3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid
[CAS# 176969-34-9]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Carboxylic acid
• Name: 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid
• Synonyms: 3-Difluoromethyl-1-methyl-1H-pyrazol-4-carboxylic acid; 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid
• Molecular Formula: C₆H₆F₂N₂O₂
• Molecular Weight: 176.12
• CAS Registry Number: 176969-34-9
• EC Number: 700-093-4
• SMILES: CN1C=C(C(=N1)C(F)F)C(=O)O

Properties

• Density: 1.5±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.534, Calc.^*
• Boiling Point: 315.9±42.0 °C (760 mmHg), Calc.^*
• Flash Point: 144.9±27.9 °C, Calc.^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H332-H335
• Safety Statements: P261-P280-P305+P351+P338

Hazard Classification

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

Discovery and Applications

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid (C₆H₆F₂N₂O₂) is a fluorinated heterocyclic carboxylic acid that has been investigated for its applications in organic synthesis, pharmaceuticals, and agrochemicals. The molecular structure consists of a pyrazole ring substituted with a difluoromethyl (-CF₂H) group at the 3-position, a methyl (-CH₃) group at the 1-position, and a carboxyl (-COOH) functional group at the 4-position. These substituents contribute to its physicochemical properties, including its acidity, hydrogen bonding potential, and metabolic stability.

The synthesis of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid follows established synthetic routes involving fluorinated precursors. The introduction of the difluoromethyl group typically relies on fluorination reagents such as diethylaminosulfur trifluoride (DAST) or related selective fluorinating agents. The carboxylation step can be achieved through metal-mediated carboxylation reactions or oxidative pathways, depending on the precursor used.

This compound has been studied for its potential role in pharmaceutical research. The presence of the difluoromethyl moiety enhances its lipophilicity and metabolic resistance, properties that are often desirable in drug design. The pyrazole core is a well-recognized scaffold in medicinal chemistry, contributing to bioactivity in enzyme inhibition and receptor binding interactions. Fluorinated pyrazole derivatives have been explored as candidates in the development of anti-inflammatory, antiviral, and fungicidal agents.

In agrochemical applications, pyrazole-containing structures are commonly incorporated into herbicides, fungicides, and insecticides. The fluorinated substituent can modulate biological activity by influencing molecular interactions with target proteins and improving the compound's persistence in agricultural environments. Some structurally related fluorinated pyrazoles have been reported in the development of crop protection agents.

Due to its functional groups, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid exhibits versatile reactivity in organic synthesis. The carboxyl group allows for further derivatization through esterification, amidation, or decarboxylation reactions, enabling the creation of more complex molecules. The difluoromethyl group can also serve as a bioisostere for hydroxyl or thiol groups, altering the electronic and steric properties of target compounds.

The handling and storage of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid require standard precautions for fluorinated organic acids. It should be kept in tightly sealed containers under controlled temperature and humidity conditions to prevent degradation. Appropriate protective measures, including gloves and ventilation, should be used when handling the substance in laboratory or industrial environments.

The role of fluorinated heterocycles in modern chemistry ensures continued interest in compounds such as 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid. Its well-defined structural features and reactivity contribute to its relevance in synthetic, pharmaceutical, and agrochemical applications.

References

2019. New relevant pesticide transformation products in groundwater detected using target and suspect screening for agricultural and urban micropollutants with LC-HRMS. Water Research, 165.
DOI: 10.1016/j.watres.2019.114972

2017. Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel difluoromethylated heterocyclic acid moieties. Monatshefte für Chemie - Chemical Monthly, 149(2).
DOI: 10.1007/s00706-017-2101-y