Trifluoroacetic acid (TFA) is a synthetic organofluorine compound with the chemical formula CF3CO2H. 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, Ka, that is approximately 34,000 times higher,[3] 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. TFA is commonly used in organic chemistry for various purposes.
Synthesis
TFA is prepared industrially by the electrofluorination of acetyl chloride or acetic anhydride, followed by hydrolysis of the resulting trifluoroacetyl fluoride:[4]
- CH
3COCl + 4 HF → CF
3COF + 3 H
2 + HCl
- CF
3COF + H
2O → CF
3COOH + HF
Where desired, this compound may be dried by addition of trifluoroacetic anhydride.[5]
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.[6]
Uses
TFA is the precursor to many other fluorinated compounds such as trifluoroacetic anhydride, trifluoroperacetic acid, and 2,2,2-trifluoroethanol.[4] 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.[7] 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.[8][9]
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.[10]
TFA is used to produce trifluoroacetate salts.[11]
Safety
Trifluoroacetic acid is a strong acid.[12] 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. [13]
Environment
Although trifluoroacetic acid is not produced biologically or abiotically,[14] it is a metabolic breakdown product of the volatile anesthetic agent halothane. It is also thought to be responsible for halothane-induced hepatitis.[15] It also may be formed by photooxidation of the commonly used refrigerant 1,1,1,2-tetrafluoroethane (R-134a).[16][17] 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.[18][19]
Trifluoroacetic acid is also formed by the degradation of pesticides that contain a CF3 group, like Flufenacet.[20] The German Umweltbundesamt has identified pesticides as the main source of TFA in water in agricultural areas. In November 2024, the Swiss authorities presented an overview of widespread groundwater contamination with TFA.[21]
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.[22] Median concentrations of a few micrograms per liter have been found in beer and tea.[23] Seawater can contain about 200 ng of TFA per liter.[24][25][26] Biotransformation by decarboxylation to fluoroform has been discussed.[27] In October 2024, a publication proposed classifying TFA as a planetary boundary threat, similar to how CFCs are treated.[28]
Toxicology
Trifluoroacetic acid is mildly phytotoxic.[29] 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.[30]
See also
- Fluoroacetic acid – highly toxic but naturally occurring rodenticide CH2FCOOH
- Difluoroacetic acid
- Trichloroacetic acid, the chlorinated analog
- Trifluoroacetone – also abbreviated TFA
References
- ^ Kreglewski, A. (1962). "Trifluoroacetic acid". Welcome to the NIST WebBook. 10 (11–12): 629–633. Retrieved 1 March 2020.
- ^ W. M. Haynes.; David R. Lide; Thomas J. Bruno, eds. (2016–2017). CRC Handbook of Chemistry and Physics. CRC Press. pp. 954–963. ISBN 978-1-4987-5429-3.
- ^ Note: Calculated from the ratio of the Ka values for TFA (pKa = 0.23) and acetic acid (pKa = 4.76)
- ^ a b G. Siegemund; W. Schwertfeger; A. Feiring; B. Smart; F. Behr; H. Vogel; B. McKusick. "Fluorine Compounds, Organic". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a11_349. ISBN 978-3-527-30673-2.
- ^ Wilfred L.F. Armarego & Christina Li Lin Chai (2009). "Chapter 4 – Purification of Organic Chemicals". Purification of Laboratory Chemicals (6th ed.). pp. 88–444. doi:10.1016/B978-1-85617-567-8.50012-3. ISBN 978-1-85617-567-8.
- ^ Gergel, Max G. (March 1977). Excuse me sir, would you like to buy a kilo of isopropyl bromide?. Pierce Chemical. pp. 88–90.
- ^ Eidman, K. F.; Nichols, P. J. (2004). "Trifluoroacetic Acid". In L. Paquette (ed.). Encyclopedia of Reagents for Organic Synthesis. New York: J. Wiley & Sons. doi:10.1002/047084289X.rt236.pub2. hdl:10261/236866. ISBN 978-0-471-93623-7.
- ^ Lundt, Behrend F.; Johansen, Nils L.; Vølund, Aage; Markussen, Jan (1978). "Removal of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic acid". International Journal of Peptide and Protein Research. 12 (5): 258–268. doi:10.1111/j.1399-3011.1978.tb02896.x. PMID 744685.
- ^ Andrew B. Hughes (2011). "1. Protection Reactions". In Vommina V. Sureshbabu; Narasimhamurthy Narendra (eds.). Amino Acids, Peptides and Proteins in Organic Chemistry: Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis. Vol. 4. pp. 1–97. doi:10.1002/9783527631827.ch1. ISBN 978-3-527-63182-7.
- ^ Stout, Steven J.; Dacunha, Adrian R. (1989). "Tuning and calibration in thermospray liquid chromatography/mass spectrometry using trifluoroacetic acid cluster ions". Analytical Chemistry. 61 (18): 2126. doi:10.1021/ac00193a027.
- ^ O. Castano; A. Cavallaro; A. Palau; J. C. Gonzalez; M. Rossell; T. Puig; F. Sandiumenge; N. Mestres; S. Pinol; A. Pomar & X. Obradors (2003). "High quality YBa2Cu3O7 thin films grown by trifluoroacetates metal-organic deposition". Superconductor Science and Technology. 16 (1): 45–53. Bibcode:2003SuScT..16...45C. doi:10.1088/0953-2048/16/1/309. S2CID 250765145.
