Trifluoroacetic anhydride
[CAS# 407-25-0]

Identification

• Classification: Chemical pesticide >> Insecticide intermediate
• Name: Trifluoroacetic anhydride
• Synonyms: 2,2,2-Trifluoroacetic anhydride; TFAA
• Molecular Formula: C₄F₆O₃
• Molecular Weight: 210.03
• CAS Registry Number: 407-25-0
• EC Number: 206-982-9
• SMILES: C(=O)(C(F)(F)F)OC(=O)C(F)(F)F

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*, 1.511 g/mL (Expl.)
• Melting point: -65 °C (Expl.)
• Boiling point: 39.5 °C 760 mmHg (Calc.)^*, 39.5 - 40 °C (Expl.)
• Flash point: -26.1±20.8 °C (Calc.)^*
• Solubility: water hydrolysis (Expl.)
• Index of refraction: 1.291 (Calc.)^*, 1.269 (Expl.)

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

Safety Data

• Hazard Symbols: GHS05;GHS07;GHS08 Danger
• Risk Statements: H314-H318-H332-H361d-H412
• Safety Statements: P203-P260-P261-P264-P264+P265-P271-P273-P280-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P317-P318-P321-P363-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H332
Skin corrosion	Skin Corr.	1A	H314
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Substances or mixtures corrosive to metals	Met. Corr.	1	H290
Skin corrosion	Skin Corr.	1	H314
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	4	H312
Serious eye damage	Eye Dam.	1	H318
Skin corrosion	Skin Corr.	1B	H314
Specific target organ toxicity - single exposure	STOT SE	3	H335
Flammable liquids	Flam. Liq.	4	H227
Acute toxicity	Acute Tox.	3	H331
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H330

• Transport Information: UN 1760; UN 3265

Discovery and Applications

Trifluoroacetic anhydride is a highly reactive organofluorine compound with the molecular formula (CF₃CO)₂O. It is the anhydride of trifluoroacetic acid and was first developed in the mid-20th century as chemists explored the synthesis and applications of fluorinated reagents. The presence of two trifluoromethyl groups strongly increases the electrophilicity of the carbonyl carbons, making the anhydride significantly more reactive than the parent acid. Trifluoroacetic anhydride is typically a colorless liquid that is highly moisture-sensitive and must be handled under anhydrous conditions to prevent hydrolysis.

The primary application of trifluoroacetic anhydride is as a reagent for introducing the trifluoroacetyl group into nucleophilic substrates such as amines, alcohols, and thiols. This reaction forms trifluoroacetamides, esters, and thioesters, which are important intermediates in organic synthesis. The trifluoromethyl group imparts strong electron-withdrawing effects, stabilizing reaction intermediates and altering chemical reactivity. Its ability to selectively introduce the trifluoroacetyl group has made it a valuable tool in the preparation of fluorinated building blocks used in pharmaceuticals, agrochemicals, and specialty chemicals.

In pharmaceutical chemistry, trifluoroacetic anhydride is widely used to synthesize trifluoromethylated derivatives of bioactive molecules. Incorporation of the trifluoroacetyl group can enhance metabolic stability, lipophilicity, and pharmacokinetic properties of drug candidates. It has been employed in the synthesis of enzyme inhibitors, antiviral agents, and central nervous system drugs, where the trifluoromethyl moiety improves biological activity and chemical robustness. Its high reactivity enables efficient functionalization under mild conditions, which is important for sensitive or complex molecules.

In agrochemical research, trifluoroacetic anhydride is used to prepare trifluoromethylated herbicides, fungicides, and insecticides. The trifluoromethyl group improves chemical and thermal stability, environmental persistence, and lipophilicity, enhancing the efficacy of the final products. The anhydride allows chemists to introduce this group efficiently into precursor molecules, facilitating the development of new biologically active compounds.

Trifluoroacetic anhydride also finds application in materials science and polymer chemistry. Fluorinated acyl groups introduced using the anhydride increase the hydrophobicity, chemical resistance, and thermal stability of polymers and specialty coatings. Its use in selective functionalization reactions provides a way to modify material properties without compromising other sensitive substituents.

Analytical chemistry benefits from trifluoroacetic anhydride as well. It is sometimes used as a derivatization reagent for improving the volatility and detectability of polar compounds in gas chromatography and mass spectrometry. The trifluoroacetyl derivatives formed are more volatile and thermally stable, allowing for better separation and detection.

The discovery and continued use of trifluoroacetic anhydride underscore its importance as a reactive fluorinated reagent. Its combination of strong electrophilicity, stability, and versatility has made it a cornerstone in organic synthesis, supporting advances in pharmaceuticals, agrochemicals, materials science, and analytical chemistry. The compound exemplifies the value of fluorinated anhydrides in modern chemical research and industrial applications.

References

2013. Synthesis of 2-Nitroglycals from Glycals Using the Tetrabutylammonium Nitrate-Trifluoroacetic Anhydride-Triethylamine Reagent System and Base-Catalyzed Ferrier Rearrangement of Acetylated 2-Nitroglycals. The Journal of Organic Chemistry, 78(16).
DOI: 10.1021/jo401165y

2012. Production of identical retention times and mass spectra for δ9-tetrahydrocannabinol and cannabidiol following derivatization with trifluoroacetic anhydride with 1,1,1,3,3,3-hexafluoroisopropanol. Journal of Analytical Toxicology, 36(1).
DOI: 10.1093/jat/bkr017

1984. Electron-Capture Capillary Gas Chromatographic Determination of Phenylpropanolamine in Human Plasma Following Derivatization with Trifluoroacetic Anhydride. Journal of Pharmaceutical Sciences, 73(9).
DOI: 10.1002/jps.2600730936