Trifluoroacetic acid

TFA is prepared industrially by the electrofluorination of acetyl chloride or acetic anhydride, followed by hydrolysis of the resulting trifluoroacetyl fluoride:{{Ullmann |author=G. Siegemund |author2=W. Schwertfeger |author3=A. Feiring |author4=B. Smart |author5=F. Behr |author6=H. Vogel |author7=B. McKusick | title = Fluorine Compounds, Organic | doi = 10.1002/14356007.a11_349}}

: {{chem|CH|3|COCl}} + 4 {{chem|HF}} → {{chem|CF|3|COF}} + 3 {{chem|H|2}} + {{chem|HCl}}

: {{chem|CF|3|COF}} + {{chem|H|2|O}} → {{chem|CF|3|COOH}} + {{chem|HF}}

Where desired, this compound may be dried by addition of trifluoroacetic anhydride.{{cite book | doi = 10.1016/B978-1-85617-567-8.50012-3 | chapter = Chapter 4 – Purification of Organic Chemicals | title = Purification of Laboratory Chemicals | edition = 6th |author1=Wilfred L.F. Armarego |author2=Christina Li Lin Chai | year = 2009 | pages = 88–444 | isbn = 978-1-85617-567-8 |name-list-style=amp }}

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.{{cite book|url=https://archive.org/details/gergel_isopropyl_bromide|title=Excuse me sir, would you like to buy a kilo of isopropyl bromide?|first=Max G.|last=Gergel|author-link=Max Gergel|date=March 1977|publisher=Pierce Chemical|pages=88–90}}

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.{{cite journal |doi=10.15227/orgsyn.060.0104 |title=2-Phenyl-2-Adamantanamine Hydrochloride |journal=Organic Syntheses |date=1981 |volume=60 |page=104|author=Asher Kalir, David Balderman

}}

It is a precursor to trifluoroacetic anhydride.

File:Trifluoroacetic acid in a beaker.jpg

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.{{cite encyclopedia|year=2004|encyclopedia=Encyclopedia of Reagents for Organic Synthesis|publisher=J. Wiley & Sons|location=New York|editor=L. Paquette|doi=10.1002/047084289X.rt236.pub2|isbn=978-0-471-93623-7|author2=Nichols, P. J.|author1=Eidman, K. F.|chapter=Trifluoroacetic Acid|hdl=10261/236866|hdl-access=free}} 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.{{cite journal | doi = 10.1111/j.1399-3011.1978.tb02896.x | title = Removal of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic acid | year = 1978 | last1 = Lundt | first1 = Behrend F. | last2 = Johansen | first2 = Nils L. | last3 = Vølund | first3 = Aage | last4 = Markussen | first4 = Jan | journal = International Journal of Peptide and Protein Research | volume = 12 | issue = 5 | pages = 258–268 | pmid = 744685}}{{cite book | doi = 10.1002/9783527631827.ch1 | chapter = 1. Protection Reactions | author = Andrew B. Hughes |editor1=Vommina V. Sureshbabu |editor2=Narasimhamurthy Narendra | volume = 4 | title = Amino Acids, Peptides and Proteins in Organic Chemistry: Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis| year = 2011 | pages = 1–97 | isbn = 978-3-527-63182-7}}

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.{{cite journal | doi = 10.1021/ac00193a027 | title = Tuning and calibration in thermospray liquid chromatography/mass spectrometry using trifluoroacetic acid cluster ions | year = 1989 | last1 = Stout | first1 = Steven J. | last2 = Dacunha | first2 = Adrian R. | journal = Analytical Chemistry | volume = 61 | pages = 2126 | issue = 18}}

