Peptidomimetic Catalysts as Chemical Probes of Weak Intermolecular Forces: An Insight into The N-H…Cl-C H-Bonding Interaction

Despite the widespread use of amide bond isosteres, there is only a limited understanding of their H-bonding mimicry of amides. With experimental and computational approaches, we have explored the hydrogen bonding acceptor potential of the chlorine substituent in chloroalkene dipeptide isosteres (CADIs). The (Z)-chloroalkene and (E)-methylalkene analogues of peptide catalysts were synthesized and employed as probe molecules to assess the H-bonding acceptor capabilities of CADIs. These peptidomimetic studies provide experimental evidence supporting the existence of an intermolecular H-bonding interaction between the chlorine substituent in CADIs and the amide proton of the carbamate substrate. These findings show the capability of peptide catalysts to experimentally evaluate weak intermolecular forces. DFT calculations elucidated that the chlorine substituent in CADIs prefers to form p-type hydrogen bonding interactions on the lateral portions of the chlorine atom, which is different from the carbonyl oxygen of amides which predominantly forms s-type H-bonds in peptide secondary structures.