Importance of C–H···O Intramolecular Hydrogen Bonding Across a Nonproteinogenic γ-Aminobenzoic Acid Residue: Stabilization of a Flat β-Strand-like Template

Abstract

This paper describes the conformational characteristics of a nonproteinogenic γ-aminobenzoic acid (γ-Abz), investigated experimentally as well as theoretically. The single crystal X-ray diffraction analysis of the model system Boc-γ-Abz-NHMe (1) revealed the existence of an unusual β-strand-like molecular structure. The two weak unconventional C–H···O intramolecular hydrogen-bonds, i.e., main-chain to main-chain: Cβ i+1–H···OC i+1 and main-chain to side-chain Cδ i+1–H···OC i interactions, evidently stabilize the flat molecular topology. The favorable antiparallel β-strand mimics are held together by a network of cross-strand N–H···O intermolecular hydrogen bonds. Interestingly, the noncovalent β-sheet-like duplexes facilitate the fabrication of offset face-to-face aromatic–aromatic interactions, whereas the dimers of dimers are aligned edge-to-edge. The two-dimensional 1H NMR ROESY experiment ascertained the extraordinary stability of the rigid β-strand template and molecular self-assembly in a nonpolar environment. The ab initio molecular modeling substantiated the crystal molecular structure as the minimum energy conformer along with weak C–H···O intramolecular hydrogen bonds. The solid-state Fourier transform infrared spectral analysis sustained the participation of both amide-NHs in intermolecular hydrogen bonding. The highly ordered supramolecular architecture, engendered from a single preorganized molecular component, exploited a variety of strong as well as weak stabilizing forces as varied as N–H···O, C–H···O, Ar···Ar, and van der Waals and/or hydrophobic interactions.

Antiparallel Self‐Association of a γ,α‐Hybrid Peptide: More Relevance of Weak Interactions

“…As illustrated in Figure , the closest van der Waals C⋅⋅⋅C approaches to the γ‐Abz C ζ atom involve two of the CH 3 groups of the t Boc moieties. Significantly, the centrosymmetric hydrophobic contacts in the unit cell, as deduced from the C⋅⋅⋅C distances, that is, C ζ /C9⋅⋅⋅C2=3.709 Å and C ζ /C9⋅⋅⋅C3=3.917 Å, are clearly at variance with those described previously across the γ‐Abz residue . We presume that such hydrophobic–lipophilic contacts– in self‐associated supramolecular structures can further enhance the strength of adjacent N−H⋅⋅⋅O H‐bonds, which may possibly shift and/or stabilize the alternate monomer–dimer equilibrium in a non‐polar environment.…”

“…Also, the simultaneous upfield shift of the Gly C α H 2 (Δ δ CαH ≈0.27 ppm) and methyl ester O CH 3 (≈0.16 ppm) signals could be a reflection of a β‐sheet‐like structure placed in a unique highly‐ordered environment, and [D 6 ]DMSO most probably disrupts the intermolecular H‐bonding. However, the observed 13 C NMR chemical shifts of the core γ‐Abz residue in CDCl 3 (Figure S3 in the Supporting Information) are rather comparable to those reported for Boc‐γ‐Abz‐NHMe . As such, we have been more interested in emphasizing the importance of weak attractive forces predisposed to play important roles in biological molecular recognition and self‐association, especially in γ‐Abz containing peptides.…”

“…Given the relevance of weak C−H⋅⋅⋅O interactions in biomolecular structures, the stabilization of preorganized β‐strand‐like molecular topology by means of two non‐conventional C β i −H⋅⋅⋅O=C i and C δ i −H⋅⋅⋅O=C i ‐1 intramolecular H‐bonds is rather fascinating. We also perceive that despite poor H‐bond geometric parameters, the C β i −H⋅⋅⋅O=C i intramolecular interaction emerges to be energetically favorable as a genuine H‐bond . In fact, several theoretical ab initio quantum mechanical calculations performed on biologically relevant model systems have indicated that energetic contributions of such non‐conventional H‐bonds may range between ≈2.0–3.0 kcal mol −1 in vacuo .…”

“…Our recent computational ab initio calculations performed on the simple core model system Boc‐γ‐Abz‐NHMe (NHMe= N ‐methylamide) revealed the probable occurrence of at least four discrete energetically favorable H‐bonded structures within 2 kcal mol −1 of the global minimum . Nevertheless, in conjunction with single‐crystal X‐diffraction analysis and one‐ and two‐dimensional (1D and 2D) 1 H NMR spectroscopy data in solution, we determined the preferred molecular conformation of the urethane‐γ‐Abz‐amide building block as fully extended β‐strand‐like structure: ϕ ≈ ψ ≈150±10° .…”

Perylene Bisimide and Naphthyl‐Based Molecular Dyads: Hydrogen Bonds Driving Co‐planarization and Anomalous Temperature‐Response Fluorescence

“…Among various H‐bonding configuration, the first weak H‐bond involving C−H⋅⋅⋅O was discovered in crystal state by Sutor and co‐workers in the early 1960s, and then confirmed by Taylor and others two decades later . Later studies reveal that the H‐bonding exists not only just in synthetic organic solids, but also in proteins, nucleic acids, and other organic systems . However, presence of intramolecular C−H⋅⋅⋅O bond in small molecules, and particularly in the solution state, is rarely reported.…”