This work describes the first determination of the absolute configuration (AC) of (−)-cubebin by means of electronic circular dichroism (ECD), supported by quantum chemical calculations. The comparison of experimental ECD with the corresponding quantum chemical prediction for the proper diastereoisomer resulted in the definitive assignment of the AC of the naturally occurring (−)-cubebin as (8R,8aR,9S). The challenging determination of the relative configuration (RC) of cubebin based only on experimental nuclear magnetic resonance (NMR) methods is stressed. Computation of the 13C and 1H NMR chemical shifts for all the possible diastereoisomers leads to values of mean absolute error and root mean square deviation that do not allow distinguishing among them. Thus, errors in stereochemical determination can easily occur even when using two-dimensional methods, which clearly demonstrate the complexity of this special case. To determine the RC of this bioactive natural compound with high level of confidence, it was necessary to combine the DP4+ method with X-ray crystallography. Therefore, employing the commonly used empirical methods to determine the AC of (−)-cubebin can easily lead to misassignment of its stereochemistry.

We reported experimental and theoretical investigation of conformers of 1,2,3-triazole derivatives, substances of exclusively synthetic origin, subject of extensive studies, because of several biological properties, such as antiviral, antimicrobial and antileishmaniasis. We reported molecular/supramolecular X-ray structures of antiophidian compounds I and II. For I and II there are two crystallographic different molecules in the unit cell (A and B). To explore the causes of the similarities in the compound’s crystal structures, intermolecular interactions were explored using the Hirshfeld surface as the fingerprint plots. In addition, density functional theory (DFT) calculations were carried out at the ωB97x-D/6-31G(d,p)-PCM-CHCl3 level aiming to contribute to the interpretation of the experimental data and complement the experimental findings. Two structures named 2A and 5B were found in good agreement with the respective X-ray solid state ones (A and B). Theoretical 1H nuclear magnetic resonance (NMR) spectra calculated for 5B rotated structure (torsion angles deviation around 40° to 90°) was in fine agreement with experimental results (in CDCl3) indicating that the solution molecular structure is considerably different from optimized equilibrium geometries and solid-state structure. Therefore, care is needed when using X-ray structures or DFT geometries to model interaction of drugs with biological targets since significant conformational changes may take place in solution.

The Z-E isomerization of γ-alkylidenebutenolide analogues to natural nostoclides and other natural butenolides was investigated using 1H nuclear magnetic resonance (NMR) and high performance liquid chromatography (HPLC) data as well as density functional theory (DFT) calculations at the wB97x-D/6-31G(d,p) level, including solvent effects with the polarizable continuum solvation approach. The experimental data supported the Z to E isomerization of γ-alkylidenebutenolides under acid catalysis. Newly prepared samples have predominantly Z configuration, which partially isomerizes to the E isomer under acidic conditions. Density functional theory studies corroborate the experimental findings. While neutral γ-alkylidenebutenolides are more stable in the Z form, protonation of the γ-lactone carbonyl group results in preferential stabilization of the E isomer.

Density functional theory calculations (ωB97X-D/6-311++G(d,p)) are employed to investigate an alternative pathway for Prins-like cyclization. Although strong acids usually catalyze this reaction, 4-amino-1,3-dioxanes are rapidly obtained in high yields without catalyst when benzenamines and acetaldehyde react at low temperatures, in aqueous medium. Considering these conditions, we applied a supermolecule model with explicit water molecules to compute the mechanism for 4-amino-1,3-dioxanes formation from the reactants. The structure of the primary solvation shell was determined by Metropolis Monte Carlo method. In the Prins-cyclization step, we found an unpredicted pathway with non-ionic transition structures or intermediates. Explicit water molecules establish a net of hydrogen bonds allowing prototropism, maintaining the electrical neutrality in the system while two protons transfer occurs. To provide data to further experimental confirmation of this hypothesis, we estimated the kinetic isotope effect for the reaction. We also investigated the use of aliphatic amines, which indicates that the reaction may be of a broader application than first observed experimentally.

The effect of γ-Al2O3 support on the NO adsorption on Pd4 clusters was investigated by means of density functional theory (DFT) calculations. Pd4 adsorbed on γ-Al2O3 (represented by a Al14O24H6 cluster) changes its preferential geometry from tetrahedral to a distorted planar structure. The alumina support promotes a higher dispersion in the palladium catalyst and reduces the NO adsorption energy to -25.6 kcal mol-1 (computed at B3LYP/LANL2DZ/6-311+G(d)), in close agreement with the experimental value of -27.2 kcal mol-1. On the bare planar Pd4 cluster the NO molecule adsorbs in a bridge arrangement, with adsorption energy of -41.2 kcal mol-1. Adsorption on the tetrahedral Pd4 cluster occur preferentially in an atop mode, with adsorption energy of -30.6 kcal mol-1. Charge density analysis show that the electron flux between the NO molecule and Pd4 depends on the adsorption form, with back-donation being stronger in the bridge adsorption mode.

A esterificação direta de naftoquinonas mostrou-se uma tarefa difícil. Metodologias mais comuns envolvem a aplicação de cloretos de acila em piridina ou anidridos, entretanto, quando ácidos de cadeia longa são utilizados tais metodologias se mostram ineficientes devido aos baixos rendimentos obtidos. Apresentamos uma nova síntese de ésteres de cadeia longa de juglona baseado na esterificação de Steglich utilizando um ácido de Lewis barato como cocatalisador. Rendimentos obtidos são consideravelmente maiores do que os reportados previamente. Química computacional foi utilizada para avaliar os efeitos do CeCl3 como cocatalisador. Os compostos preparados foram testados como inibidores de deposição de parafinas em petróleo. Éster palmítico da juglona foi capaz de reduzir 4 ºC na temperatura de início de aparecimento de cristais (WAT) do óleo estudado, representando uma redução de 1,5% m/m de parafinas normais precipitadas.

Direct esterification on naphthoquinone presented itself as a hard task. Usual methodologies apply acyl chloride in pyridine or anhydrides but with long-chain esters this procedure proved to be ineffective because of the low yields obtained. We present a new synthesis of long-chain esters of juglone based on Steglich esterification using a cheap Lewis acid as cocatalyst. Yields obtained are considerably better than those found previously. Computational chemistry was used to evaluate the effects of CeCl3 as cocatalyst. Prepared compounds were tested as wax deposition inhibitors in crude oil. Palmitic ester of juglone was able to lower 4 ºC on the wax appearance temperature (WAT) of the studied oil, representing a reduction of precipitated normal paraffin of 1.5% m/m.