Brønsted Acid-Lewis Acid (BA-LA) Induced Final Deprotection/Peptide Resin Cleavage in Fmoc/ t- Bu Solid-Phase Peptide Synthesis: HCl/FeCl 3 and AcOH/FeCl 3 as Viable PFAS-Free Alternatives for TFA.

The widely used Fmoc/ t -Bu solid-phase peptide synthesis (SPPS) is hampered by relying on corrosive, per/polyfluoroalkyl substance (PFAS) classified trifluoroacetic acid (TFA) as a universal protecting group (PG) removal/resin cleavage reagent. We report that suitable combinations of Brønsted acids (BAs) and Lewis acids (LAs) such as HCl/FeCl 3 and AcOH/FeCl 3 constitute viable alternatives for TFA as PFAS-free cleavage agents. Using water miscible dimethyl carbonate (DMC) and acetonitrile (MeCN) as solvents enabled diluting cleavage mixtures with suitable aqueous solutions, allowing for direct use in purification in which removal of >99.99% iron from an HCl/FeCl 3 induced cleavage was demonstrated.