Ethyl difluoroacetate
[CAS# 454-31-9]

Identification

• Classification: Chemical reagent >> Organic reagent >> Ester >> Ethyl ester compound
• Name: Ethyl difluoroacetate
• Synonyms: ethyl 2,2-difluoroacetate
• Molecular Formula: C₄H₆F₂O₂
• Molecular Weight: 124.09
• CAS Registry Number: 454-31-9
• EC Number: 207-223-4
• SMILES: CCOC(=O)C(F)F

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*, 1.242 g/mL (Expl.)
• Boiling point: 76.0±25.0 °C 760 mmHg (Calc.)^*, 99.2 °C (Expl.)
• Flash point: 1.1±18.1 °C (Calc.)^*, 25 °C (Expl.)
• Index of refraction: 1.336 (Calc.)^*, 1.347 (Expl.)

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

Safety Data

• Hazard Symbols: GHS02;GHS05;GHS09 Danger
• Risk Statements: H225-H226-H314-H318-H411
• Safety Statements: P210-P233-P240-P241-P242-P243-P260-P264-P264+P265-P273-P280-P301+P330+P331-P302+P361+P354-P303+P361+P353-P304+P340-P305+P354+P338-P316-P317-P321-P363-P370+P378-P391-P403+P235-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin corrosion	Skin Corr.	1B	H314
Flammable liquids	Flam. Liq.	2	H225
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Serious eye damage	Eye Dam.	1	H318
Flammable liquids	Flam. Liq.	3	H226
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Skin corrosion	Skin Corr.	1C	H314
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	4	H312
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H302

• Transport Information: UN 2924

Discovery and Applications

Ethyl difluoroacetate is a fluorinated ester with the molecular formula CHF₂COOCH₂CH₃. It is the ethyl ester of difluoroacetic acid and is part of the class of organofluorine compounds that exhibit unique chemical and electronic properties due to the presence of the difluoromethyl group. The two fluorine atoms attached to the alpha carbon increase the electrophilicity of the carbonyl carbon, influence the acidity of adjacent protons, and modify the overall reactivity of the ester. Ethyl difluoroacetate is generally a colorless liquid, soluble in a range of organic solvents, and reacts under nucleophilic substitution, hydrolysis, and condensation conditions.

The main application of ethyl difluoroacetate is as a building block in organic synthesis. It serves as a convenient source of the difluoroacetyl group for introducing difluoromethyl functionalities into more complex molecules. The compound undergoes nucleophilic acyl substitution reactions with alcohols, amines, and thiols to form esters, amides, and thioesters, which are key intermediates for pharmaceuticals, agrochemicals, and specialty chemicals. The electron-withdrawing effect of the difluoromethyl group enhances chemical stability and influences the reactivity and selectivity of downstream products.

In medicinal chemistry, ethyl difluoroacetate is used to synthesize difluoromethylated derivatives of drug candidates. The difluoromethyl moiety can act as a bioisostere of methyl or hydroxyl groups, improving metabolic stability, lipophilicity, and pharmacokinetic properties. The ester functionality allows controlled acylation reactions under mild conditions, enabling selective functionalization of sensitive intermediates. This has applications in the development of enzyme inhibitors, antiviral agents, and other bioactive compounds, where the incorporation of fluorinated groups enhances chemical robustness and biological activity.

In agrochemical research, ethyl difluoroacetate is employed as an intermediate for the synthesis of herbicides, fungicides, and insecticides. Introduction of the difluoromethyl group improves the chemical and thermal stability, lipophilicity, and biological activity of final products. Its reactivity as an ester allows for efficient transfer of the difluoroacetyl group to precursor molecules, streamlining the preparation of bioactive intermediates.

The compound also has applications in materials science and specialty chemical synthesis. Fluorinated esters derived from ethyl difluoroacetate are used to introduce difluoromethyl groups into polymers, coatings, and functionalized materials. Fluorination improves hydrophobicity, chemical resistance, and thermal stability, while the ester functionality allows for selective incorporation into complex molecular architectures.

The discovery and continued use of ethyl difluoroacetate highlight its significance as a versatile fluorinated reagent. Its combination of chemical reactivity, electron-withdrawing effects, and stability makes it an important intermediate in modern organic synthesis, supporting applications in pharmaceuticals, agrochemicals, materials science, and specialty chemicals. The compound demonstrates how the incorporation of fluorinated functional groups can expand the utility and performance of simple esters in both research and industrial applications.

References

2025. The features and advancements of electrodes and electrolyte materials for lithium-ion batteries. Journal of Solid State Electrochemistry, 29(6).
DOI: 10.1007/s10008-025-06251-y

2017. Fluorinated solvents for high-voltage electrolyte in lithium-ion battery. Journal of Solid State Electrochemistry, 21(6).
DOI: 10.1007/s10008-017-3508-4

2011. Synthesis of new fluorine-containing pyrazolo[3,4-b]pyridinones as promising drug precursors. Russian Chemical Bulletin, 60(4).
DOI: 10.1007/s11172-011-0114-y