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In the early 2000s, the first articles regarding the calculation of NMR parameters for natural products appeared in the literature. Since then, modelling 1H and 13C chemical shifts and spin–spin coupling constants for this class of compounds has experienced a remarkable increase in precision, accessibility, and application, leading to considerable advances in the field. More recently, significant contributions from several authors have led to continuous growth in this research field, updating and broadening the simulation of NMR parameters, in particular with the application of new techniques for data treatment. Nowadays, such studies are routinely found in the high impact literature. In this review, we intend to cover the general guidelines and the main advances in NMR calculations of natural products published since 2012. We intend to address the bottlenecks of quantum chemical calculations of NMR parameters, including mathematical definitions, updates, and a discussion of relevant examples, and to highlight novel tools, for example DU8+, CP3, DP4, DP4+ and J-DP4. We will cover all aspects of NMR simulation focusing on natural products, from the fundamentals to the new computational toolboxes available, combining advanced quantum chemical calculations with complex upstream data processing and machine learning.

The regioselective formation of α- and β-lapachone via hetero-Diels–Alder reactions was investigated by experimental and computational approaches. The experimentally observed α-selectivity was explored in detail, revealing that the lower energy barrier for the formation of α-lapachone is a result of lower Pauli repulsion throughout the reaction path, when compared to the β-isomer. By comparing equivalent points on both α- and β-lapachone potential energy surfaces (PES), according to the activation strain model (ASM) and energy decomposition analysis (EDA), we were able to demonstrate that the Pauli repulsion term increases more significantly when going from reactants to TSβ than to TSα, resulting in lower interaction energy in the early stages of the reaction path and in a later transition state for β-lapachone. Moreover, we confirmed that regio- and diastereoselectivity trends previously reported for other quinone methide intermediates are also observed for 3-methylene-1,2,4-naphthotriones, such as small endo/exo diastereoselectivity, as well as pronounced ortho/meta regioselectivity for reactions performed with dienophile containing electron-releasing groups. The results presented here provide a deeper understanding of the reactivity of quinone methide derivatives, aiding the future rational design of the reaction condition, structural modification of possible quinone methide intermediates, and the development of more selective synthetic routes for quinone derivatives.

Nonlinear optical materials have been investigated recently due to their potential technological applications in information storage and communications. In this context, semi-organic crystals can effectively combine the desired nonlinear optical properties of amino acids with the promising mechanical and thermal properties of inorganic materials. In this work, we have synthesized and characterized a semi-organic crystal of the amino acid l-histidine and hydrofluoric acid and investigated the chemical interactions between the organic and inorganic moieties. The crystal of l-histidine bis(fluoride) has been produced by slow solvent evaporation and characterized by X-ray diffraction (XRD) crystallography and thermogravimetric and differential thermal analyses. The XRD conducted using the Rietveld method shows that the unit cell is orthorhombic with the P21212 space group and contains four l-histidine bis(fluoride) units. Both differential thermal analysis and temperature-dependent XRD show that the crystals are thermally stable up to 191°C and do not undergo phase transition. The computational Hirshfeld surface analysis of the crystal structure reveals the main intermolecular interactions. Density functional theory has been employed to calculate the ionic interaction energy and electrostatic potential maps and confirm the spontaneity of ionic association at 191°C. The combined experimental and computational results show that the thermal stability of the semi-organic l-histidine bis(fluoride) crystal makes it suitable for nonlinear optical applications in optical sensing and communication systems. Graphical abstract

We report thermodynamic, geometric, and electronic parameters for the interaction between neutral ligands and the [Hg(H2O)]2+ dication, using the B3LYP/6–311 + G(d,p) approach. Gibbs free energies for the interaction were employed to rank the affinity order of the several neutral ligands. To identify the parameters that characterize the affinity between the two fragments, the metal-ligand interaction was analyzed according to the EDA, NBO, and QTAIM decomposition schemes. The phosphine oxide showed the highest affinity for the Hg(H2O)2+ dication, mainly due to the P=O bond polarization. Ligands containing the sulfur atom, characterized by a high covalent component for the metal-ligand interaction, are the following in the interaction order. According to the Gibbs free energy for substitution of one water molecule in the [Hg(H2O)2]2+ complex, the sequence for the affinity order is: phosphine oxide > thioketone > thioesther > lactam > amide > amine > carboxylic acid > thiophene > ketone > esther > thiol > thiocyanate > ammonia > disulfide > aldehyde > ether > haloydrin > alcohol > enol > azide.

