L'acido trifluoroacetico (TFA) è un acido organico forte con la formula chimica C₂HF₃O₂. Si tratta di un acido carbossilico fluorurato contenente tre atomi di fluoro attaccati alla struttura carboniosa. Il TFA viene comunemente utilizzato in vari settori, tra cui quello farmaceutico, biotecnologico e chimico, grazie alle sue proprietà chimiche uniche.

Composizione chimica e struttura

Il TFA è un composto organo fluorurato con la seguente struttura:

• Formula chimica: C₂HF₃O₂

• Struttura: La struttura del TFA consiste in un atomo di carbonio centrale legato a tre atomi di fluoro e a un gruppo carbossilico (-COOH). La presenza di fluoro rende l'acido molto reattivo e gli conferisce forti proprietà acide.

La presenza di fluoro nella molecola aumenta la forza dell’acido, rendendo il TFA più volatile rispetto ad altri acidi carbossilici, il che lo rende utile in una vasta gamma di applicazioni.

Proprietà fisiche

• Aspetto: Il TFA si presenta come un liquido incolore e volatile a temperatura ambiente.

• Odore: Ha un odore pungente e irritante.

• Solubilità: È altamente solubile in acqua e in molti solventi organici, come etanolo, acetone e cloroformio.

• Punto di ebollizione: Il TFA ha un punto di ebollizione di circa 72,5°C (162,5°F), il che lo rende relativamente volatile.

• pH: Essendo un acido forte, il TFA ha un pH molto basso, il che lo rende altamente corrosivo per alcuni materiali.

Benefici e funzioni

• Solvente: Il TFA è comunemente usato come solvente nella sintesi di peptidi e in altre reazioni chimiche grazie alla sua capacità di dissolvere una vasta gamma di sostanze, inclusi proteine e altri composti organici.

• Agente di separazione nella sintesi di peptidi: Viene frequentemente utilizzato nella sintesi di peptidi per separare i peptidi dalla resina di supporto, poiché è molto efficace nel rompere il legame tra la resina e il peptide.

• Analisi chimica: Il TFA viene utilizzato nella preparazione di campioni per tecniche analitiche come la spettrometria di massa (MS) e la cromatografia, dove la sua capacità di dissolvere molecole idrofobiche è utile.

• Catalizzatore: In alcune reazioni chimiche, il TFA agisce come catalizzatore, promuovendo reazioni come esterificazione e acilazione.

Applicazioni

Farmaceutica e Biotecnologia

• Sintesi di peptidi: Il TFA è ampiamente utilizzato nella sintesi di peptidi e proteine, in particolare nella sintesi solida di peptidi (SPPS), dove funge da agente per separare il peptide dalla resina.

• Analisi chimica: Il TFA viene utilizzato nella preparazione di campioni per cromatografia ad alte prestazioni (HPLC) e spettrometria di massa (MS) poiché aiuta a migliorare la solubilità di peptidi e proteine in queste analisi.

Cosmetici

• Formulazioni: Il TFA viene talvolta utilizzato nella formulazione di prodotti cosmetici, come esfolianti e peeling chimici, grazie alle sue forti proprietà acide.

Applicazioni Industriali

• Agente per la pulizia: Grazie alla sua forte acidità e solubilità nei solventi organici, il TFA è utilizzato come agente per la pulizia in laboratori per rimuovere ioni metallici, polvere e altri contaminanti dalle attrezzature da laboratorio.

Considerazioni ambientali e di sicurezza

• Corrosivo: Il TFA è altamente corrosivo e deve essere maneggiato con cautela. Può causare gravi ustioni e irritazioni alla pelle, agli occhi e alle vie respiratorie.

• Tossicità: Il TFA deve essere utilizzato in ambienti ben ventilati e con l'adeguata protezione, come guanti, occhiali protettivi e camici da laboratorio, per ridurre il rischio di esposizione. L’ingestione o l'inalazione di TFA può causare gravi problemi di salute.

