Pyrazole is a class of organic compound that comprises two nitrogen atoms that are placed adjacent to three carbon atoms in a ring structure. The simplest of this compound – Pyrazole – is expressed as C3H3N2H. Noteworthy, these compounds are utilized as dyes or medicines. Examples include tartrazine, used as a yellow dye; antipyrine, used as febrifuge and analgesic; phenylbutazone, employed in the treatment of arthritis; and various other dyes utilized as sensitizing instruments in photography.
However, most pyrazoles are not self-occurring. Instead, they are usually prepared through a synthesis of other compounds – Hydrazine. In light of this, this essay examines the procedure for the synthesis of pyrazole from hydrazine. It also takes a cursory look at the application of the compound to pharmacology.
Hydrazine is an organic compound made from the joining of two ammonia molecules and the loss of H2. It is expressed through the chemical formula – N2H4. It has an ammonia-like odor and is colorless. It has a boiling point of 236.3oF (133.5o C), and a melting point of 35.6oF (2.0o C).
First isolated in 1889 by Theodor Curtius, and although an immensely toxic and unstable liquid, hydrazine has two significant properties that make it relevant to science. First, it is a reducing agent that is applied industrially; for instance, it is used to reduce the risk of pipe corrosion or oxidization of various power stations. Second, it is utilized as a catalyst for polymerization, applied as fuel cells, and precursors for multiple organic syntheses, such as the fusion of pyrazole, among others.
Procedure of Synthesis of Pyrazole from Hydrazine
This process involves the creation of a cyclocondensation reaction by combining hydrazine – which acts as a bidentate nucleophile – with a carbon unit such as a 1,3-dicarbonyl derivative, or a 1,3-dicarbonyl compound, or an α,β-unsaturated ketone. (Karrouchi et al., 2018)
Synthesis through 1,3 Diketones
This is a rapid and straightforward approach to synthesis pyrazoles by combining hydrazine with a 1,3-dicarbonyl compound. This approach was first performed in 1883 when a hydrazine derivative was reacted with β-diketone 1 to produce two regioisomers 2 and 3 (Knorr, 1883). Later, a green and more effective procedure – short reaction duration, 95% yield, and effortless work-up process – was developed. It involved the compression of ethyl acetoacetate (4) with ethyl phenylhydrazine 5 (Girish et al., 2014).
Synthesis through Acetylenic Ketones
This process has been in existent for over 100 years (Moureu and Delange, 1901). It involves the combination of acetylenic ketones 16 with hydrazine derivatives 17 to synthesize pyrazoles. This reaction, in turn, also produces two regioisomers – 18 and 19. (Karrouchi et al., 2018)
Similarly, when phenylhydrazine 5 is used and reacted with diacetylene ketones 20, it produces two regioisomers – 21 and 22 – in a ration of approximately 3:2. However, when hydrazine hydrate was utilized as a nucleophile, the result was that only regioisomer 21 was separated. And this is likely a result of the bonding of the ethyl ester group to hydrogen (Baldwin et al., 2001).
Synthesis through Vinyl Ketones
This involves the creation of a cyclocondensation reaction between a hydrazine derivative and an α,β-ethylenic ketone. This, in turn, results in a composite of pyrazolines, which produces a pyrazole ring after oxidization.
Also, the synthesis of 3,5-diaryl-1H-pyrazoles can be achieved through this process. This will involve the combination of hydrogen peroxide with β-arylchalcones 33 and which in turn produces epoxides 34. Afterward, hydrazine hydrate is then added, which produces pyrazoline intermediates 35. It is then dehydrated to build pyrazoles 36 (Bhat et al., 2015).
In the same vein, the fusion of 1,3,5-trisubstituted pyrazoles can also be achieved through this process. It involves the combination of phenylhydrazine with the α, β-ethylenic ketone 41. This is done in acetic acid and with iodine present. This, in turn, will result in the composite of pyrazole 42 with a 70% yield (Ponnala and Prasad, 2006).
Synthesis through Vinyl Ketones Having a Leaving Group
This involves a process whereby an α, β-ethylenic ketones which have a leaving group, is combined with a hydrazine derivative to create pyrazoline. After this, the leaving group is then removed to produce the required pyrazole. (Karrouchi et al., 2018)
For instance, the synthesis of 1-methyl(aryl)-3-phenyl-5-alkyl(aryl)pyrazoles 50 can be achieved through a regioselective compression reaction. This is done by combining phenylhydrazine and methyl with α-benzotriazolylenones 48. This results in an intermediate pyrazoline 49, which is then treated through a basic medium to produce the required pyrazoles. This is done through the excision of benzotriazole, and this synthesis is achieved at a 50 – 94% yield rate (Katrizky et al., 2001).
Noteworthy, the use of benzotriazole is advantageous because the proton in the α-position becomes more acidic than usual. And as such, it allows access to the tetrasubstituted pyrazoles 50 by permitting functionalization in all 4 positions of the pyrazoline nucleus.
Applications of Pyrazole to Pharmacology
Pyrazole is of high relevance to pharmacology. It has multiple applications to specific pharmacological activity. Prominent among them include.