- ^ Henne, Albert L; Fox, Charles J (1951). "Ionization constants of fluorinated acids". Journal of the American Chemical Society. 73 (5): 2323–2325. doi:10.1021/ja01149a122.
- ^ "Safety Data Sheet - Trifluoroacetic Acid - Version 6.8". Sigma-Aldrich. Retrieved 25 November 2024.
- ^ Joudan, Shira; De Silva, Amila O.; Young, Cora J. (2021). "Insufficient evidence for the existence of natural trifluoroacetic acid". Environmental Science: Processes & Impacts. 23 (11): 1641–1649. doi:10.1039/D1EM00306B. hdl:10315/40884. ISSN 2050-7887. PMID 34693963. S2CID 239768006.
- ^ "Halothane", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31643481, retrieved 15 July 2021
- ^ Scientific Assessment of Ozone Depletion: 2010 (PDF). Global Ozone Research and Monitoring Project. World Meteorological Organization.
- ^ Wallington, T. J.; Hurley, M. D.; Fracheboud, J. M.; Orlando, J. J.; Tyndall, G. S.; Sehested, J.; Møgelberg, T. E.; Nielsen, O. J. (1996). "Role of Excited CF3CFHO Radicals in the Atmospheric Chemistry of HFC-134a". The Journal of Physical Chemistry. 100 (46): 18116–18122. doi:10.1021/jp9624764.
- ^ "Degradation products of fluorinated greenhouse gases". Umweltbundesamt. 19 June 2023. Retrieved 27 September 2024.
- ^ "TFA as an atmospheric breakdown product". Fluorocarbons. European FluoroCarbons Technical Committee, (Cefic sector group). 6 December 2023. Retrieved 27 September 2024.
- ^ Joerss, Hanna; Freeling, Finnian; van Leeuwen, Stefan; Hollender, Juliane; Liu, Xingang; Nödler, Karsten; Wang, Zhanyun; Yu, Bochi; Zahn, Daniel; Sigmund, Gabriel (1 November 2024). "Pesticides can be a substantial source of trifluoroacetate (TFA) to water resources". Environment International. 193: 109061. doi:10.1016/j.envint.2024.109061. ISSN 0160-4120.
- ^ FOEN, Federal Office for the Environment. "TFA in groundwater". www.bafu.admin.ch. Retrieved 5 February 2025.
- ^ Hosea, Leana; Salvidge, Rachel (1 May 2024). "Rapidly rising levels of TFA 'forever chemical' alarm experts". The Guardian. ISSN 0261-3077. Retrieved 29 May 2024.
- ^ Marco Scheurer, Karsten Nödler (2021). "Ultrashort-chain perfluoroalkyl substance trifluoroacetate (TFA) in beer and tea – An unintended aqueous extraction". Food Chemistry. 351: 129304. doi:10.1016/j.foodchem.2021.129304. ISSN 0308-8146. PMID 33657499. S2CID 232115008.
- ^ Frank, H.; Christoph, E. H.; Holm-Hansen, O.; Bullister, J. L. (January 2002). "Trifluoroacetate in ocean waters". Environ. Sci. Technol. 36 (1): 12–5. Bibcode:2002EnST...36...12P. doi:10.1021/es0221659. PMID 11811478.
- ^ Scott, B. F.; MacDonald, R. W.; Kannan, K.; Fisk, A.; Witter, A.; Yamashita, N.; Durham, L.; Spencer, C.; Muir, D. C. G. (September 2005). "Trifluoroacetate profiles in the Arctic, Atlantic, and Pacific Oceans". Environ. Sci. Technol. 39 (17): 6555–60. Bibcode:2005EnST...39.6555S. doi:10.1021/es047975u. PMID 16190212.
- ^ Frank, Hartmut; Christoph, Eugen H.; Holm-Hansen, Osmund; Bullister, John L. (2002). "Trifluoroacetate in Ocean Waters". Environmental Science & Technology. 36 (1): 12–15. Bibcode:2002EnST...36...12F. doi:10.1021/es0101532. ISSN 0013-936X. PMID 11811478.
- ^ Visscher, Pieter T.; Culbertson, Charles W.; Oremland, Ronald S. (June 1994). "Degradation of trifluoroacetate in oxic and anoxic sediments". Nature. 369 (6483): 729–731. Bibcode:1994Natur.369..729V. doi:10.1038/369729a0.
- ^ Arp, Hans Peter H.; Gredelj, Andrea; Glüge, Juliane; Scheringer, Martin; Cousins, Ian T. (12 November 2024). "The Global Threat from the Irreversible Accumulation of Trifluoroacetic Acid (TFA)". Environmental Science & Technology. 58 (45): 19925–19935. doi:10.1021/acs.est.4c06189.
- ^ Boutonnet, Jean Charles; Bingham, Pauline; Calamari, Davide; Rooij, Christ de; Franklin, James; Kawano, Toshihiko; Libre, Jean-Marie; McCul-Loch, Archie; Malinverno, Giuseppe; Odom, J Martin; Rusch, George M; Smythe, Katie; Sobolev, Igor; Thompson, Roy; Tiedje, James M (1999). "Environmental risk assessment of trifluoroacetic acid". International Journal of Human and Ecological Risk Assessment. 5 (1): 59–124. Bibcode:1999HERA....5...59B. doi:10.1080/10807039991289644.
- ^ Garry, Michael (1 July 2024). "German Chemicals Office Submits Proposal to EU Linking TFA to Reproductive Toxicity". Natural Refrigerants. Retrieved 5 February 2025.
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