Wax deposition is one of the major flow problems for petroleum transportation and production. In this context, the development of more efficient methods to remediate paraffin precipitation has received great attention within the oil industries. In the present study, eight new long-chain esters were prepared in less than four synthetic steps and in high yields (84–97%). Seven of them contain naphthoquinone nuclei, and one presents a cyclohexyl group. The new molecules were tested as non-polymer wax precipitation inhibitors and pour point depressants. Calorimetric experiments were employed to identify the effect of four pre-determined chemical groups within the molecules and to set out the best components for maximized inhibition: (i) the length of alkyl chain in the ester group, (ii) the length of the alkyl chain separating the polar nuclei and the ester group, (iii) the heteroatom bonded to the polar nuclei, and (iv) the importance of the naphthoquinone nuclei. After determination of the pour point and wax appearance temperature (WAT) of Brazilian oils by differential scanning calorimetry (DSC), the highest efficiency was observed for naphthoquinone esters derived from stearic and palmitic acids when containing two methylene groups as a separator and nitrogen as the heteroatom. These new additives present better results than the commercially available polymer-based inhibitors in all tested samples, even when applied at smaller concentrations, compared to many other polymer-based inhibitors reported in the literature. The importance of the naphthoquinone moiety as the polar portion of the inhibitor was confirmed when it was replaced by a cyclohexyl group. Molecular modeling and X-ray diffraction studies were also carried out to rationalize the relationship between structure and activity and the action mechanism of these new chemical additives.

The density functional theory is employed to determine the efficiency of 11 exchange-correlation (XC) functionals to compute the 1 H and 13 C NMR chemical shifts of p -tert-butylcalix[4]arene (ptcx4, R 1 = C(CH 3 ) 3 ) and congeners using the 6-31G(d,p) basis set. The statistical analysis shows that B3LYP, B3PW91 and PBE1PBE are the best XC functionals for the calculation of 1 H chemical shifts. Moreover, the best results for the 13 C chemical shifts are obtained using the LC-WPBE, M06-2X and w B97X-D functionals. The performance of these XC functionals is tested for three other calix[4]arenes: p -sulfonic acid calix[4]arene ( sfxcx4 - R 1 = SO 3 H), p -nitro-calix[4]arene ( ncx4 , R 1 = NO 2 ) and calix[4]arene ( cx4 - R 1 = H). For 1 H chemical shifts B3LYP, B3PW91 and PBE1PBE yield similar results, although B3PW91 shows more consistency in the calculated error for the different structures. For 13 C NMR chemical shifts, the XC functional that stood out as best is LC-WPBE. Indeed, the three functionals selected for each of 1 H and 13 C show good accuracy and can be used in future studies involving the prediction of 1 H and 13 C chemical shifts for this type of compounds.

We synthesized ten enamine naphthoquinones with yields ranging from 43 to 76%. These compounds were screened for their in vitro antiproliferative activities by MTT assay against four types of human cancer cell lines: HCT116, PC3, HL60 and SNB19. The naphthoquinones bearing the picolylamine (7) and quinoline (12) moieties were the most actives (IC50 < 24 μM for all the cell lines), which were comparable or better to the values obtained for the control drugs. In silico evaluations allowed us to develop a qualitative Structure-Activity Relationship which suggest that electrostatic features, particularly the C2-C3 internuclear repulsion and the molecular dipole moment, relate to the biological response. Furthermore, Molecular Docking simulations indicate that the synthetic compounds have the potential to act as anticancer molecules by inhibiting topoisomerase-II and thymidylate synthase.

