Structural Comparison of Homologous Reduced Peptide, Reduced Azapeptide, Iminoazapeptide, and Methyleneoxypeptide Analogues

The homologous RCO-Pro-Xaa-NHR‘ model pseudodipeptides containing the reduced peptide (CαCH2NHCα), reduced azapeptide (CαCH2NHNα), methyleneoxy (CαCH2OCα), and iminoazapeptide (CαCHNNα) surrogate of the middle amide group have been prepared. Their structural analysis has been carried out in solution by 1H NMR and IR spectroscopy and in the solid state by X-ray diffraction. The last three fragments, not protonated in the pH range 2−12, and the reduced fragment in its neutral amine form induce quite similar molecular structures characterized by a hydrogen bond between NHR‘ and the N/O atom replacing the amide NH group and closing a five-membered cycle. The neutral amine or protonated ammonium state of the reduced amide fragment, with a pK a value of about 7, depends on the environment. Protonation induces a conformational transition due to the strong proton donating properties of the ammonium group which interacts with the RCO carbonyl.