Analgesic and Anti-Inflammatory Activity
The pyrazole also functions as an analgesic and anti-inflammatory agent. According to Kamble et al., compound 294 displayed high COX-II inhibition (78.91±0.80 %). Similarly, according to Behkit et al., compound 295 showed substantial anticoagulant activity like that of indomethacin (LD50 > 500 mg/Kg). It also displayed a considerable exercise of selective inhibition against the COX-2 enzyme.
The pyrazole also functions as an anti-diabetic agent. In this light, various tests have been carried out to determine the potency of Pyrazole compounds. According to Cottineau et al., compound 441 constitutes the best hypoglycemic agent. Also, compound 445 was recognized as showing a reasonably strong binding activity against the PPARγ (Choi et al., 2010).
Today, Pyrazole is among the most analyzed group of organic compounds in the azole family. This is because the compound has diverse pharmacological applications, especially in areas such as anti-obesity, antidepressant, antipsychotic CDPPB, and anti-inflammatory, among others. However, as pyrazoles do not occur as of nature, it became necessary to explore its synthesis.
To this end, various methods have evolved to achieve the synthesis of pyrazoles, such as through multicomponent reactions and dipolar cycloadditions. Regardless, the leading process remains the synthesis of pyrazole from hydrazine.
Baldwin, J.E.; Pritchard, G.J.; Rathmell, R.E. The reactions of diacetylenic ketones with nitrogen nucleophiles; facile preparation of alkynyl substituted pyrimidines and pyrazoles. J. Chem. Soc. Perkin Trans. 1 2001, 2906–2908, doi:10.1039/B108645F.
Bekhit, A.A.; Ashour, H.M.A.; Abdel Ghany, Y.S.; Bekhit, A.-A.; Baraka, A. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur. J. Med. Chem. 2008, 43, 456–463, doi:10.1016/j.ejmech.2007.03.030.
Bhat, B.A.; Puri, S.C.; Qurishi, M.A.; Dhar, K.L.; Qazi, G.N. Synthesis of 3,5‑diphenyl‑1H‑pyrazoles. Synth. Commun. 2005, 35, 1135–1142, doi:10.1081/SCC-200054225.
Choi, J.; Park, Y.; Lee, H.S.; Yang, Y.; Yoon, S. 1,3-Diphenyl-1H-pyrazole derivatives as a new series of potent PPARγ partial agonists. Bioorg. Med. Chem. 2010, 18, 8315–8323, doi:10.1016/j.bmc.2010.09.068.
Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J. Synthesis and hypoglycemic evaluation of substituted pyrazole-4-carboxylic acids. Bioorg. Med. Chem. Lett. 2002, 12, 2105–2108, doi:10.1016/ S0960-894X(02)00380-3.
Girish, Y.R.; Kumar, K.S.S.; Manasa, H.S.; Shashikanth, S. ZnO: An Ecofriendly, Green Nano‑catalyst for the Synthesis of Pyrazole Derivatives under Aqueous Media. J. Chin. Chem. Soc. 2014, 61, 1175–1179, doi:10.1002/jccs.201400170.
Kamble, R. D.; Meshram, R. J.; Hese, S. V.; More, R. A.; Kamble, S. S.; Gacche, R. N.; Dawane, B. S. Synthesis and in silico investigation of thiazoles bearing pyrazoles derivatives as anti-inflammatory agents. Comput. Biol. Chem. 2016, 61, 86-96, https://doi.org/10.1016/j.compbiolchem.2016.01.007.
Karrouchi, K., Radi, S., Ramli, Y., Taoufik, J., Mabkhot, Y. N., Al-Aizari, F. A., & Ansar, M. (2018). Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Molecules (Basel, Switzerland), 23(1), 134. Retrieved from https://doi.org/10.3390/molecules23010134
Katritzky, A.R.; Wang, M.; Zhang, S.; Voronkov, M.V.; Steel, P.J. Regioselective synthesis of polysubstituted pyrazoles and isoxazoles. J. Org. Chem. 2001, 66, 6787–6791, doi:10.1021/jo0101407.
Knorr, L. Einwirkung von acetessigester auf phenylhydrazin. Eur. J. Inorg. Chem. 1883, 16, 2597–2599, doi:10.1002/cber.188301602194.
Moureu, C.; Delange, R. Over some Acetylenketone and over a new method to the synthesis of β-Diketones. Bull. Soc. Chim. Fr. 1901, 25, 302–313.
Ponnala, S.; Prasad, S.D. Iodine‑Mediated Synthesis of 2‑Arylbenzoxazoles, 2‑Arylbenzimidazoles, and 1,3,5‑Trisubstituted Pyrazoles. Synth. Commun. 2006, 36, 2189–2194, doi:10.1080/00397910600638879.
The Editors of Encyclopaedia Britannica (1998) Hydrazine, Encyclopaedia Britannica, Inc. Retrieved from https://www.britannica.com/science/hydrazine
The Editors of Encyclopaedia Britannica (2008) Pyrazole, Encyclopaedia Britannica, Inc. Retrieved from https://www.britannica.com/science/pyrazole
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