TFA is used to produce trifluoroacetate salts.{{cite journal |author1=O. Castano |author2=A. Cavallaro |author3=A. Palau |author4=J. C. Gonzalez |author5=M. Rossell |author6=T. Puig |author7=F. Sandiumenge |author8=N. Mestres |author9=S. Pinol |author10=A. Pomar |author11=X. Obradors |name-list-style=amp | title = High quality YBa₂Cu₃O₇ thin films grown by trifluoroacetates metal-organic deposition | journal = Superconductor Science and Technology | year = 2003 | volume = 16 | issue = 1 | pages = 45–53 | doi = 10.1088/0953-2048/16/1/309 | bibcode = 2003SuScT..16...45C |s2cid=250765145 }}

Trifluoroacetic acid is a strong acid.{{cite journal |last1=Henne |first1=Albert L |last2=Fox |first2=Charles J |year=1951 |title=Ionization constants of fluorinated acids |url=http://rave.ohiolink.edu/etdc/view?acc_num=osu1486550192262315 |journal=Journal of the American Chemical Society |volume=73 |issue=5 |pages=2323–2325 |doi=10.1021/ja01149a122|bibcode=1951JAChS..73.2323H }} 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.{{cite web |title=Safety Data Sheet - Trifluoroacetic Acid - Version 6.8 |url=https://www.sigmaaldrich.com/AU/en/sds/SIGALD/T6508?userType=undefined |publisher=Sigma-Aldrich |access-date=25 November 2024}}

Trifluoroacetic acid is mildly phytotoxic.{{cite journal |last1=Boutonnet |first1=Jean Charles |last2=Bingham |first2=Pauline |last3=Calamari |first3=Davide |last4=Rooij |first4=Christ de |last5=Franklin |first5=James |last6=Kawano |first6=Toshihiko |last7=Libre |first7=Jean-Marie |last8=McCul-Loch |first8=Archie |last9=Malinverno |first9=Giuseppe |last10=Odom |first10=J Martin |last11=Rusch |first11=George M |last12=Smythe |first12=Katie |last13=Sobolev |first13=Igor |last14=Thompson |first14=Roy |last15=Tiedje |first15=James M |year=1999 |title=Environmental risk assessment of trifluoroacetic acid |journal=International Journal of Human and Ecological Risk Assessment |volume=5 |issue=1 |pages=59–124 |bibcode=1999HERA....5...59B |doi=10.1080/10807039991289644}} 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.{{Cite web |last=Garry |first=Michael |date=2024-07-01 |title=German Chemicals Office Submits Proposal to EU Linking TFA to Reproductive Toxicity |url=https://naturalrefrigerants.com/german-chemicals-office-submits-proposal-to-eu-linking-tfa-to-reproductive-toxicity/ |access-date=2025-02-05 |website=Natural Refrigerants |language=en-US}}

