Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

Abstract

Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1 H-and 13 C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1 H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the OPEN ACCESSMolecules 2013, 18 11684 electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the ΔG ≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond-related conformations.

Novel Potent Imidazo[1,2-a]pyridine-N-Glycinyl-Hydrazone Inhibitors of TNF-α Production: In Vitro and In Vivo Studies

“…In a study involving compounds 1f and 1 g, the 1 H-NMR spectra obtained in DMSO- d 6 at 90°C showed that the two species were in rapid equilibrium (Figures S12–S13 and S15–S16 in File S1). Interestingly, a complete coalescence of the signals was achieved at 90°C, and the reversibility of the changes was verified, indicating the presence of conformational isomers [22], [23]. Indeed, a Monte Carlo conformational search performed on derivative 1 g followed by energy calculations of the selected conformers according to the Hartree-Fock 3–21G method indicated a slight difference in energy (ΔE =  −19.83 kJ.mol -1 ) between the synperiplanar and antiperiplanar conformers in the favor of the former (Figure 3).…”

Crystal Structures of 1-Aryl-1H- and 2-Aryl-2H-1,2,3-triazolyl Hydrazones. Conformational Consequences of Different Classical Hydrogen Bonds

“…In Figure 3b Index ranges bond (E C=N and Z C=N ), making four possible arrangements in all about the C(O)−NH−N=CH-aryl fragment. [32][33][34][35] While the triazolyl ring is planar in all compounds, none of the compounds is planar overall. The deviation from planarity is relatively small for the 2H-1,2,3-triazolyl compounds, 2a, 2b and 3, as shown by the angles between the aryl rings in Table 3, and very much larger for 1a and 1b (see Figure 4).…”

Design, synthesis, and molecular docking of novel 2‐arylbenzothiazole multiangiokinase inhibitors targeting breast cancer

“…Different practical and computational experiments reported in the literature displayed the existence of the formed N ‐acylhydrazones in the sterically less hindered geometric E isomer and the duplication of signals was attributed to the presence of cis and trans conformers on CO–NH. [ 59–63 ] Based on the reported findings, the duplication of signals in the obtained nuclear magnetic resonance (NMR) spectra of 9a – n and 10a , b was rationalized to the presence of a mixture of cis and trans conformers C and D in ratios between 2:1 and 3:1 in the used NMR solvent (Figure 4; for further details see Section 4 and the Supporting Information Data).…”