Trifluoroacetic acid: Application, synthesis and toxicity

Trifluoroacetic acid (TFA) is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with a vinegar like odor. It is a stronger acid than acetic acid, having an acid ionisation constant 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. TFA is widely used in organic chemistry for various purposes. Its appearance is as follows:

Figure 1 Appearance of Trifluoroacetic acid.

Chemical synthesis

95% H₂O₂ (1.70 g, 47.5 mmol H₂O₂) was added dropwise into a well-stirred solution of RfCOOK (0.047 mmol) in freshly distilled bis-(perfluoroacyl) anhydride (100 mmol) at 0°C. After addition of the H₂O₂, the reaction mixture was stirred for 10 min at 0°C. A 31% (mol) solution of bis-(perfluoroacyl) peroxide (BPFAP) in perfluorocarboxylic acid was obtained. It is possible to use less concentrated H2O2. In this case the solution of bis(perfluoroacyl) peroxide in perfluorocarboxylic acid would be less concentrated to a corresponding degree. For example 8% (mol) solution of BPFAP in perfluorocarboxylic acid was obtained when 30% H₂O₂ (1.77 g, 15.6 mmol H₂O₂) was added dropwise into a well-stirred solution of RfCOOK (0.047 mmol) in freshly distilled bis(perfluoroacyl) anhydride (100 mmol) at 0°C. After addition of the H₂O₂, the reaction mixture was stirred for 10 min at 0°C. TFA yield: 40%. The concentration of TFA was measured by ¹⁹F NMR spectra. ¹⁹F chemical shifts are given relative to external CFCl3. ¹⁹F NMR (CF3COOH, 282.2 MHz): δ -72.8.

Toxicity

[2]Lundt et al (1978). Removal of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic acid. International Journal of Peptide and Protein Research. 12 (5): 258–268.

[3]Stout et al (1989). Tuning and calibration in thermospray liquid chromatography/mass spectrometry using trifluoroacetic acid cluster ions. Analytical Chemistry. 61 (18): 2126.

[4]Krasutsky et al (2001). A Novel Catalytic Pathway for Perfluoroacyl Peroxide Synthesis. Organic Letters, 3(19), 2997-2999.

[5]Safety data sheet for Trifluoroacetic acid from EMD Millipore, revision date 10/27/2014.

[6]GPS Safety Summary: Trifluoroacetic Acid. Retrieved October 18, 2016.