Importance of C-H···O Intramolecular Hydrogen Bonding Across a Nonproteinogenic γ‑Aminobenzoic Acid Residue: Stabilization of a Flat β‑Strand-like Template M. Ramesh, † P. V. Bharatam, † P. Venugopalan, ‡ and R. Kishore* ,§ † Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector - 67, S.A.S. Nagar - 160 062, Punjab, India ‡ Department of Chemistry, Panjab University, Sector 14, Chandigarh - 160 014, India § Protein Science & Engineering Division, CSIR-Institute of Microbial Technology, Sector 39-A, Chandigarh - 160 036, India * S Supporting Information 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: C β i+1 -H···OC i+1 and main-chain to side-chain C δ 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 1 H 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. ■ INTRODUCTION In recent years, identification and characterization of non- proteinogenic amino acids and stable molecular building blocks that can mimic folded-unfolded secondary structural features of proteins and polypeptides have been receiving considerable research interest. 1 In particular, the design and construction of unusual well-defined weakly hydrogen-bonded peptide con- formations with readily available nonproteinogenic unsubsti- tuted γ-amino acid residues, i.e., γ-aminobutyric acid (γ-Abu or GABA) 2 and γ-aminobenzoic acid (γ-Abz), 3 are attracting much attention. While the existence of γ-Abu residue(s) has been described in several well-characterized peptide antibio- tics, 2h the natural occurrence of a γ-Abz containing biomolecule is yet to be documented. 3 Nevertheless, the earliest isolation and characterization of two biotransformation products of γ- Abz, i.e., N-formyl-γ-Abz-OH and N-acetyl-γ-Abz-OH, by cell suspension cultures of Solanum laciniatum, clearly highlight its biological and biochemical relevance and significance. 4 There- fore, we anticipate that the collections of conformational characteristics of the γ-Abz residue can provide discerning guidelines for designing and/or stabilizing biologically relevant specific peptide conformations and peptide mimics. 5 In marked contrast to a structurally flexible γ-Abu moiety, the γ-Abz residue can essentially be regarded as a conformationally restricted chemical entity. As depicted in Figure 1, unlike γ-Abu moiety, the direct insertion of an aromatic benzene-ring spacer in the γ-Abz residue ‘freezes’ the central two torsion angles to a fully extended conformation, i.e., θ 1 ≈ θ 2 ≈ 180°. Such chemical diversity seems to be attractive and analogous to the one shown by vinylogous γ-amino-acids with an (E)-ethenyl unit. 6 Consequently, the conformational variability of the γ-Abz residue is primarily restricted to changes in the ϕ, ψ torsion angles. We anticipate that the geometrically well-defined nonproteinogenic organic template of peptidic nature can exert dramatic influence on the preferred molecular con- formation of γ-Abz containing peptides 3 specially, while constructing novel hydrogen-bonded three-dimensional supra- molecular self-assemblies. For instance, the trans-orientations, i.e., ϕ ≈ ψ ≈ 180 ± 20°, are likely to construct a β-strand-like topology, whereas the cis-orientations, i.e., ϕ ≈ ψ ≈ 0 ± 20°, Received: January 13, 2013 Revised: March 5, 2013 Published: March 13, 2013 Article pubs.acs.org/crystal © 2013 American Chemical Society 2004 dx.doi.org/10.1021/cg400069q | Cryst. Growth Des. 2013, 13, 2004-2012