sites.chem.colostate.edu/diverdi/all_courses/CRC%20reference%20data/dissociation%20constants%20of%20organic%20acids%20and%20bases.pdf" target="_blank">http://sites.chem.colostate.edu/diverdi/all_courses/CRC%20reference%20data/dissociation%20constants%20of%20organic%20acids%20and%20bases.pdf</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Knorr, L. (1883). "Action of ethyl acetoacetate on phenylhydrazine. I". Chemische Berichte. 16: 2597–2599. doi:10.1002/cber.188301602194. <a href="/wiki/Ludwig_Knorr" target="_blank">/wiki/Ludwig_Knorr</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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. <a href="/wiki/Hans_von_Pechmann" target="_blank">/wiki/Hans_von_Pechmann</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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. <a href="/wiki/Curr._Org._Chem." target="_blank">/wiki/Curr._Org._Chem.</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="https://doi.org/10.1002/jhet.3155" target="_blank">https://doi.org/10.1002/jhet.3155</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Eicher, T.; Hauptmann, S. (2003). The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications (2nd ed.). Wiley-VCH. 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