• Impatto ambientale: Il TFA deve essere smaltito con attenzione, in quanto può essere dannoso per l'ambiente se rilasciato in acqua o nel suolo. Deve essere neutralizzato prima dello smaltimento secondo le normative di sicurezza.

Molecular Formula  C₂HF₃O₂    CF₃COOH

Molecular Weight  

CAS     76-05-1

UNII    E5R8Z4G708

EC Number  200-929-3

DTXSID9041578

Synonyms:

Perfluoroacetic acid

Trifluoroethanoic acid

Bibliografia__________________________________________________________________________

Arp HPH, Gredelj A, Glüge J, Scheringer M, Cousins IT. The Global Threat from the Irreversible Accumulation of Trifluoroacetic Acid (TFA). Environ Sci Technol. 2024 Nov 12;58(45):19925-19935. doi: 10.1021/acs.est.4c06189. 

Abstract. Trifluoroacetic acid (TFA) is a persistent and mobile substance that has been increasing in concentration within diverse environmental media, including rain, soils, human serum, plants, plant-based foods, and drinking water. Currently, TFA concentrations are orders of magnitude higher than those of other per- and polyfluoroalkyl substances (PFAS). This accumulation is due to many PFAS having TFA as a transformation product, including several fluorinated gases (F-gases), pesticides, pharmaceuticals, and industrial chemicals, in addition to direct release of industrially produced TFA. Due to TFA's extreme persistence and ongoing emissions, concentrations are increasing irreversibly. What remains less clear are the thresholds where irreversible effects on local or global scales occur. There are indications from mammalian toxicity studies that TFA is toxic to reproduction and that it exhibits liver toxicity. Ecotoxicity data are scarce, with most data being for aquatic systems; fewer data are available for terrestrial plants, where TFA bioaccumulates most readily. Collectively, these trends imply that TFA meets the criteria of a planetary boundary threat for novel entities because of increasing planetary-scale exposure, where potential irreversible disruptive impacts on vital earth system processes could occur. The rational response to this is to instigate binding actions to reduce the emissions of TFA and its many precursors.

Guo Z, Attar AA, Qiqige Q, Lundgren RJ, Joudan S. Photochemical Formation of Trifluoroacetic Acid: Mechanistic Insights into a Fluoxetine-Related Aryl-CF3 Compound. Environ Sci Technol. 2025 Jan 21;59(2):1367-1377. doi: 10.1021/acs.est.4c10777. 

Abstract. Trifluoroacetic acid (TFA) is a ubiquitous environmental contaminant; however, its sources are poorly constrained. One understudied source is from the photochemical reactions of aromatic compounds containing -CF3 moieties (aryl-CF3) including many pharmaceuticals and agrochemicals. Here, we studied the aqueous photochemistry of 4-(trifluoromethyl)phenol (4-TFMP), a known transformation product of the pharmaceutical fluoxetine. When exposed to lamps centered at UV-B, 4-TFMP formed up to 9.2% TFA at a steady state under acidic conditions and 1.3% under alkaline conditions. TFA yields of fluoxetine were similar to 4-TFMP for acidic and neutral pH, but higher at alkaline pH, suggesting that fluoxetine may have a mechanism of TFA formation in addition to via the 4-TFMP intermediate. Use of an 13CF3 isotopologue of 4-TFMP allowed for the tracking of TFA formation, which formed via multiple oxidative additions prior to oxidative ring cleavage. The oxidation is mediated by reactive oxygen species (ROS) generated through self-sensitized photolysis, with singlet oxygen and hydroxyl radicals as the key ROS. In addition to the TFA formation mechanism, other photochemical reactions of 4-TFMP resulted in defluorination and dimerization. Overall, this work expands our understanding of how TFA forms from aryl-CF3 compounds to better understand the total global burden of TFA.

