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 (<b>1</b>), glycylglycine (<b>2</b>), glycyl-l-alanine (<b>3</b>), and l-alanylglycine (<b>4</b>). We find that dipeptides (<b>2</b>) and (<b>4</b>) are stable for at least two months in 98% w/w sulfuric acid, with no signs of reactivity. The dipeptides (<b>1</b>) and (<b>3</b>) are unstable and immediately begin complex solvolysis, which is mechanistically different from acid-catalyzed peptide bond hydrolysis. We show that the solvolysis of dipeptides (<b>1</b>) and (<b>3</b>) in 98% w/w sulfuric acid leads to the formation of alaninamide (<b>6</b>) and glicinamide (<b>7</b>), respectively. We propose that the mechanism of solvolysis of dipeptides (<b>1</b>) and (<b>3</b>) 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 (<b>5</b>) to solvolysis in 98% w/w sulfuric acid.