Evolution of Amide Stacking in Larger γ-Peptides: Triamide H-Bonded Cycles

Abstract

The single-conformation spectroscopy of two model γ-peptides has been studied under jet-cooled conditions in the gas phase. The methyl-capped triamides, Ac-γ(2)-hPhe-γ(2)-hAla-NHMe and Ac-γ(2)-hAla-γ(2)-hPhe-NHMe, were probed by resonant two-photon ionization (R2PI) and resonant ion-dip infrared (RIDIR) spectroscopies. Four conformers of Ac-γ(2)-hPhe-γ(2)-hAla-NHMe and three of Ac-γ(2)-hAla-γ(2)-hPhe-NHMe were observed and spectroscopically interrogated. On the basis of comparison with the predictions of density functional theory calculations employing a dispersion-corrected functional (ωB97X-D/6-311++G(d,p)), all seven conformers have been assigned to particular conformational families. The preference for formation of nine-membered rings (C9) observed in a previous study [James, W. H., III et al., J. Am. Chem. Soc. 2009, 131, 14243] of the smaller analog, Ac-γ(2)-hPhe-NHMe, carries over to these triamides, with four of the seven conformers forming C9/C9 sequential double-ring structures, and one conformer a C9/C14 bifurcated double ring. The remaining two conformers form C7/C7/C14 H-bonded cycles involving all three amide NH groups, unprecedented in other peptides and peptidomimetics. The amide groups in these structures form a H-bonded triangle with the two trimethylene bridges forming loops above and below the molecule's midsection. The structure is a natural extension of amide stacking, with the two terminal amides blocked from forming the amide tristack by formation of the C14 H-bond. Pair interaction energy decomposition analysis based on the fragment molecular orbital method (FMO-PIEDA) is used to determine the nonbonded contributions to the stabilization of these conformers. Natural bond orbital (NBO) analysis identifies amide stacking with a pair of n → π* interactions between the nitrogen lone pairs and π* orbitals on the carbonyl of the opposing amide groups.