The authors acknowledge FAPERJ for providing research grants and financial support. MB thanks the School of Chemistry and EaStCHEM for support and for access to a computer cluster maintained by Dr H. Früchtl. JWMC acknowledges CNPq for a research grant. The experimental work was supported via our membership of the UK Catalysis Hub consortium funded by EPSRC (grants EP/K014706/2, EP/K014668/1, EP/K014854/1 and EP/K014714/1). SPN gratefully acknowledges the European Commission for support in the form of an ERC Advanced Researcher grant (227817-FUNCAT). A new mechanism is proposed for the Ni-catalysed carboxylation of organoboronates with CO2. DFT investigations at the PBE0-D3 level have shown that direct CO2 addition to the catalysts [Ni(NHC)(Allyl)Cl] (1NHC, NHC = IMe, IPr, SIPr and IPr*) is kinetically disfavored and formation of the Aresta-type intermediate is unlikely to occur. According to the mechanism proposed here, the carboxylation process starts with addition of the borate species to 1NHC, followed by transmetalation, CO2 cycloaddition and carboxylation. The rate-determining step was identified as being the transmetalation process, with computed relative free energy barriers of 34.8, 36.8 and 33.5 kcal mol-1 for 1IPr, 1SIPr and 1IPr*, respectively Postprint

We quantum chemically explore and analyze 1,3-dipolar cycloadditions of hydrazoic acid and methyl azide with a number of substituted alkenes R-HC=CH2 (R = CH3, OH, OCH3, NH2, CN and NO2) using dispersion-corrected DFT at wB97X-D/6-311++G(d,p). Our purpose is to uncover the physical factors behind the computed trends in reactivity, regioselectivity (1,4 vs. 1,5 addition) and preferred stereochemistry (endo vs. exo). To this end, we use the activation strain model (ASM) and quantitative molecular orbital (MO) theory. One of our main findings is that introducing electron-donating groups in the dipolarophile, R = CH3, OH, OCH3 or NH2, favors the 1,5-cycloaddition. On the other hand, the presence of electron-withdrawing groups, R = CN or NO2, leads to 1,4-addition. Besides, we find a general preference for endo addition, a result that consolidates the endo rule. Trends in the regiochemistry are dictated by the inverse and regular HOMO-LUMO gap, respectively, between dipole and dipolarophile.

The Sn-Cl chemical bond of four organotin halides (Me3SnCl, Et3SnCl, Bu3SnCl, and Ph3SnCl) was studied by using relativistic density functional theory in combination with a quantitative energy decomposition analysis to explain the formation of charged species. The σ orbital is the dominant contributor to the stabilization of the Sn-Cl bond, and the π-orbital interactions also have a significant contribution to the stabilization of Ph3Sn+ cation when the aromatic groups are bonded to the tin atom. The aromaticity of the phenyl groups delocalizes the positive charge, donating electrons to tin atom by conjugation. Although Me3SnCl and Ph3SnCl are constituted by groups which the size of the substituents is different, the interaction energies obtained with the energy decomposition analysis present similar values, which also occur with the thermodynamic parameters. Graphical abstract Organotin compounds have widely studied as a potential antitumoral agent. The mechanism in triorganotin compounds includes the formation of cation species, R3Sn+. This article studies the influence of the R groups on the rupture of Sn-Cl bond using the fragment analysis and quantitative energy decomposition analysis.

Molecules carrying the azido functionality are widely used as intermediates in medicinal chemistry. Pyrrolobenzodiazepines are molecules with a broad range of interesting pharmacological properties. Due to the wide importance of azido-PBD as a key intermediate in many synthetic pathways, in this work we have investigated the effect of a variety of experimental parameters on the mechanism of nucleophilic substitution reaction for introducing an azide group into the PBD scaffold. This study was carried out by combined experimental and DFT approaches, showing that SN2 and double SN2 pathways are possible and highly dependent on the reaction temperature.

