Pyrazole
[CAS# 288-13-1]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: Pyrazole
• Synonyms: 1,2-Diazole; 1H-Pyrazole
• Molecular Formula: C₃H₄N₂
• Molecular Weight: 68.08
• CAS Registry Number: 288-13-1
• EC Number: 206-017-1
• SMILES: C1=CNN=C1

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Melting point: 66 - 70 °C (Expl.)
• Boiling point: 187.0±9.0 °C 760 mmHg (Calc.)^*, 186 - 188 °C (Expl.)
• Flash point: 87.5±11.7 °C (Calc.)^*
• Index of refraction: 1.528 (Calc.)^*
• Water solubility: SOLUBLE

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS06;GHS07;GHS08 Danger
• Risk Statements: H302-H311-H315-H318-H319-H335-H372-H412
• Safety Statements: P260-P261-P262-P264-P264+P265-P270-P271-P273-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P305+P354+P338-P316-P317-P319-P321-P330-P332+P317-P337+P317-P361+P364-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H302
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Acute toxicity	Acute Tox.	3	H311
Serious eye damage	Eye Dam.	1	H318
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

Pyrazole is a five-membered heteroaromatic compound composed of three carbon atoms and two adjacent nitrogen atoms in the ring. Its molecular formula is C₃H₄N₂, and it has a planar structure with aromatic character, similar to other azoles. The presence of the two nitrogen atoms at positions 1 and 2 distinguishes it from other simple azoles such as imidazole and pyrazine. One nitrogen atom is pyrrole-like (bearing a hydrogen atom), while the other is pyridine-like and contributes a lone pair to the aromatic system.

Pyrazole was first synthesized in the 19th century by German chemist Ludwig Knorr in the course of his work on isomeric phenylhydrazones and related compounds. The name “pyrazole” was proposed based on its structural resemblance to “pyrrole” and the presence of the azo (–N=N–) functionality in related derivatives. Knorr’s pioneering work laid the foundation for the chemistry of 1,2-diazoles and contributed significantly to the study of nitrogen-containing heterocycles.

Pyrazole itself is a colorless, crystalline solid with a melting point of around 70–72 °C. It is moderately soluble in water and soluble in most polar organic solvents. Due to its aromaticity and the presence of two nitrogen atoms, pyrazole exhibits both basic and weakly acidic behavior. The NH proton of the pyrrole-like nitrogen is weakly acidic and can be deprotonated under basic conditions, forming pyrazolide anions.

Pyrazole and its derivatives are of great significance in pharmaceutical, agricultural, and materials chemistry. The pyrazole ring serves as a core structure in a wide range of biologically active molecules. Substituted pyrazoles have been developed for use as analgesics, anti-inflammatory agents, antipyretics, and antidiabetic drugs. For example, celecoxib, a widely used selective COX-2 inhibitor for the treatment of arthritis, contains a pyrazole ring as a central feature of its structure.

In agrochemicals, pyrazole derivatives have been employed as fungicides, herbicides, and insecticides. Their biological activity often arises from the ability of the nitrogen atoms to coordinate with metal ions or participate in hydrogen bonding with biological targets, thereby influencing enzyme function or receptor interactions.

The chemistry of pyrazole allows for a wide range of functionalization at all ring positions. Electrophilic substitution reactions generally occur at the 4-position due to electron density distribution, while nucleophilic substitution can be directed by the nature of substituents and ring activation. Pyrazoles can also be synthesized via the cyclization of 1,3-dicarbonyl compounds with hydrazines, a reaction known as the Knorr pyrazole synthesis. This method remains one of the most widely used routes for preparing substituted pyrazoles in both laboratory and industrial settings.

Beyond pharmaceuticals and pesticides, pyrazole derivatives are also investigated in materials science. Their ability to coordinate with transition metals makes them useful as ligands in organometallic chemistry and in the design of coordination polymers and metal-organic frameworks (MOFs). In these applications, pyrazole ligands can tune the properties of metal complexes, including their redox behavior, photophysical characteristics, and catalytic activity.

Analytical methods used to study pyrazoles include NMR spectroscopy, where the characteristic chemical shifts of the NH and aromatic protons can be identified, along with infrared spectroscopy to detect NH stretching frequencies. Mass spectrometry and X-ray crystallography are also employed to elucidate the structure and confirm substitution patterns.

In summary, pyrazole is a fundamental nitrogen-containing heterocycle with a broad range of applications in organic synthesis, drug development, agrochemistry, and materials science. Its stability, aromaticity, and ease of derivatization make it a valuable scaffold in modern chemistry.

References

2007. Design, Synthesis, and X-ray Structure of Potent Memapsin 2 (β-Secretase) Inhibitors with Isophthalamide Derivatives as the P2-P3-Ligands. Journal of Medicinal Chemistry, 50(7).
DOI: 10.1021/jm061338s

2005. Dipeptidyl peptidase IV inhibitors derived from beta-aminoacylpiperidines bearing a fused thiazole, oxazole, isoxazole, or pyrazole. Bioorganic & Medicinal Chemistry Letters, 15(9).
DOI: 10.1016/j.bmcl.2005.03.012

2003. Synthesis and muscarinic activities of O-[(Benzyl- or benzoyl-pyrazolyl)propynyl]-oximes of N-methylpiperidinone, 3-tropinone, and 3-quinuclidinone. Bioorganic & Medicinal Chemistry, 11(9).
DOI: 10.1016/s0968-0896(03)00111-1