Trifluoroacetic acid
[CAS# 76-05-1]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives >> Acyclic carboxylic acid
• Name: Trifluoroacetic acid
• Synonyms: TFA
• Molecular Formula: C₂HF₃O₂
• Molecular Weight: 114.02
• CAS Registry Number: 76-05-1
• EC Number: 200-929-3
• SMILES: C(=O)(C(F)(F)F)O

Properties

• Density: 1.6±0.1 g/cm³, Calc.^*, 1.535 g/mL (Expl.)
• Melting point: -15.4 °C (Expl.)
• Index of Refraction: 1.294, Calc.^*, 1.3 (Expl.)
• Boiling Point: 72.2±35.0 °C (760 mmHg), Calc.^*, 72.4 °C (Expl.)
• Flash Point: -2.5±25.9 °C, Calc.^*, 100 °C (Expl.)

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

Safety Data

• Hazard Symbols: GHS05;GHS07 Danger
• Risk Statements: H290-H302-H314-H318-H332-H412
• Safety Statements: P234-P260-P261-P264-P264+P265-P270-P271-P273-P280-P301+P317-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P317-P321-P330-P363-P390-P405-P406-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Acute toxicity	Acute Tox.	4	H332
Skin corrosion	Skin Corr.	1A	H314
Serious eye damage	Eye Dam.	1	H318
Substances or mixtures corrosive to metals	Met. Corr.	1	H290
Acute toxicity	Acute Tox.	4	H302
Skin corrosion	Skin Corr.	1B	H314
Flammable liquids	Flam. Liq.	2	H225
Acute toxicity	Acute Tox.	3	H301

• Transport Information: UN 2699

Discovery and Applications

Trifluoroacetic acid (TFA), with the chemical formula C₂HF₃O₂, is a highly fluorinated organic carboxylic acid that plays an important role in organic synthesis and industrial applications. This compound is characterized by the presence of three fluorine atoms attached to a central carbon atom, along with a carboxyl group (-COOH). Trifluoroacetic acid is a colorless, corrosive liquid that is known for its strong acidity and its ability to act as a versatile reagent in various chemical processes.

The discovery of trifluoroacetic acid dates back to the early 20th century. It was first synthesized in the 1930s, with early reports describing the preparation of TFA through the fluorination of acetic acid or acetic anhydride using fluorine gas. Since its discovery, the compound has been widely studied due to its unique chemical properties and its usefulness in various fields of chemistry.

One of the primary applications of trifluoroacetic acid is in organic synthesis, where it is often used as a reagent for the introduction of the trifluoromethyl group (-CF₃) into organic molecules. The trifluoromethyl group imparts unique properties to the molecule, including increased stability, altered reactivity, and enhanced lipophilicity. Trifluoroacetic acid is employed in the synthesis of a wide range of fluorinated compounds, which find uses in pharmaceuticals, agrochemicals, and materials science.

In pharmaceutical chemistry, TFA is commonly used as a solvent and reagent in peptide synthesis. Its strong acidic nature makes it useful in the deprotection of certain protective groups, particularly in the synthesis of peptides and proteins. In this application, trifluoroacetic acid is often employed to remove the t-butoxycarbonyl (Boc) protective group, a crucial step in the synthesis of peptides. TFA is preferred in peptide chemistry because it can efficiently cleave the Boc group without causing significant side reactions, thereby providing high yields of the desired product.

In addition to peptide synthesis, trifluoroacetic acid is also employed in the synthesis of other bioactive molecules, including pharmaceuticals and agrochemicals. It is used in the preparation of fluorinated drugs, where the introduction of a trifluoromethyl group can enhance the compound's metabolic stability and bioactivity. Fluorinated drugs, such as those used in cancer treatment, antiviral therapy, and central nervous system disorders, often rely on TFA as a reagent in their synthesis.

Trifluoroacetic acid has also found applications in the field of analytical chemistry. It is frequently used as a solvent and reagent in high-performance liquid chromatography (HPLC), particularly in the separation of polar and nonpolar compounds. Its ability to dissolve a wide range of organic compounds, combined with its strong acidity, makes it an effective solvent for HPLC analyses, especially for the separation of fluorinated compounds.

In materials science, trifluoroacetic acid is used in the synthesis of fluorinated polymers and materials. These polymers are highly resistant to solvents, acids, and high temperatures, making them ideal for use in harsh industrial environments. TFA is employed as a monomer or as a reagent in the preparation of fluoropolymer coatings, adhesives, and films that possess unique chemical and thermal properties.

Another important application of trifluoroacetic acid is in the field of catalysis. TFA is often used as a catalyst or catalyst promoter in various chemical reactions. Its strong acidity can facilitate a range of reactions, including esterification, acylation, and the synthesis of heterocyclic compounds. It is also used in the production of fluorinated fine chemicals and specialty chemicals, where its ability to activate reactants makes it an essential tool in chemical synthesis.

Trifluoroacetic acid has also been investigated for its role in environmental and industrial processes. It is used in the production of fluorinated solvents and is involved in the preparation of other fluorine-containing compounds that are used in the manufacturing of refrigerants, pesticides, and coatings. Despite its widespread use, the environmental impact of trifluoroacetic acid and its potential for bioaccumulation in aquatic systems has raised concerns. As a result, the proper handling and disposal of TFA are emphasized in industrial settings.

In conclusion, trifluoroacetic acid is a highly valuable compound in organic synthesis and industrial chemistry. Its ability to introduce the trifluoromethyl group into organic molecules, its role in peptide synthesis, and its use in the preparation of fluorinated compounds make it an indispensable tool in pharmaceutical and materials science. As a solvent and reagent, TFA is widely utilized in the synthesis of bioactive molecules and in analytical techniques like HPLC. Its strong acidity and versatile reactivity continue to make trifluoroacetic acid a crucial component in various chemical processes.

References

2025. Synthesis of single-crystalline sp2-carbon-linked covalent organic frameworks through imine-to-olefin transformation. Nature Chemistry, 17(1).
DOI: 10.1038/s41557-024-01690-y

2025. Solvent-Dependent Photoluminescence Emission and Colloidal Stability of Carbon Quantum dots from Watermelon Peels. Journal of Fluorescence, 35(1).
DOI: 10.1007/s10895-023-03528-1

2025. Application of Proteomics Technology Based on LC-MS Combined with Western Blotting and Co-IP in Antiviral Innate Immunity. Methods in molecular biology (Clifton, N.J.), 2791.
DOI: 10.1007/978-1-0716-4108-8_11