Four unique gas phase mechanisms for peptide bond formation between two glycine molecules have been mapped out with quantum mechanical electronic structure methods. Both concerted and stepwise mechanisms, each leading to a cis and trans glycylglycine product (four mechanisms total), were examined with the B3LYP and MP2 methods and Gaussian atomic orbital basis sets as large as aug-cc-pVTZ. Electronic energies of the stationary points along the reaction pathways were also computed with explicitly correlated MP2-F12 and CCSD(T)-F12 methods. The CCSD(T)-F12 computations indicate that the electronic barriers to peptide bond formation are similar for all four mechanisms (ca. 32–39 kcal mol–1 relative to two isolated glycine fragments). The smallest barrier (32 kcal mol–1) is associated with the lone transition state for the concerted mechanism leading to the formation of a trans peptide bond, whereas the largest barrier (39 kcal mol–1) was encountered along the concerted pathway leading to the cis configuration of the glycylglycine dipeptide. Two significant barriers are encountered for the stepwise mechanisms. For both the cis and trans pathways, the early electronic barrier is 36 kcal mol–1 and the subsequent barrier is approximately 1 kcal mol–1 lower. A host of intermediates and transition states lie between these two barriers, but they all have very small relative electronic energies (ca. ±4 kcal mol–1). The isolated cis products (glycylglycine + H2O) are virtually isoenergetic with the isolated reactants (within −1 kcal mol–1), whereas the trans products are about 5 kcal mol–1 lower in energy. In both products, however, the water can hydrogen bond to the dipeptide and lower the energy by roughly 5–9 kcal mol–1. This study indicates that the concerted process leading to a trans configuration about the peptide bond is marginally favored both thermodynamically (exothermic by ca. 5 kcal mol–1) and kinetically (barrier height ≈ 32 kcal mol–1) according to the CCSD(T)-F12/haTZ electronic energies. The other pathways have slightly larger barrier heights (by 4–8 kcal mol–1).
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