A mixture of the E and Z isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate was synthesized and characterized by elemental analysis, attenuated total reflectance-Fourier transform infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy. The structure of the Z isomer was determined by single crystal X-ray diffraction, which revealed a three-dimensional supramolecular network governed by C H⋯N, C H⋯O, and C H⋯F hydrogen bonds and π⋯π stacking interactions. The combination of these interactions plays an important role in stabilizing the self-assembly process and the molecular conformation. Hirshfeld surface analysis indicated the roles of the noncovalent interactions in the crystal packing, which were quantified by fingerprint plots and DFT calculations.

Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.

Glycerine is a by-product from biodiesel production. After transesterification using methanol, the oil from Jatropha seeds produces high amounts of stearic and palmitic methyl esters and about 10%wt. in glycerol. This chapter deals with the different aspects of the valorization of glycerine for the production of propylene glycol (1,2-PD). After introducing the subject, we evaluate the glycerol and 1,2-PD markets, particularly for pharmaceutical use. We then describe the processes of aqueous-phase hydrogenolysis (APH), aqueous-phase reforming (APR), and catalytic hydrogen transfer (CTH) applied to glycerol and describe some thermodynamics aspects and metal catalysts applied to these processes. Finally, we discuss some detailed kinetic models and application of molecular modeling to this reaction.

Hydrogen sulfide, H2S, stand as one of the major issues in petroleum industry. Aqueous solutions of triazines are the most utilized non-regenerative H2S scavenger. Although they present a theoretical capture capacity of 3 mol of H2S per mole of triazine, it effectively scavenges only 2 mol. Herein, we employed Density Functional Theory at CAM-B3LYP/6–311++G(2d,2p) level of calculation to rationalize the full mechanism for capture of H2S by hexahydro-1,3,5-triazines, in particular the reason why the reaction stops at the second equivalent of H2S. For the capture of the first equivalent of H2S, we found an unprecedented SN1 pathway to be less energetic than SN2, the most commonly accepted in literature. For capture of a second H2S molecule, however, both mechanisms are energetically similar. High barriers were found for the capture of the third molecule of H2S, related to the lower electrophilicity of the carbon atom bonded to nitrogen and sulfur atoms.

The single crystal structure of seven tri- and tetracyclic ozonides derived from 8-oxabicycle[3.2.1]oct-6-en-3-ones have been characterized by X-ray diffraction method. Five ozonides ( 4 , 5 , 6 , 7 and 8 ) crystallize in the monoclinic crystal system with P2 1 /c space group. Compound 3 crystallize in the unusual centrosymmetric space group R 3 ¯ m, which represents ∼0.04% of the total number of structures know. The supramolecular structure of 3 forms infinite channels in a hexagram fashion, resulting in a honeycomb-like structure. Semi-empirical (PM6) and density functional theory methods (DFT) with the B3LYP functional and the 6-31G(d) basis set were used to optimize the geometries and compute structural parameters (bond lengths, angles and dihedral angles) that could be compared to the refined crystal structure. The theoretical results show good agreements with the experimental structure.

A series of B3LYP/6-311+G(d,p) calculations of the affinity of monodentate ligands for [Cd(H2O)3]2+ are performed. Three types of ligands containing O (phosphine oxide, lactam, amide, carboxylic acid, ester, ketone, aldehyde, ether, halohydrin, enol, furan), N (thiocyanate, amine, ammonia, azide), and S (thioester, thioketone, thiol, thiophene, disulfide) interacting atoms are investigated. The results show that phosphine oxide has the largest affinity for the cadmium cation due to the polarization of the P=O bond. As the P atom has a large atomic radius, the O atom can polarize the electronic cloud enhancing its amount of electronic charge and favoring the interaction with Cd2+. The affinity order found is phosphine oxide > thioester > lactam > amide > carboxylic acid > ester > thioketone > ketone > thiocyanate > amine > ammonia > aldehyde > ether > thiol > thiophene > enol > halohydrin > disulfide > azide > furan ligands. These results were also corroborated by the functional M06-2X. The electronic effects (resonance and induction) of neighboring groups of the interacting atom modulate the strength of metal-ligand binding. For almost all the O-donor ligands the electrostatic component has the same magnitude as the covalent term, while for the N- and S-donor ligands the covalent term is predominant. The polarization term accounts for twice the exchange term as part of the covalent component. The dispersion term varies less than 2 kcal mol−1 for the complexes analyzed. The Pauli repulsion term is correlated with the metal ligand distance, increasing in the compounds with decreased metal-ligand bond length. The charge between the interacting atoms is also strongly correlated with both the interacting strength and the electrostatic interaction component. The natural bond orbital analysis highlights correlations of the bond order, and S and P contributions of the interacting metal-ligand orbital with the coordination strength.

