Influence of Solvents upon Diketopiperazine Formation of FPG₈K

Ion mobility spectrometry (IMS) and mass spectrometry (MS) techniques were used to monitor diketopiperazine (DKP) formation from the peptide FPG₈K at multiple defined temperatures in methanol, ethanol, propanol, and water, with the motivation to study the effect of solvent polarity on spontaneous solution dissociation. The reaction rate increases with decreasing solvent polarity. The observed rates of trans → cis isomerization of Phe¹–Pro² and the cis-Pro² isomer dissociation result in the cis isomer growing in abundance relative to the trans isomer throughout the reaction in all solvents. Analysis of rate constants derived from the data using a sequential unimolecular kinetics model that includes hidden intermediate states yields transition state thermodynamic values for both trans → cis isomerization of Phe¹–Pro² and dissociation. The measured thermochemistry appears to be closely correlated with these solvents’ dielectric constants: a lower solvent dielectric constant accelerates the reaction by reducing the enthalpic barrier, albeit with slight entropic restriction.