Impact of nanoconfinement on acetylacetone Equilibria in Ordered Mesoporous Silicates.

Nanoconfinement is one of the most intriguing nanoscale effects and affects several physical and chemical properties of molecules and materials, including viscosity, reaction kinetics, and glass transition temperature. In this work, liquid nuclear magnetic resonance (NMR) was used to analyze the behavior of 2,4-pentadienone in ordered mesoporous materials with a pore diameter of between 3 and 10 nm. The liquid NMR results showed meaningful changes in the hydrogen chemical shift and the keto-enol chemical equilibrium, which were associated with the pore diameter, allowing the authors to observe the effects of nanoconfinement. An interesting phenomenon was observed where the chemical equilibria of 2,4-pentadienone confined in a mesoporous material with a pore diameter of 3.5 nm was similar to that obtained with free (bulk) 2,4-pentadienone in larger pore materials. Another interesting result was observed for the enthalpy and entropy of the tautomeric equilibria of 2,4-pentadienone confined in mesoporous materials with a 5.5 nm pore diameter being -7.9 kJ mol-1 and -15.9 J mol-1.K. These values are similar to those obtained by dimethyl sulfoxide. This phenomenon indicates the possible use of ordered mesoporous materials as a reaction substitute in organic solvents. It was further observed that while the values of enthalpy (ΔH) and entropy (ΔS) had been modified by confinement, the Gibbs free energy (ΔG) value remained closer to that observed in free (bulk) 2,4-pentadienone. It is expected that this study will help in understanding the effects of nanoconfinement and provide a simple method to employ NMR techniques to analyze these phenomena.

Characterization of amide bond conformers for a novel heterocyclic template of N-acylhydrazone derivatives.

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 ¹H- and ¹³C-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 ¹H-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 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 DG(≠) 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.

Discovery of novel orally active anti-inflammatory N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that inhibit TNF-α production.

Herein, we describe the synthesis and pharmacological evaluation of novel N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that were designed as novel prototypes of p38 mitogen-activated protein kinase (MAPK) inhibitors. All of the novel synthesized compounds described in this study were evaluated for their in vitro capacity to inhibit tumor necrosis factor α (TNF-α production in cultured macrophages) and in vitro MAPK p38α inhibition. The two most active anti-TNF-α derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide (4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-(4-chlorobenzylidene)acetohydrazide (4f), were evaluated to determine their in vivo anti-hyperalgesic profiles in carrageenan-induced thermal hypernociception model in rats. Both compounds showed anti-inflammatory and antinociceptive properties comparable to SB-203580 used as a standard drug, by oral route at a dose of 100 µmol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-α levels in vivo by 57.3 and 55.8%, respectively.

Anisotropic and hydrogen bonding effects in phenylglyoxamides and mandelamides: theoretical and NMR conformational evaluation.

Interesting anisotropic effects were observed for phenylglyoxamides and their respective mandelamides. Such effects were observed in experimental (1)H and (13)C NMR (in CDCl(3), CD(3)OD, and DMSO-d(6) solvents) and in some cases with good correlation to theoretical (1)H and (13)C NMR DFT-GIAO (B3LYP/6-311++G**//B3LYP/6-31G*) calculations. A systematic conformational analysis of these compounds was performed in a two-step methodology, using PM3 and DFT (B3LYP/6-31G*) calculations; with good accomplishment and computational time economy. It was observed that intramolecular hydrogen bonding plays a significant role in the conformation of such compounds. Finally, a geminal nonequivalence of an N-CH(2) moiety, in one of the alkyl side chain (R1 = R2), was found for the tertiary mandelamides studied.