trifluoroacetic acid

Trifluoroacetic acid (TFA) is a synthetic organofluorine compound with the chemical formula CF₃CO₂H. It belongs to the subclass of per- and polyfluoroalkyl substances (PFASs) known as ultrashort-chain perfluoroalkyl acids (PFAAs). TFA is not produced biologically or abiotically and is commonly used in organic chemistry for various purposes. It is the most abundant PFAS found in the environment.

It is a haloacetic acid, with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms. It is a colorless liquid with a vinegar-like odor. TFA is a stronger acid than acetic acid, having an acid ionisation constant, ''K''_a, that is approximately 34,000 times higher, as the highly electronegative fluorine atoms and consequent electron-withdrawing nature of the trifluoromethyl group weakens the oxygen-hydrogen bond (allowing for greater acidity) and stabilises the anionic conjugate base.

Synthesis

TFA is prepared industrially by the electrofluorination of acetyl chloride or acetic anhydride, followed by hydrolysis of the resulting trifluoroacetyl fluoride:

: + 4 → + 3 +

: + → +

Where desired, this compound may be dried by addition of trifluoroacetic anhydride.

An older route to TFA proceeds via the oxidation of 1,1,1-trifluoro-2,3,3-trichloropropene with potassium permanganate. The trifluorotrichloropropene can be prepared by Swarts fluorination of hexachloropropene.

Reactions

Being a strong acid, TFA does not exist as such in water. Instead TFA fully converts to trifluoroacetate, concomitant with the protonation of water.

It protonates several weakly basic anions, e.g. azide to give hydrazoic acid.

It is a precursor to trifluoroacetic anhydride.

TFA is the precursor to many other fluorinated compounds such as trifluoroacetic anhydride, trifluoroperacetic acid, and 2,2,2-trifluoroethanol. It is a reagent used in organic synthesis because of a combination of convenient properties: volatility, solubility in organic solvents, and its strength as an acid. TFA is also less oxidizing than sulfuric acid but more readily available in anhydrous form than many other acids. One complication to its use is that TFA forms an azeotrope with water (b. p. 105 °C).

TFA is used as a strong acid to remove protecting groups such as Boc used in organic chemistry and peptide synthesis.

At a low concentration, TFA is used as an ion pairing agent in liquid chromatography ( HPLC) of organic compounds, particularly peptides and small proteins. TFA is a versatile solvent for NMR spectroscopy (for materials stable in acid). It is also used as a calibrant in mass spectrometry.

TFA is used to produce trifluoroacetate salts.

Safety

Trifluoroacetic acid is a strong acid. TFA is harmful when inhaled, causes severe skin burns and is toxic for aquatic organisms even at low concentrations.

Skin burns are severe, heal poorly and can be necrotic. Vapour fumes have an LC₅₀ of 10.01 mg/L, tested on rats over 4 hours. Inhalation symptoms include mucus irritation, coughing, shortness of breath and possible formation of oedemas in the respiratory tract. Exposure damages the kidneys.

Toxicology

Trifluoroacetic acid is mildly phytotoxic. In July 2024, the German Chemical Agency submitted a proposal to the European Chemicals Agency (ECHA) to link trifluoroacetic acid and its salts to reproductive toxicity and as suspected of damaging fertility.

Environment

Uncertainties remain in our understanding of the potential impacts on the environment of TFA. A debate is ongoing regarding its ecological risk due to its persistence, ubiquity in the environment and increasing concentrations globally. TFA exposure is widespread and increasing and it is the most abundant PFAS found in the environment. TFA does not have well-established health advisories or regulatory limits as other PFAAs.

Although trifluoroacetic acid is not produced biologically or abiotically, it is a metabolic breakdown product of the volatile anesthetic agent halothane. It is also thought to be responsible for halothane-induced hepatitis. It also may be formed by photooxidation of the commonly used refrigerant 1,1,1,2-tetrafluoroethane (R-134a). Moreover, it is formed as an atmospheric degradation product of almost all fourth-generation synthetic refrigerants, also called hydrofluoroolefins (HFO), such as 2,3,3,3-tetrafluoropropene.

Trifluoroacetic acid is also formed by the degradation of pesticides that contain a CF₃ group, like Flufenacet. The German Umweltbundesamt has identified pesticides as the main source of TFA in water in agricultural areas.

Trifluoroacetic acid degrades very slowly in the environment and has been found in increasing amounts as a contaminant in water, soil, food, and the human body. Median concentrations of a few micrograms per liter have been found in beer and tea. Seawater can contain about 200 ng of TFA per liter. Biotransformation by decarboxylation to fluoroform has been discussed. In October 2024, a publication proposed classifying TFA as a planetary boundary threat, similar to how CFCs are treated.

Water contamination in Europe

TFA has emerged as a significant environmental contaminant across European waterways since its discovery in 2016 by researchers at the Karlsruhe Water Technology Center in Germany. Unlike other PFAS compounds, TFA's high water solubility allows it to spread rapidly through rivers and precipitation rather than binding to soil or organic matter.

TFA concentrations in European water sources have increased dramatically since the 1990s. German studies documented a fivefold increase in TFA levels in rainfall since the 1990s, while Danish groundwater showed more than tenfold increases over the same period. Research by the anti-pesticide network PAN Europe found that TFA accounted for 98 percent of all PFAS detected in water samples from 10 EU countries.

The German Environment Agency estimated that pesticide use releases approximately 500 metric tonnes of TFA annually in Germany alone, while refrigerants account for around 1,170 metric tonnes per year. In November 2024, the Swiss authorities presented an overview of widespread groundwater contamination with TFA.

Regulatory response

In 2024, the German Federal Institute for Risk Assessment formally requested that the European Chemicals Agency (ECHA) reclassify TFA as "presumed" toxic to human reproduction, based on studies showing damage to animal fetuses. ECHA opened a public consultation on this reclassification request and is expected to make recommendations to the European Commission regarding labeling and control measures.

The contamination has proven extremely difficult to address due to TFA's resistance to conventional water treatment methods. The only effective removal technique is reverse osmosis, which is prohibitively expensive and wastes up to 25 percent of treated water while producing concentrated brine that requires indefinite containment.

See also

* Fluoroacetic acidhighly toxic but naturally occurring rodenticide CH₂FCOOH
* Difluoroacetic acid
* Trichloroacetic acid, the chlorinated analog
* Trifluoroacetone – also abbreviated TFA

References

{{DEFAULTSORT:Trifluoroacetic Acid
Perfluorocarboxylic acids
*
Reagents for organic chemistry
Organic compounds with 2 carbon atoms