Solomon KR, Velders GJ, Wilson SR, Madronich S, Longstreth J, Aucamp PJ, Bornman JF. Sources, fates, toxicity, and risks of trifluoroacetic acid and its salts: Relevance to substances regulated under the Montreal and Kyoto Protocols. J Toxicol Environ Health B Crit Rev. 2016;19(7):289-304. doi: 10.1080/10937404.2016.1175981.

Abstract. Trifluoroacetic acid (TFA) is a breakdown product of several hydrochlorofluorocarbons (HCFC), regulated under the Montreal Protocol (MP), and hydrofluorocarbons (HFC) used mainly as refrigerants. Trifluoroacetic acid is (1) produced naturally and synthetically, (2) used in the chemical industry, and (3) a potential environmental breakdown product of a large number (>1 million) chemicals, including pharmaceuticals, pesticides, and polymers. The contribution of these chemicals to global amounts of TFA is uncertain, in contrast to that from HCFC and HFC regulated under the MP. TFA salts are stable in the environment and accumulate in terminal sinks such as playas, salt lakes, and oceans, where the only process for loss of water is evaporation. Total contribution to existing amounts of TFA in the oceans as a result of the continued use of HCFCs, HFCs, and hydrofluoroolefines (HFOs) up to 2050 is estimated to be a small fraction (<7.5%) of the approximately 0.2 μg acid equivalents/L estimated to be present at the start of the millennium. As an acid or as a salt TFA is low to moderately toxic to a range of organisms. Based on current projections of future use of HCFCs and HFCs, the amount of TFA formed in the troposphere from substances regulated under the MP is too small to be a risk to the health of humans and environment. However, the formation of TFA derived from degradation of HCFC and HFC warrants continued attention, in part because of a long environmental lifetime and due many other potential but highly uncertain sources.

Zhang J, Zhang Y, Li J, Hu J, Ye P, Zeng Z. Monitoring of trifluoroacetic acid concentration in environmental waters in China. Water Res. 2005 Apr;39(7):1331-9. doi: 10.1016/j.watres.2004.12.043.

Abstract. It is critically important and extremely meaningful to determine the concentration of TFA in the environmental water in China. This will create background reference for the effects of analyzing the extensive employment of the substitutes to CFCs in China. In this paper a set of analytical methods was described for use in monitoring of trifluoroacetic acid (TFA) concentration of environmental waters including collecting, pre-treatment measures, preserving, concentrating and derivatization of samples from different kinds of environmental waters. The GC with electrical capture detector (ECD) and headspace auto sampler were used in the analysis. The lowest detection limit of the instrument is 0.0004 ng methyl trifluoroacetic acid (MTFA), and the lowest detected concentration with the method is 3.0 ng/ml TFA. TFA collected in various environmental water samples (including rainfall, inland surface water, ground water, and waste water) from nine provinces and autonomous regions in China have been determined by applying the analytical methods created and defined in this work. The results indicate that the concentrations of TFA in nine rainfalls and three snowfalls through the period from 2000 to 2001 ranged from 25 to 220 ng/l, the TFA concentration in the inland surface water samples ranged from 4.7 to 221 ng/l, the concentration of TFA in groundwater samples collected in Beijing was 10 ng/l, and the TFA concentration in coastal water samples ranged from 4.2 to 190.1 ng/l.

Baqar M, Zhao M, Saleem R, Cheng Z, Fang B, Dong X, Chen H, Yao Y, Sun H. Identification of Emerging Per- and Polyfluoroalkyl Substances (PFAS) in E-waste Recycling Practices and New Precursors for Trifluoroacetic Acid. Environ Sci Technol. 2024 Sep 10;58(36):16153-16163. doi: 10.1021/acs.est.4c05646. 

