Difluoroacetic anhydride
[CAS# 401-67-2]

Identification

• Classification: Chemical reagent >> Organic reagent >> Carboxylic anhydride
• Name: Difluoroacetic anhydride
• Synonyms: Difluoro-acetic acid anhydride; 2,2-Difluoro-acetic acid 1,1'-anhydride
• Molecular Formula: C₄H₂F₄O₃
• Molecular Weight: 174.05
• CAS Registry Number: 401-67-2
• EC Number: 674-863-2
• SMILES: C(C(=O)OC(=O)C(F)F)(F)F

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*, 1.4 g/mL (Expl.)
• Boiling point: 93.6±35.0 °C 760 mmHg (Calc.)^*, 125 - 127 °C (Expl.)
• Flash point: 11.3±20.8 °C (Calc.)^*
• Index of refraction: 1.314 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS02;GHS05;GHS07 Danger
• Risk Statements: H225-H290-H302-H312-H314-H318-H332-H335-H412
• Safety Statements: P210-P233-P234-P240-P241-P242-P243-P260-P261-P264-P264+P265-P270-P271-P273-P280-P301+P317-P301+P330+P331-P302+P352-P302+P361+P354-P303+P361+P353-P304+P340-P305+P354+P338-P316-P317-P319-P321-P330-P362+P364-P363-P370+P378-P390-P403+P233-P403+P235-P405-P406-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin corrosion	Skin Corr.	1B	H314
Serious eye damage	Eye Dam.	1	H318
Acute toxicity	Acute Tox.	4	H332
Flammable liquids	Flam. Liq.	2	H225
Skin corrosion	Skin Corr.	1	H314
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - single exposure	STOT SE	3	H335
Substances or mixtures corrosive to metals	Met. Corr.	1	H290

Discovery and Applications

Difluoroacetic anhydride is a reactive organofluorine compound with the molecular formula (CHF₂CO)₂O. It is the anhydride derivative of difluoroacetic acid and was developed as part of efforts in the mid-20th century to expand the toolbox of fluorinated reagents for organic synthesis. The presence of two difluoromethyl groups bonded to carbonyl carbons makes the molecule highly electrophilic, and the anhydride functionality increases its reactivity compared with the parent acid. Difluoroacetic anhydride is typically a colorless to pale yellow liquid that is sensitive to moisture and requires careful handling under anhydrous conditions.

The main application of difluoroacetic anhydride is as a reagent in organic synthesis for the introduction of the difluoroacetyl group into nucleophiles such as amines, alcohols, and thiols. The strong electron-withdrawing effect of the difluoromethyl group stabilizes reaction intermediates and allows the formation of amides, esters, and thioesters with high efficiency. This reactivity makes it a valuable tool in the preparation of fluorinated building blocks, which are important in pharmaceuticals, agrochemicals, and specialty chemicals. Compounds containing difluoromethyl groups often exhibit enhanced metabolic stability, lipophilicity, and biological activity, making them attractive targets for medicinal chemistry.

In pharmaceutical research, difluoroacetic anhydride has been employed to synthesize difluoromethylated derivatives of bioactive molecules. The difluoroacetyl group can be introduced selectively into drug candidates to improve pharmacokinetic properties, such as absorption, distribution, and resistance to enzymatic degradation. Its use is particularly important in designing enzyme inhibitors, antiviral agents, and compounds targeting central nervous system disorders. By providing a convenient and reactive source of difluoroacetyl functionality, the anhydride allows for streamlined synthesis of complex molecules.

In agrochemical applications, difluoroacetic anhydride is used to prepare fluorinated herbicides, fungicides, and insecticides. The introduction of difluoromethyl groups can enhance chemical stability, increase lipophilicity, and modify biological activity, contributing to improved efficacy and environmental persistence. Its reactivity allows for the synthesis of intermediates that can be further transformed into biologically active agents.

Difluoroacetic anhydride has also been applied in materials science and polymer chemistry. Fluorinated acyl groups can be incorporated into monomers or polymer backbones to impart hydrophobicity, thermal stability, and chemical resistance to specialty polymers and coatings. The anhydride is used under controlled conditions to selectively functionalize molecules without affecting sensitive substituents.

The development and use of difluoroacetic anhydride highlight its significance as a reactive fluorinated reagent in modern chemistry. Its strong electrophilicity, combined with the stabilizing effects of the difluoromethyl groups, make it a versatile intermediate for the synthesis of pharmaceuticals, agrochemicals, and specialty materials. The compound exemplifies the utility of fluorinated anhydrides in introducing unique chemical functionality that enhances reactivity, stability, and biological performance.

References

2024. General radical difluoromethylation using difluoroacetic anhydride via photoredox catalysis. Science China Chemistry, 67(6).
DOI: 10.1007/s11426-023-1937-4

2019. Synthesis and structural study of 2-(haloalkyl)-3-methylchromones. Monatshefte für Chemie - Chemical Monthly, 150(10).
DOI: 10.1007/s00706-019-02512-5

2016. Efficient synthesis of tri- and difluoroacetyl hydrazides as useful building blocks for non-symmetrically substituted, fluoroalkylated 1,3,4-oxadiazoles. Chemistry of Heterocyclic Compounds, 52(2).
DOI: 10.1007/s10593-016-1845-3