The affinity of the pentaaqua Mg(2+) cation for a set of para-substituted imino [HN = CHC₆H₄(R)] and thiocarbonyl [S = CHC₆H₄(R)] ligands (R = H, F, Cl, Br, OH, OCH₃, CH₃, CN, NH₂ and NO₂) was analyzed with DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6-DH2) methods. The interaction enthalpy was calculated to quantify the affinity of the Mg(2+) cation for the ligands. Additionally, geometric and electronic parameters were correlated with the intensity of the metal-ligand interaction. The imino ligands have stronger interaction with the pentaaqua Mg(2+) cation than the thiocarbonyl derivatives. The electronic nature of the substituent is the main parameter that determines the interaction enthalpy. Ligands with electron donor substituents have more exothermic interaction enthalpies than those with electron withdrawing groups. The HSBA analysis showed that the interaction between the Mg(2+) cation and hard bases (imino ligands) is stronger than with soft bases (thiocarbonyl derivatives). The EDA analysis showed that the electrostatic, covalent and repulsion components of the interaction are the most affected by the substituent, whereas the dispersion and exchange components are almost constant.

The quantum theory of atoms in molecules (QTAIM) and density functional theory (DFT) calculations were employed to investigate the structure and tautomeric equilibrium of epiclusianone, a polyisoprenylated benzophenone with interesting biological activities. Two different exchange-correlation functionals were employed, namely ωB97x-D and M06-2x, including implicit solvent models (benzene and DMSO). Our results for the thermodynamic properties show that the isomer in which the H atom is bonded to the oxygen away from the benzene ring is the most stable tautomer form of the epiclusianone, thus confirming previous charge density analysis from X-ray diffraction data (Martins et al. J Braz Chem Soc 18(8):1515–1523, 2007).

Starting from 2-hydroxy-1,4-naphthoquinone (lawsone), we synthesized eight new 6H-dibenzo[b,h]xanthene derivatives selectively under solvent-free conditions. Spectroscopic investigations confirmed that only the isomer 6H-dibenzo[b,h]xanthene was obtained in all eight cases. Computational studies provide a rationalization for the selective appearance of these isomers having as an intermediate an addition product.

Many natural products have been used as a model for the development of new drugs and agrochemicals. Following this strategy 11 rubrolide analogues, bearing electron-withdrawing and -donating groups at both benzene rings, were prepared starting from commercially available mucobromic acid. The ability of all compounds to inhibit the photosynthetic electron transport chain in the chloroplast was investigated. The rubrolide analogues were effective in interfering with the light-driven ferricyanide reduction by isolated chloroplasts. The IC(50) values of the most active derivatives are in fact only 1 order of magnitude higher than those of commercial herbicides sharing the same mode of action, such as Diuron (0.27 μM). QSAR studies indicate that the most efficient compounds are those having higher ability to accept electrons, either by a reduction process or by an electrophilic reaction mechanism. The results obtained suggest that the rubrolide analogues represent promising candidates for the development of new active principles targeting photosynthesis to be used as herbicides.

