On peptide bond formation from protonated glycine dimers in the gas phase: computational insight into the role of protonation

Peptide bond formation from the pure protonated glycine dimer, H⁺(Gly)₂, and from the mixed protonated glycine-diglycine dimer, H⁺Gly₂(Gly), was recently found experimentally to occur in gas-phase experiments in the absence of any catalyst and especially under anhydrous conditions [<i>J. Phys. Chem. A</i>, 2023, <b>127</b>, 775]. In this contribution we further examine the conditions of such unimolecular reactions by means of density-functional theory calculations at the DFT/M06 2X/6-311G++(2df,p) level, focusing in particular on the role played by the protonation site. Two pathways, stepwise and concerted, are identified for the pure protonated dimer, and six pathways are examined for the mixed dimer. The lowest-energy barriers for peptide bond formation are generally found when the reaction occurs precisely at the protonation site. In contrast, the highest barrier is obtained when the dipeptide is protonated away from the reaction site, in which case the peptide bond is formed similarly as with two neutral glycine molecules as the reaction partners. Protonated glycine monomers can also be hydrogen-bonded with the dipeptide, leading to energy barriers that lie inbetween those extreme cases.