Mechanism for Peptide Bond Solvolysis in 98% w/w Concentrated Sulfuric Acid

We propose a mechanism for the solvolysis of the peptide bond in 98% (w/w) concentrated sulfuric acid based on the assessment of reactivity of four dipeptides at room temperature: l-alanyl-l-alanine (1), glycylglycine (2), glycyl-l-alanine (3), and l-alanylglycine (4). We find that dipeptides (2) and (4) are stable for at least two months in 98% w/w sulfuric acid, with no signs of reactivity. The dipeptides (1) and (3) are unstable and immediately begin complex solvolysis, which is mechanistically different from acid-catalyzed peptide bond hydrolysis. We show that the solvolysis of dipeptides (1) and (3) in 98% w/w sulfuric acid leads to the formation of alaninamide (6) and glicinamide (7), respectively. We propose that the mechanism of solvolysis of dipeptides (1) and (3) proceeds via dehydrogenation of the side chain methyl group (-CH₃) of the C-terminal alanine. Consequently, the substitution of the -CH₃ group of the C-terminal alanine with -CF₃ stabilizes the l-alanyl-DL-trifluoroalanine dipeptide (5) to solvolysis in 98% w/w sulfuric acid.