The affinities of Mg(2+) for various substituted carbonyl ligands were determined at the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) levels of theory. Two sets of carbonyl ligands were studied: monosubstituted [aldehydes R-CHO and RPh-CHO] and homodisubstituted [ketones R(2)C=O and (RPh)(2)C=O], where R = NH(2), OCH(3), OH, CH(3), H, F, Cl, Br, CN, or NO(2)). In the (RPh)(2)CO case, the R group was bonded to the para position of a phenyl ring. The enthalpies of interaction between the ligands and a pentaaquomagnesium(II) complex were calculated to determine the affinity of each ligand for the Mg(2+) cation and to correlate with geometrical and electronic parameters. These parameters exhibited the same trends for all of the ligands studied, showing that the affinity of Mg(2+) for electron-donating ligands is higher than its affinity for electron-withdrawing ligands. In the complexes, electron-donating groups increase both the electrostatic and the covalent components of the Mg-ligand interaction. This behavior correlates with the Mg-O(carbonyl) distance and the ligand electron-donor strength.

DFT (B3LYP/6-31+G(d)) calculations of Mg2+ affinities for a set of phosphoryl ligands were performed. Two types of ligands were studied: a set of trivalent [O = P(R)] and a set of pentavalent phosphoryl ligands [O = P(R)3] (R = H, F, Cl, Br, OH, OCH3, CH3, CN, NH2 and NO2), with R either bound directly to the phosphorus atom or to the para position of a phenyl ring. The affinity of the Mg2+ cation for the ligands was quantified by means of the enthalpy for the substitution of one water molecule in the [Mg(H2O)6]2+ complex for a ligand. The enthalpy of substitution was correlated with electronic and geometric parameters. Electron-donor groups increase the interaction between the cation and the ligand, while electron-acceptor groups decrease the interaction enthalpy.

The affinity of the Ca(2+) ion for a set of substituted carbonyl ligands was analyzed with both the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) methods. Two types of ligands were studied: a set of monosubstituted [O=CH(R)] and a set of disubstituted ligands [O=C(R)(2)] (R=H, F, Cl, Br, OH, OCH(3), CH(3), CN, NH(2) and NO(2)), with R either directly bound to the carbonyl carbon atom or to the para position of a phenyl ring. The interaction energy was calculated to quantify the affinity of the Ca(2+) cation for the ligands. Geometric and electronic parameters were correlated with the intensity of the metal-ligand interaction. The electronic nature of the substituent is the main parameter that determines the interaction energy. Donor groups make the interaction energy more negative (stabilizing the complex formed), while acceptor groups make the interaction energy less negative (destabilizing the complex formed).

B3LYP/6–31 + G(d) calculations were employed to investigate the mechanism of the transesterification reaction between a model monoglyceride and the methoxide and ethoxide anions. The gas-phase results reveal that both reactions have essentially the same activation energy (5.9 kcal mol−1) for decomposition of the key tetrahedral intermediate. Solvent effects were included by means of both microsolvation and the polarizable continuum solvation model CPCM. Both solvent approaches reduce the activation energy, however, only the microsolvation model is able to introduce some differentiation between methanol and ethanol, yielding a lower activation energy for decomposition of the tetrahedral intermediate in the reaction with methanol (1.1 kcal mol−1) than for the corresponding reaction with ethanol (2.8 kcal mol−1), in line with experimental evidences. Analysis of the individual energy components within the CPCM approach reveals that electrostatic interactions are the main contribution to stabilization of the transition state.

Vegetal oil, also known as triglycerides, is a mixture of fatty acid triesters of glycerol. In the triglycerides alkyl chains of Jatropha curcas oil, predominate the palmitic, oleic and linoleic fatty acids. The process usually used to convert these triglycerides to biodiesel is called transesterification. The overall process is a sequence of three equivalent, consecutive and reversible reactions, in which di- and monoglycerides are formed as intermediates. Semi-empirical AM1 molecular orbital calculations were used to investigate the reaction pathways of base-catalyzed transesterification of glycerides of palmitic, oleic and linoleic acid. The most probable pathway and the rate determining-step of the reactions were estimated from the molecular orbital calculations. Our results suggest the formation of only one tetrahedral intermediate, which in a subsequent step rearranges to form the products. The rate determining-step is the break of this tetrahedral intermediate.

