Trifluoroacetic Acid in Complex Matrices: A Critical Review of Analytical Strategies, Uncertainties, and Standardization Needs

Trifluoroacetic acid (TFA), the shortest perfluoroalkyl carboxylic acid, is the most prevalent ultra-short-chain PFAS in the environment. Its high polarity, strong acidity, water solubility, persistence, and mobility promote widespread occurrence across aquatic, terrestrial, agricultural, food, plant, and biological matrices. These same properties make reliable determination challenging because TFA shows poor reversed-phase retention, limited enrichment potential, few confirmatory ions, and frequent laboratory/background contamination. This review critically evaluates extraction and analytical strategies for TFA determination, including direct injection, dilute-and-shoot, SPE, solvent-based extraction, LC-MS/MS, IC-MS/MS, HILIC and mixed-mode LC-MS/MS, CE-MS/MS, HRMS, and fluorine-balance approaches. No single method is universally optimal: background contamination is often limited in low-concentration water samples, extraction efficiency dominates uncertainty in soils, plants, and foods, and ion suppression is critical in biological fluids. Direct injection is generally preferable for clean water and supports interlaboratory-validated methods, whereas complex matrices require matrix-specific extraction, with acetonitrile/water and isotope dilution among the most reliable options. Acidified methanol may cause esterification artifacts, and SPE methods adapted from long-chain PFAS are often unsuitable. The review proposes a matrix-specific extraction hierarchy and a minimum reporting checklist to improve harmonization and data comparability.