Difluoroacetic acid
[CAS# 381-73-7]

Identification

• Classification: Chemical reagent >> Organic reagent >> Fatty acid
• Name: Difluoroacetic acid
• Synonyms: 2,2-difluoroacetic acid
• Molecular Formula: C₂H₂F₂O₂
• Molecular Weight: 96.03
• CAS Registry Number: 381-73-7
• EC Number: 206-839-0
• SMILES: C(C(=O)O)(F)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*, 1.526 g/mL (Expl.)
• Melting point: -1 °C (Expl.)
• Boiling point: 136.1±25.0 °C 760 mmHg (Calc.)^*, 132 - 134 °C (Expl.)
• Flash point: 78.9 °C (Calc.)^*, 78 °C (Expl.)
• Index of refraction: 1.314 (Calc.)^*, 1.344 (Expl.)

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

Safety Data

• Hazard Symbols: GHS05 Danger
• Risk Statements: H314
• Safety Statements: P260-P264-P280-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P321-P363-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin corrosion	Skin Corr.	1B	H314
Skin corrosion	Skin Corr.	1A	H314
Serious eye damage	Eye Dam.	1	H318
Flammable liquids	Flam. Liq.	4	H227
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Substances or mixtures corrosive to metals	Met. Corr.	1	H290

• Transport Information: UN 3265

Discovery and Applications

Difluoroacetic acid is a small organofluorine carboxylic acid with the molecular formula CHF₂COOH. It is part of the broader class of halogenated acetic acids and was first investigated in the mid-20th century as chemists explored the chemical and physical properties of fluorinated carboxylic acids. The introduction of two fluorine atoms at the alpha carbon dramatically increases the acidity of the carboxyl group and strongly withdraws electrons, affecting both reactivity and stability. This unique electronic effect distinguishes difluoroacetic acid from non-fluorinated or monofluorinated analogues and has led to its use as a specialized reagent in organic synthesis.

The primary application of difluoroacetic acid is in the preparation of fluorinated organic compounds. The acidic proton and highly electron-withdrawing difluoromethyl group make it a versatile building block for chemical transformations such as esterification, amidation, and nucleophilic substitution. In medicinal chemistry, derivatives of difluoroacetic acid are valued because the difluoromethyl group can act as a bioisostere of hydroxyl or methyl groups, providing enhanced metabolic stability, lipophilicity, and pharmacokinetic properties in drug molecules. The acid itself is rarely used therapeutically, but it serves as a precursor in the synthesis of pharmaceuticals, agrochemicals, and other biologically active compounds.

Difluoroacetic acid has been employed in agrochemical synthesis for the production of herbicides, fungicides, and insecticides. Fluorinated acetic acid derivatives contribute to enhanced environmental persistence and improved biological activity of these compounds. The electron-withdrawing effects of the difluoromethyl group can also influence the acidity and reactivity of adjacent functional groups, making it a useful intermediate in constructing more complex molecules for crop protection applications.

In materials science, difluoroacetic acid can be used to introduce fluorine-containing groups into polymers and specialty chemicals. The incorporation of difluoromethyl substituents improves thermal stability, chemical resistance, and hydrophobicity, enhancing the performance of coatings, membranes, and other high-performance materials. Its solubility in polar solvents and strong acidity allow for its use in controlled reactions where fluorinated building blocks are needed.

Difluoroacetic acid has also been studied as a reagent in analytical chemistry. It is sometimes employed in derivatization reactions to improve the volatility or detectability of polar compounds in gas chromatography or mass spectrometry. Its strong electron-withdrawing properties facilitate the formation of stable derivatives, making it useful for accurate analysis of complex mixtures.

The discovery and utilization of difluoroacetic acid illustrate the significant role of fluorinated small molecules in modern chemistry. Its combination of high acidity, strong electron-withdrawing effects, and versatile reactivity make it an important intermediate in organic synthesis, supporting applications in pharmaceuticals, agrochemicals, materials science, and analytical chemistry. The compound exemplifies how the introduction of fluorine atoms can enhance chemical and physical properties, expanding the utility of simple carboxylic acids in research and industry.

References

2023. Structural insights into hydrolytic defluorination of difluoroacetate by microbial fluoroacetate dehalogenases. The FEBS Journal, 290(14).
DOI: 10.1111/febs.16903

2023. Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids. Nature Chemistry, 15(11).
DOI: 10.1038/s41557-023-01365-0

2021. Toward better understanding vacuum ultraviolet—iodide induced photolysis via hydrogen peroxide formation, iodine species change, and difluoroacetic acid degradation. Frontiers of Environmental Science & Engineering, 15(6).
DOI: 10.1007/s11783-021-1489-0