Abstract. Electronic waste is an emerging source of per- and polyfluoroalkyl substance (PFAS) emissions to the environment, yet the contribution from hazardous recycling practices in the South Asian region remains unclear. This study detected 41 PFAS in soil samples from e-waste recycling sites in Pakistan and the total concentrations were 7.43-367 ng/g dry weight (dw) (median: 37.7 ng/g dw). Trifluoroacetic acid (TFA) and 6:2 fluorotelomer sulfonic acid emerged as the dominant PFAS, constituting 49% and 13% of the total PFAS concentrations, respectively. Notably, nine CF3-containing emerging PFAS were identified by the high-resolution mass spectrometry (HRMS)-based screening. Specifically, hexafluoroisopropanol and bistriflimide (NTf2) were consistently identified across all the samples, with quantified concentrations reaching up to 854 and 90 ng/g dw, respectively. This suggests their potential association with electronic manufacturing and recycling processes. Furthermore, except for NTf2, all the identified emerging PFAS were confirmed as precursors of TFA with molar yields of 8.87-40.0% by the TOP assay validation in Milli-Q water. Overall, this study reveals significant emission of PFAS from hazardous e-waste recycling practices and emphasizes the identification of emerging sources of TFA from precursor transformation, which are essential for PFAS risk assessment.

Jubilut GN, Cilli EM, Tominaga M, Miranda A, Okada Y, Nakaie CR. Evaluation of the trifluoromethanosulfonic acid/trifluoroacetic acid/thioanisole cleavage procedure for application in solid-phase peptide synthesis. Chem Pharm Bull (Tokyo). 2001 Sep;49(9):1089-92. doi: 10.1248/cpb.49.1089. 

Abstract. As an extension of our investigation of peptidyl-resin linkage stability towards different cleavage procedures used in the solid-phase peptide synthesis (SPPS) technique, the present paper evaluated the trifluoromethanesulfonic acid (TFMSA)/trifluoroacetic acid (TFA)/thioanisole method, varying the type of resin (benzhydrylamine-resin, BHAR; methylbenzhydrylamine-resin, MBHAR and 4-(oxymethyl)-phenylacetamidomethyl-resin, PAMR) and peptide resin-bound residue (Gly and Phe). The vasoactive angiotensin II (AII, DRVYIHPF) and its [Gly8]-AII analogue linked to those resins used routinely in tert-butyloxycarbonyl (Boc)-SPPS chemistry were submitted comparatively to a time course study towards TFMSA/TFA cleavage. At 0 degrees C, [Gly8]-AII was completely removed from all resins in less than 6 h, but the hydrophobic Phe8 moiety-containing AII sequence was only partially cleaved (not more than 15%) from BHAR or MBHAR in this period. At 25 degrees C, [Gly8]-AII cleavage time decreased to less than 2 h irrespective of the solid support, and quantitative removal of AII from PAMR and MBHAR occurred in less than 3 h. However, about 10-15 h seemed to be necessary for cleavage of AII from BHAR, and in this extended cleavage reaction a significant increase in peptide degradation rate was observed. Regardless of the cleavage temperature used, the decreasing order of acid stability measured for resins was BHAR>MBHAR>PAMR. Collectively, these findings demonstrated the feasibility of applying TFMSA/TFA solution as a substitute for anhydrous HF at the cleavage step in Boc-SPPS methodology. Care should be taken however, as the cleavage efficacy depends on multiple factors including the resin, peptide sequence, the time and temperature of reaction.

Valenti LE, Paci MB, De Pauli CP, Giacomelli CE. Infrared study of trifluoroacetic acid unpurified synthetic peptides in aqueous solution: trifluoroacetic acid removal and band assignment. Anal Biochem. 2011 Mar 1;410(1):118-23. doi: 10.1016/j.ab.2010.11.006. Epub 2010 Nov 13. PMID: 21078284.

Zhou J, Saeidi N, Wick LY, Xie Y, Kopinke FD, Georgi A. Efficient removal of trifluoroacetic acid from water using surface-modified activated carbon and electro-assisted desorption. J Hazard Mater. 2022 Aug 15;436:129051. doi: 10.1016/j.jhazmat.2022.129051. Epub 2022 May 14. PMID: 35580494.