Combined Utilization of 1H NMR, IR, and Theoretical Calculations To Elucidate the Conformational Preferences of Some l‑Histidine Derivatives

The conformational preferences of amino acids and their derivatives have been the subject of many investigations, because protein folding pathways that determine three-dimensional geometries are primarily restricted by the conformational space of each amino acid residue. Here we systematically describe the conformational behavior of l-histidine methyl ester (His–OMe) and its N-acetylated derivative (Ac–His–OMe) in the isolated phase and in solution. To this end, we employed spectroscopic techniques (1H NMR and IR), supported by quantum chemical calculations. Initially, the energetically favorable conformers, their energies, and structural properties obtained by density functional theory (DFT) and Møller–Plesset perturbation theory (MP2) calculations in the isolated phase and in solution via the implicit solvation model IEF-PCM were presented. Next, experimental 3 J HH spin–spin coupling constants obtained in different aprotic nonpolar and polar solvents were compared with the theoretically predicted ones for each conformer at the IEF-PCM/ωB97X-D/EPR-III level. A joint analysis of these data allowed the elucidation of the conformational preferences of the compounds in solution. Infrared data were also employed as a complement to estimate the His–OMe conformer populations. Finally, the quantum theory of atoms in molecules (QTAIM), the noncovalent interactions (NCI), and the natural bond orbitals (NBO) analyses were used to determine the intramolecular interactions that govern the relative conformational stabilities.