Uncertainties remain in our understanding of the potential impacts on the environment of TFA.{{Cite journal |last1=Hanson |first1=Mark L. |last2=Madronich |first2=Sasha |last3=Solomon |first3=Keith |last4=Sulbaek Andersen |first4=Mads P. |last5=Wallington |first5=Timothy J. |date=2024-10-01 |title=Trifluoroacetic Acid in the Environment: Consensus, Gaps, and Next Steps |url=https://academic.oup.com/etc/article/43/10/2091/7829385 |journal=Environmental Toxicology and Chemistry |language=en |volume=43 |issue=10 |pages=2091–2093 |doi=10.1002/etc.5963 |pmid=39078279 |bibcode=2024EnvTC..43.2091H |issn=0730-7268}}{{cite news |last1=Nilsson, Müller and Hancock |title=Europe's fight to get rid of 'forever chemicals' |url=https://www.ft.com/content/a36c8faf-248a-4468-bcad-ab2b1c572901 |access-date=2 June 2025 |publisher=Financial Times |date=2 June 2025}} 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,{{Cite journal |last1=Joudan |first1=Shira |last2=De Silva |first2=Amila O. |last3=Young |first3=Cora J. |date=2021 |title=Insufficient evidence for the existence of natural trifluoroacetic acid |journal=Environmental Science: Processes & Impacts |language=en |volume=23 |issue=11 |pages=1641–1649 |doi=10.1039/D1EM00306B |pmid=34693963 |issn=2050-7887|hdl=10315/40884 |s2cid=239768006 |hdl-access=free }} it is a metabolic breakdown product of the volatile anesthetic agent halothane. It is also thought to be responsible for halothane-induced hepatitis.{{Citation|title=Halothane|date=2012|url=http://www.ncbi.nlm.nih.gov/books/NBK548151/|work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|place=Bethesda (MD)|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31643481|access-date=2021-07-15}} It also may be formed by photooxidation of the commonly used refrigerant 1,1,1,2-tetrafluoroethane (R-134a).{{Cite book |url=https://ozone.unep.org/sites/default/files/2019-05/00-SAP-2010-Assement-report.pdf |title=Scientific Assessment of Ozone Depletion: 2010 |publisher=World Meteorological Organization |series=Global Ozone Research and Monitoring Project |issue=52}}{{Cite journal |last1=Wallington |first1=T. J. |last2=Hurley |first2=M. D. |last3=Fracheboud |first3=J. M. |last4=Orlando |first4=J. J. |last5=Tyndall |first5=G. S. |last6=Sehested |first6=J. |last7=Møgelberg |first7=T. E. |last8=Nielsen |first8=O. J. |date=1996 |title=Role of Excited CF₃CFHO Radicals in the Atmospheric Chemistry of HFC-134a |journal=The Journal of Physical Chemistry |language=en |volume=100 |issue=46 |pages=18116–18122 |doi=10.1021/jp9624764}} 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.{{cite web | title=Degradation products of fluorinated greenhouse gases | website=Umweltbundesamt | date=2023-06-19 | url=https://www.umweltbundesamt.de/en/topics/climate-energy/fluorinated-greenhouse-gases-fully-halogenated-cfcs/emissions-degradation-products/degradation-products-of-fluorinated-greenhouse | access-date=2024-09-27}}{{cite web | title=TFA as an atmospheric breakdown product | website=Fluorocarbons | date=2023-12-06 | url=https://www.fluorocarbons.org/environment/environmental-impact/tfa-as-an-atmospheric-breakdown-product/ | publisher=European FluoroCarbons Technical Committee, (Cefic sector group)| access-date=2024-09-27}}

