Trifluoroacetic acid

Trifluoroacetic acid
Names
	Preferred IUPAC name Trifluoroacetic acid
	Other names 2,2,2-Trifluoroacetic acid; 2,2,2-Trifluoroethanoic acid; Perfluoroacetic acid; Trifluoroethanoic acid; TFA
Identifiers
CAS Number	76-05-1 ;
3D model (JSmol)	Interactive image;
Beilstein Reference	742035
ChEBI	CHEBI:45892 ;
ChEMBL	ChEMBL506259 ;
ChemSpider	10239201 ;
ECHA InfoCard	100.000.846
Gmelin Reference	2729
PubChem CID	6422;
RTECS number	AJ9625000;
UNII	E5R8Z4G708 ;
CompTox Dashboard (EPA)	DTXSID00881311, DTXSID00893893 DTXSID9041578, DTXSID00881311, DTXSID00893893 ;
	InChI InChI=1S/C2HF3O2/c3-2(4,5)1(6)7/h(H,6,7) Key: DTQVDTLACAAQTR-UHFFFAOYSA-N ; InChI=1/C2HF3O2/c3-2(4,5)1(6)7/h(H,6,7) Key: DTQVDTLACAAQTR-UHFFFAOYAP;
	SMILES FC(F)(F)C(=O)O;
Properties
Chemical formula	C2HF3O2
Molar mass	114.023 g·mol−1
Appearance	colorless liquid
Odor	Pungent/Vinegar
Density	1.489 g/cm3, 20 °C
Melting point	−15.4 °C (4.3 °F; 257.8 K)
Boiling point	72.4 °C (162.3 °F; 345.5 K)
Solubility in water	miscible
Vapor pressure	0.0117 bar (1.17 kPa) at 20 °C
Acidity (pKa)	0.52
Conjugate base	trifluoroacetate
Magnetic susceptibility (χ)	-43.3·10−6 cm3/mol
Hazards
	Occupational safety and health (OHS/OSH):
Main hazards	Highly corrosive
	GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H314, H332, H412
Precautionary statements	P260, P261, P264, P271, P273, P280, P301+P330+P331, P303+P361+P353, P304+P312, P304+P340, P305+P351+P338, P310, P312, P321, P363, P405, P501
NFPA 704 (fire diamond)	3 1 1
Safety data sheet (SDS)	External MSDS
Related compounds
Related perfluorinated acids	Heptafluorobutyric acid; Perfluorooctanoic acid; Perfluorononanoic acid
Related compounds	Acetic acid; Trichloroacetic acid
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

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, K_a, 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.

Environment

Although trifluoroacetic acid is not produced biologically or abiotically,^[13] it is a metabolic breakdown product of the volatile anesthetic agent halothane. It is also thought to be responsible for halothane-induced hepatitis.^[14] It also may be formed by photooxidation of the commonly used refrigerant 1,1,1,2-tetrafluoroethane (R-134a).^{[citation needed]} 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.^[15]^[16]

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.^[17] Median concentrations of a few micrograms per liter have been found in beer and tea.^[18] Seawater can contain about 200 ng of TFA per liter.^[19]^[20]^[21] Biotransformation by decarboxylation to fluoroform has been discussed.^[22]

Trifluoroacetic acid is mildly phytotoxic.^[23]

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 K_a values for TFA (pK_a = 0.23) and acetic acid (pK_a = 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 978-3527306732.
^ 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.
^ 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
^ "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.
^ 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.
^ 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.

[Welcome_to_the_NIST_WebBook-1] Kreglewski, A. (1962). "Trifluoroacetic acid". Welcome to the NIST WebBook. 10 (11–12): 629–633. Retrieved 1 March 2020.

[2] 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.

[3] Note: Calculated from the ratio of the K_a values for TFA (pK_a = 0.23) and acetic acid (pK_a = 4.76)

[Ullmann-4] 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 978-3527306732.

[5] 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.

[6] Gergel, Max G. (March 1977). Excuse me sir, would you like to buy a kilo of isopropyl bromide?. Pierce Chemical. pp. 88–90.

[7] 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.

[8] 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.

[9] 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.

[10] 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.

[11] 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.

[12] 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.

[13] 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.

[14] "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

[u875-15] "Degradation products of fluorinated greenhouse gases". Umweltbundesamt. 19 June 2023. Retrieved 27 September 2024.

[x312-16] "TFA as an atmospheric breakdown product". Fluorocarbons. European FluoroCarbons Technical Committee, (Cefic sector group). 6 December 2023. Retrieved 27 September 2024.

[17] 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.

[18] 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.

[19] 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.

[20] 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.

[21] 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.

[22] 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.

[23] 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.

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