3-(difluoromethyl)-1H-pyrazole
[CAS# 1007468-17-8]

Identification

• Classification: Organic raw materials >> Heterocyclic compound
• Name: 3-(difluoromethyl)-1H-pyrazole
• Synonyms: 5-(difluoromethyl)-1H-pyrazole
• Molecular Formula: C₄H₄F₂N₂
• Molecular Weight: 118.08
• CAS Registry Number: 1007468-17-8
• EC Number: 832-017-1
• SMILES: C1=C(NN=C1)C(F)F

Properties

• Boiling point: 214.5±30.0 ºC 760 mmHg

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H312-H315-H319-H332-H335
• Precautionary Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P317-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	4	H332
Specific target organ toxicity - single exposure	STOT SE	3	H335

Discovory and Applicatios

3-(Difluoromethyl)-1H-pyrazole is a fluorinated heterocyclic compound composed of a pyrazole ring bearing a difluoromethyl group (–CHF₂) at the 3-position. The pyrazole ring is a five-membered aromatic system containing two adjacent nitrogen atoms at the 1- and 2-positions, known for its presence in numerous biologically active molecules. The introduction of the difluoromethyl group significantly alters the compound’s chemical and biological properties, contributing to its importance in medicinal and agrochemical research.

The discovery of 3-(difluoromethyl)-1H-pyrazole and related compounds is linked to the ongoing exploration of fluorinated heterocycles for pharmaceutical and crop protection purposes. The difluoromethyl group is a bioisostere of hydroxyl, thiol, or methyl groups and is often used to modulate the electronic and lipophilic properties of molecules. Its presence enhances metabolic stability, alters hydrogen-bonding profiles, and can improve binding affinity to biological targets, making it a valuable feature in drug design.

Synthetically, 3-(difluoromethyl)-1H-pyrazole can be prepared by several methods, including the condensation of hydrazines with β-difluorinated carbonyl precursors or via cyclization reactions involving 1,3-dicarbonyl compounds bearing difluoromethyl substituents. Another route involves nucleophilic substitution reactions using difluoromethylated building blocks under mild conditions, which can yield the target compound with good regioselectivity and functional group tolerance.

In medicinal chemistry, pyrazole derivatives are frequently used as core structures in drug development. The incorporation of a difluoromethyl group at the 3-position has been shown to enhance the pharmacological profile of these molecules. Compounds containing the 3-(difluoromethyl)-1H-pyrazole motif have been studied for a wide range of biological activities, including anti-inflammatory, antitumor, antifungal, and insecticidal properties. The pyrazole ring can serve as a privileged structure that mimics purine bases or participates in hydrogen bonding with enzyme active sites.

The use of 3-(difluoromethyl)-1H-pyrazole is particularly notable in the development of agrochemicals, where it has been incorporated into fungicides, herbicides, and insecticides. The compound's physicochemical properties enable it to interact effectively with biological membranes and enzymatic systems in target organisms, while its fluorinated group can improve environmental stability and resistance to metabolic degradation.

Because of its electron-withdrawing nature, the difluoromethyl group also influences the acidity of the N–H proton on the pyrazole ring, affecting the molecule’s reactivity and binding characteristics. This property is exploited in the design of compounds that act as enzyme inhibitors or receptor antagonists, especially in targets where hydrogen bonding and electronic complementarity are essential for high-affinity binding.

In conclusion, 3-(difluoromethyl)-1H-pyrazole is a valuable and well-established compound in chemical and pharmaceutical research. Its structure combines the bioactive pyrazole core with a strategically important fluorinated substituent, making it suitable for applications in drug design, agrochemical development, and synthetic chemistry. Its stability, reactivity, and biological relevance continue to make it a subject of study and use in various domains of applied chemistry.

References

2009. N-trifluoromethylazoles. Chemistry of Heterocyclic Compounds, 45(4).
DOI: 10.1007/s10593-009-0289-4

2023. Pharmacophore variants of the macrocyclic peptide triazole inactivator of HIV-1 Env. Medicinal Chemistry Research, 32(8).
DOI: 10.1007/s00044-023-03092-0

2024. Design, Synthesis, Antifungal and Antibacterial Activities of Novel Difluoromethyl Pyrazole Derivatives. Russian Journal of General Chemistry, 94(4).
DOI: 10.1134/s1070363224040248