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
PubChemCID	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	114.023g·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)	-43.3·10−6cm3/mol
Hazards
	Occupational safety and health(OHS/OSH):
Main hazards	Highly corrosive
	GHSlabelling:
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 theirstandard state(at 25 °C [77 °F], 100 kPa). verify(what is?) Infobox references

Trifluoroacetic acid(TFA) is anorganofluorinecompound with thechemical formulaCF₃CO₂H. It is ahaloacetic acid,with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms. It is a colorless liquid with avinegar-like odor. TFA is a stronger acid than acetic acid, having anacid ionisation constant,K_a,that is approximately 34,000 times higher,^[3]as the highlyelectronegativefluorine atoms and consequentelectron-withdrawing natureof thetrifluoromethylgroup weakens the oxygen-hydrogen bond (allowing for greater acidity) and stabilises theanionic conjugate base.TFA is widely used inorganic chemistryfor various purposes.

Synthesis

TFA is prepared industrially by theelectrofluorinationofacetyl chlorideoracetic anhydride,followed by hydrolysis of the resultingtrifluoroacetyl fluoride:^[4]

CH
₃COCl+ 4HF→CF
₃COF+ 3H
₂+HCl

CF
₃COF+H
₂O→CF
₃COOH+HF

Where desired, this compound may be dried by addition oftrifluoroacetic anhydride.^[5]

An older route to TFA proceeds via the oxidation of 1,1,1-trifluoro-2,3,3-trichloropropene withpotassium permanganate.The trifluorotrichloropropene can be prepared bySwarts fluorinationofhexachloropropene.^[6]

Uses

TFA is the precursor to many other fluorinated compounds such astrifluoroacetic anhydride,trifluoroperacetic acid,and2,2,2-trifluoroethanol.^[4]It is areagentused inorganic synthesisbecause of a combination of convenient properties: volatility, solubility in organic solvents, and its strength as an acid.^[7]TFA is also less oxidizing thansulfuric acidbut more readily available in anhydrous form than many other acids. One complication to its use is that TFA forms anazeotropewith water (b. p. 105 °C).

TFA is popularly used as a strong acid to removeprotecting groupssuch asBocused in organic chemistry andpeptide synthesis.^[8]^[9]

At a low concentration, TFA is used as an ion pairing agent inliquid chromatography(HPLC) of organic compounds, particularlypeptidesand smallproteins.TFA is a versatile solvent forNMR 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 corrosive strong acid^[12]but it does not pose the hazards associated withhydrofluoric acidbecause thecarbon-fluorine bondis notlabile.TFA is harmful when inhaled, causes severe skin burns and is toxic for aquatic organisms even at low concentrations.

The reaction of TFA with bases and metals, especiallylight metals,is strongly exothermic. For example, reaction of TFA withlithium aluminium hydride(LAH) may result in anexplosion.^[13]

TFA is a metabolic breakdown product of thevolatile anesthetic agent halothane.It is thought to be responsible for halothane-inducedhepatitis.^[14]

Environment

No known natural processes generate trifluoroacetic acid.^[15]In the environment, trifluoroacetic acid may be formed byphotooxidationof the commonly usedrefrigerant 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 calledhydrofluoroolefins(HFO), such as2,3,3,3-tetrafluoropropene.^{[citation needed]}

Trifluoroacetic aciddegrades very slowlyin the environment, and has been found in increasing amounts as a contaminant in water, soil, food, and the human body.^[16]Median concentrations of a few micrograms per liter have been found in beer and tea.^[17]Sea water contains about 200 ng of TFA per liter.^[18]^[19]^[20]No biodegradation mechanism for the compound is known in water,^[21]althoughbiotransformationapparentlydecarboxylatesthe acid tofluoroform.^[22]

Trifluoroacetic acid is mildlyphytotoxic.^[23]

References

^Kreglewski, A. (1962)."Trifluoroacetic acid".Welcome to the NIST WebBook.10(11–12): 629–633.Retrieved1 March2020.
^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 theK_avalues for TFA (pK_a= 0.23) and acetic acid (pK_a= 4.76)
^^a ^bG. 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 YBa₂Cu₃O₇thin 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 forTrifluoroacetic acid(PDF) from EMD Millipore, revision date 10/27/2014.
^"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,retrieved15 July2021
^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.
^Hosea, Leana; Salvidge, Rachel (1 May 2024)."Rapidly rising levels of TFA 'forever chemical' alarm experts".The Guardian.ISSN 0261-3077.Retrieved29 May2024.
^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.
^"Refreshingly cool, potentially toxic".Ludwig-Maximilians-Universität (LMU) Munich.2014.Retrieved26 July2018.
^Kirschner, E., Chemical and Engineering News 1994, 8.
^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.Retrieved1 March2020.

[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 theK_avalues 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 YBa₂Cu₃O₇thin 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.

[Merck-13] Safety data sheet forTrifluoroacetic acid(PDF) from EMD Millipore, revision date 10/27/2014.

[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,retrieved15 July2021

[15] 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.

[16] Hosea, Leana; Salvidge, Rachel (1 May 2024)."Rapidly rising levels of TFA 'forever chemical' alarm experts".The Guardian.ISSN 0261-3077.Retrieved29 May2024.

[17] 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.

[18] 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.

[19] 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.

[20] 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.

[LMU2014-21] "Refreshingly cool, potentially toxic".Ludwig-Maximilians-Universität (LMU) Munich.2014.Retrieved26 July2018.

[22] Kirschner, E., Chemical and Engineering News 1994, 8.

[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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Synthesis

Uses

Safety

Environment

See also

References