Competition between Amide Stacking and Intramolecular H Bonds in γ-Peptide Derivatives: Controlling Nearest-Neighbor Preferences

Resonant two-photon ionization (R2PI), IR-UV holeburning (IR-UV), and resonant ion-dip infrared spectroscopy (RIDIRS) have been used to record mass-selected, single-conformation ultraviolet and infrared spectra of three simple diamide derivatives of gamma-amino adds as isolated molecules cooled in a supersonic expansion. This work builds on an earlier study of Ac-gamma(2)-hPhe-NHMe (James, W. H., III, et al. J. Am. Chem. Soc. 2009, 131, 14243), which showed that this methyl-capped gamma-peptide forms amide-stacked conformations that are similar in stability to H-bonded conformations containing a C9 ring and more stable than C7 H-bonded ring structures. Among the gamma-peptides discussed here, Ac-gamma(2)-hPhe-N(Me)(2) contains an additional methyl group relative to the previously studied Ac-gamma(2)-hPhe-NHMe and therefore lacks the amide NH group responsible for C9 ring formation. Three conformations of Ac-gamma(2)-hPhe-N(Me)(2) are observed, all of which are amide-stacked structures. In a second new molecule, Ac-gamma(2)-hPhe-NH(iPr), the C-terminal NHMe group of Ac-gamma(2)-hPhe-NHMe is replaced with an NH(iPr) group. Three conformations of Ac-gamma(2)-hPhe-NH(iPr) are observed, all of which are C9 H-bonded structures. The dramatic difference between C-terminal NHMe and NH(iPr) reveals the delicate balance of noncovalent forces within these gamma-peptides. The third molecule we examined is a gabapentin-derived diamide (designated 1), which contains a phenylacyl group at the N-terminus and an N(Me)(2) group at the C-terminus; the latter precludes C9 H bonding. Comparison of 1 with Ac-gamma(2)-hPhe-N(Me)(2) allows us to examine the impact of the backbone substitution pattern (monosubstitution at carbon-2 vs disubstitution at carbon-3) on the competition between the C7 H-bonded and the amide-stacked conformation. In this case, only C7 rings are observed. The different gas-phase behaviors observed among the molecules analyzed here offer insight on the intrinsic conformational propensities of the gamma-peptide backbone, information that provides a foundation for future foldamer design efforts.