Trifluoroacetic acid is also formed by the degradation of pesticides that contain a CF₃ group, like Flufenacet.{{Cite journal |last1=Joerss |first1=Hanna |last2=Freeling |first2=Finnian |last3=van Leeuwen |first3=Stefan |last4=Hollender |first4=Juliane |last5=Liu |first5=Xingang |last6=Nödler |first6=Karsten |last7=Wang |first7=Zhanyun |last8=Yu |first8=Bochi |last9=Zahn |first9=Daniel |last10=Sigmund |first10=Gabriel |date=2024-11-01 |title=Pesticides can be a substantial source of trifluoroacetate (TFA) to water resources |journal=Environment International |volume=193 |pages=109061 |doi=10.1016/j.envint.2024.109061 |pmid=39442319 |bibcode=2024EnInt.19309061J |issn=0160-4120|doi-access=free }} 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.{{Cite news |last1=Hosea |first1=Leana |last2=Salvidge |first2=Rachel |date=2024-05-01 |title=Rapidly rising levels of TFA 'forever chemical' alarm experts |url=https://www.theguardian.com/environment/2024/may/01/rapidly-rising-levels-of-tfa-forever-chemical-alarm-experts |access-date=2024-05-29 |work=The Guardian |language=en-GB |issn=0261-3077}} Median concentrations of a few micrograms per liter have been found in beer and tea.{{Cite journal|last=Marco Scheurer, Karsten Nödler|date=2021|title=Ultrashort-chain perfluoroalkyl substance trifluoroacetate (TFA) in beer and tea – An unintended aqueous extraction|journal=Food Chemistry|volume=351|pages=129304|doi=10.1016/j.foodchem.2021.129304|pmid=33657499|s2cid=232115008|issn=0308-8146}} Seawater can contain about 200 ng of TFA per liter.{{cite journal | pmid = 11811478 | volume=36 | issue=1 | title=Trifluoroacetate in ocean waters |date=January 2002 | journal=Environ. Sci. Technol. | pages=12–5|bibcode = 2002EnST...36...12P |doi = 10.1021/es0221659 | doi-access= | last1=Frank | first1=H. | last2=Christoph | first2=E. H. | last3=Holm-Hansen | first3=O. | last4=Bullister | first4=J. L. }}{{cite journal | pmid = 16190212 | volume=39 | issue=17 | title=Trifluoroacetate profiles in the Arctic, Atlantic, and Pacific Oceans |date=September 2005 | journal=Environ. Sci. Technol. | pages=6555–60|bibcode = 2005EnST...39.6555S |doi = 10.1021/es047975u | last1=Scott | first1=B. F. | last2=MacDonald | first2=R. W. | last3=Kannan | first3=K. | last4=Fisk | first4=A. | last5=Witter | first5=A. | last6=Yamashita | first6=N. | last7=Durham | first7=L. | last8=Spencer | first8=C. | last9=Muir | first9=D. C. G. }}{{Cite journal|last1=Frank|first1=Hartmut|last2=Christoph|first2=Eugen H.|last3=Holm-Hansen|first3=Osmund|last4=Bullister|first4=John L.|date=2002|title=Trifluoroacetate in Ocean Waters|journal=Environmental Science & Technology|volume=36|issue=1|pages=12–15|doi=10.1021/es0101532|pmid=11811478|bibcode=2002EnST...36...12F|issn=0013-936X}} Biotransformation by decarboxylation to fluoroform has been discussed.{{Cite journal |last1=Visscher |first1=Pieter T. |last2=Culbertson |first2=Charles W. |last3=Oremland |first3=Ronald S. |date=June 1994 |title=Degradation of trifluoroacetate in oxic and anoxic sediments |journal=Nature |volume=369 |issue=6483 |pages=729–731 |doi=10.1038/369729a0|bibcode=1994Natur.369..729V }} In October 2024, a publication proposed classifying TFA as a planetary boundary threat, similar to how CFCs are treated.{{cite journal |last1=Arp |first1=Hans Peter H. |last2=Gredelj |first2=Andrea |last3=Glüge |first3=Juliane |last4=Scheringer |first4=Martin |last5=Cousins |first5=Ian T. |title=The Global Threat from the Irreversible Accumulation of Trifluoroacetic Acid (TFA) |journal=Environmental Science & Technology |date=12 November 2024 |volume=58 |issue=45 |pages=19925–19935 |doi=10.1021/acs.est.4c06189|bibcode=2024EnST...5819925A |doi-access=free |pmid=39475534 |pmc=11562725 }}

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.{{cite news |date=2025 |title=Forever chemicals pose growing threat to Europe's water |url=https://www.ft.com/content/a36c8faf-248a-4468-bcad-ab2b1c572901 |publisher=Financial Times}} 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.{{cite news |date=2025 |title=Forever chemicals pose growing threat to Europe's water |url=https://www.ft.com/content/a36c8faf-248a-4468-bcad-ab2b1c572901 |publisher=Financial Times}} In November 2024, the Swiss authorities presented an overview of widespread groundwater contamination with TFA.{{Cite web |last=FOEN |first=Federal Office for the Environment |title=TFA in groundwater |url=https://www.bafu.admin.ch/bafu/en/home/topics/water/info-specialists/state-of-waterbodies/state-of-groundwater/groundwater-quality/tfa-im-grundwasser.html |access-date=2025-02-05 |website=www.bafu.admin.ch |language=en}}

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.

• Fluoroacetic acid{{snd}}highly toxic but naturally occurring rodenticide CH₂FCOOH
• Difluoroacetic acid
• Trichloroacetic acid, the chlorinated analog
• Trifluoroacetone – also abbreviated TFA

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Category:Perfluorocarboxylic acids

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Category:Reagents for organic chemistry

Category:Organic compounds with 2 carbon atoms