Solvent effects on diketopiperazine formation from N-terminal peptide residues

The kinetics of diketopiperazine formation from the peptide H-Ala-Pro-NH2 w ith the unprotected amino group in the form of its trifluoroacetate salt ha ve been investigated in a large number of solvents, including aprotic and h ydroxylic solvents. The first-order rate constant is considerably affected by the solvent properties, its value spanning more than three orders of mag nitude. Moreover, alkylammonium carboxylate salts are efficient catalysts o f the reaction. The correlation with Kamlet-Taft solvent parameters shows t hat the reaction rate is retarded by solvents with a high capacity to stabi lise solutes that are charged or dipolar, and that are hydrogen donors and/ or acceptors. Solvents with high cohesive energy density values significant ly increase the reaction rate. These results are discussed in terms pf a pr oton switch in the rate determining step and of solvation stabilisation of the initial state of the peptide and of the transition state of the rate-li miting step.