Physical Properties 

Pyrazole is a colorless crystalline solid with a pyridine-like odor and weak base, with a pKb  of 11.5. It is partially  soluble in water with an mp of 70°C and a bp of 188°C. In concentrated solution it exists in dimeric form due to intermolecular hydrogen bonding. 

UV (ethanol) λnm (ε): 210 (3.53). 1 H NMR (CCl4 ), δ (ppm): C3 –H, 7.61; C4 –H, 6.31; C5 –H, 7.61; N–H, 12.64. 13C NMR (CDCl3 ), δ (ppm): C3 , 134.3; C4 , 105.2, C5 , 135.3. 

Chemical Reactivity

Pyrazole has two ring nitrogen atoms in which N1  is pyrrolic and N2  is pyridine-like. The N1  nitrogen is  not reactive but is deprotonated in the presence of a base-forming anion. The presence of both electronegative nitrogen atoms in the pyrazole ring reduces the electron density of the C3 - and C5 -positions leaving  electron density of C4 -position unaltered. Thus the C4 -position is vulnerable to electrophilic attack. The C3 electrophilic-position may undergo deprotonation in the presence of a strong base leading to ring opening.  Protonation of pyrazole in strong acid leads to pyrazolium cations, which undergo electrophilic substitution  preferentially at C3  rather than C4 . The pyrazole anion is not reactive toward nucleophiles but is mostly reactive to electrophiles. 

The pyrazole ring is resistant to oxidation and reduction but the groups, such as alkyl and formyl attached to the  ring, are oxidized to respective acids. Only electrolytic oxidation, ozonolysis, and a strong base cause ring opening.

Pyrazole is a five-membered, sp2 -hybridized and delocalized 6π-electron heteroaromatic ring system with two  adjacent nitrogen atoms and three carbon atoms. When a lone pair of electrons is not part of the aromatic system  and extended in the plane of the ring, it is responsible for the basicity of the molecule and resembles amines. The  delocalized lone pair of electrons on the ring nitrogen connected with hydrogen participating in the aromatic sextet  is nonbasic. Parent pyrazole has a planar structure with three possible tautomeric forms: A, B, and C. It exists as a  dimer in concentrated solution due to hydrogen bonding.

The bond lengths and bond angles are calculated by microwave spectra and are found consistent with structural  formulae. The C3-C4  bond length is longest among the rest of the bonds and the angle C5N1N2  is the highest  (113.0 degrees) among the rest of the internal bond angles. The calculated electron densities on the ring atom revealed that C4  has maximum electron density and is prone to electrophilic substitution reactions, while the C3 -  and C5 -positions have poor electron density and will be susceptible to nucleophilic attack. The ionization energy  of pyrazole is 9.15 eV.

Importance of Pyrazoles

Diverse pharmacological activities are associated with pyrazole and its derivatives and have great significance  in medicinal chemistry. They are useful building blocks for the construction of various pharmaceuticals, bleaching  agents, dyes, and agrochemicals to control various pests and herbs. These are also used as bifunctional ligands to  prepare metal catalysts. As pharmaceuticals they have antimalarial, antipyretic, antitubercular, anticancer, antiinflammatory, antidepressant, anticonvulsant, antihyperglycemic, and antioxidant properties. 

Some of the important pyrazole-based drugs in clinical use are as shown in the following scheme.

Synthesis

The therapeutic importance of pyrazoles has made them a very popular scaffold for the construction of newer  entities with better pharmacological profiles. There are numerous approaches for the construction of parent and  substituted pyrazoles: 

1. From 1,3-diketones with hydrazines
2. From α-enones and α-ynones
3. From alkynes
4. By ring transformation reactions
5. From ketene N,S- and S,S-acetals.
6. Miscellaneous reactions

Reaction of 1,3-Diketones With Hydrazines

Condensation of 1,3-diketones with hydrazine hydrate and aryl hydrazines separately yielded  3,5-disubstituted and 1,3,5-trisubstituted pyrazoles, respectively. The reaction is exothermic and requires  cooling during running the reaction. Unsymmetrical 1,3-diketones on reaction with hydrazine give a mixture  of structural isomers and the pathway of reaction depends on the nature of the substituent as well as pH of  the medium.

A convenient synthesis of pyrazole has been developed through condensation of 1,3-diketones with acid hydrazide in the presence of Sc(OTf)3  as catalyst in 93% yields.

From α-Enones and α-Ynones

Synthesis of various substituted pyrazoles has been developed by the reaction of β-ethylenic carbonyl compounds with substituted hydrazines and also by condensation–cyclization of α,β-unsaturated carbonyl compounds  with hydrazine hydrate.

From Alkynes

Terminal alkyne reacting with N-alkylated tosylhydrazone in the presence of AlCl3  afforded 1,3,5-pyrazoles in  very good yields with complete regioselectivity and compatibility of functional groups.

By Ring Transformation Reactions

  (a) 3-Benzoyl-2-substituted 5-phenylfurans on reaction with hydrazine in ethylene glycol afforded 4-benzoylmethyl- 3(5)-phenylpyrazoles in moderate yields.

 (b) A reaction of 3-acyl-2H-pyran-2,4-diones with phenylhydrazine in benzene at reflux gave corresponding hydrazine, which on refluxing in acetic acid afforded 5-pyrazolone derivatives in good yields. However, pyran on  reaction with 2 equivalents of hydrazine 4-pyrazolyl pyrazolones were isolated.

From Oxoketene and Cyanoketene N,S- and N,N-acetals

Oxoketene and cyanoketene N,S- and S,S-acetals are versatile precursors for the construction of a variety of substituted pyrazoles on reaction with ambiphilic nucleophiles such as hydrazine and substituted  hydrazines.