Scope and Limitations of the Use of Methanesulfonic Acid (MSA) as a Green Acid for Global Deprotection in Solid‐Phase Peptide Synthesis

N,N-dimethylformamide (DMF) and trifluoroacetic acid (TFA) are the two solvents/reagents most widely used in solid-phase peptide synthesis (SPPS). While DMF is already regulated in Europe, TFA - a member of the polyfluoroalkyl substances (PFAS) family - is expected to face similar restrictions soon. These compounds break down slowly and pose risks to human health and the environment. Herein, the use of the so-called "green acid par excellence", methanesulfonic acid (MSA), in substitution of TFA is discussed. As MSA is stronger than TFA, it is diluted with a solvent for use. The effectivity of MSA depends on the solvents used. When dichloromethane (DCM) is used, 1.5 % MSA removes all side-chain protecting groups, except the trityl (Trt) group of His. In the presence of acetic acid (AcOH) and dimethylcarbonate (DMC), more concentrated solutions of MSA (8-16 %) are required. The removal of the Trt group of Asn/Gln continues to be a challenge even with these solutions, and aspartimide formation can occur in Asp-containing peptides.