Experimental 1 H chemical shift analysis for the camphor-based chiral γ-amino alcohol 2 shows a difference of 0.9 ppm for the two diastereotopic hydrogens H 11a and H 11b . In contrast, for the exo adduct ( 1 ) and its acetate ( 3 ) these hydrogens have very similar chemical shifts. DFT calculations followed by NBO analysis show that these differences in chemical shifts arise as a consequence of an intramolecular hydrogen bond O H⋯N in 2 , which restricts its conformational mobility. In the most stable conformer of 2 , the interaction of the nitrogen lone-pair with the vicinal σ * (C H 11a ) antibonding orbital shifts that hydrogen downfield by 0.9 ppm. This is confirmed by experimental NMR studies based on NULL.

An efficient method is proposed for obtaining tetrahydrobenzo[a]xanthene-11-ones and tetrahydro-[1,3]-dioxolo[4,5-b]xanthen-9-ones. The method is based on the use of p-sulfonic acid calix[n]arenes as catalysts under solvent-free conditions. The antiproliferative activity of fifty-nine xanthenones against six human cancer cells was studied. The capacity of all compounds to inhibit cancer cell growth was dependent on the histological origin of the cells. QSAR studies indicate that among compounds derived from β-naphthol the most efficient compounds against glioma (U251) and renal (NCI-H460) cancer cells are those having higher hydrogen bonding donor ability.

Theoretical calculations and gas-phase mass spectrometric studies were performed for the reaction of the naked (NO2+) and monosolvated (CH3NO2.NO2+) nitronium ion with several monosubstituted aromatic compounds. From these studies, we propose a general model for regioselectivity based on the single-electron transfer (SET) mechanism and an alternative mechanistic scheme for electrophilic aromatic nitration. This scheme considers the SET and the polar (Ingold-Hughes) mechanisms as extremes in a continuum pathway, the occurrence and extents of both mechanisms being governed mainly by the ability, or lack of ability, of the aromatic compound to transfer an electron to NO2+.

In this work we describe a systematic and comparative study of the 17 O NMR and related parameters of 17 polycyclic compounds: bicyclic, tricyclic, tetracyclic ( endo–endo and endo–exo fusion ), pentacyclic compounds (ketone; endo and exo -alcohols), hexacyclic alcohol. Concentration, temperature and solvent effects on the 17 O NMR chemical shifts and the relaxation rate are also described. We compare all experimental 17 O NMR chemical shifts with chemical shifts calculated from gauge-independent atomic orbitals within density functional theory (GIAO-DFT). Correlations between calculated and experimental 17 O NMR chemical shifts for respective functional groups were carried out and linear equations for chemical shift predictions were generated.

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. 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.

Aromatic nitration is one of the most relevant class of reactions in organic chemistry. It has been intensively studied by both experimental, including works in the condensed as well as in the gas phase, and theoretical procedures. However, the published results do not seem to converge to an unique mechanism. Electrophilic substitution and electron transfer, in an exclusive way, are both proposed as the main mechanism for the reaction. We review these proposals and discuss the most recent findings.

Short stereoselective syntheses of both 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones from natural α-amino acids are described.

Lawsone (I) is used as starting material for the optimized reductive alkylation process to yield the title compounds including phthiocol (IIa) and lapachol (IIIb).

Through-space NMR shieldings were calculated for trinuclear metal-carbonyl compounds [M(3)(CO)(12)] (M = Fe, Ru, Os), employing the nucleus-independent chemical shift approach. The through-space shieldings were visualized as a contour plot of iso-chemical shielding surfaces, and were applied to quantify the overall anisotropic effect of the carbonyl groups, as well as to identify the influence of the transition metal on the scopes of the corresponding anisotropy cones. The shielding surfaces show that the anisotropic effect of the carbonyl groups at equatorial positions changes depending on the metal. This effect was associated with pi-backdonation from the metal to the carbonyl groups in that position, in agreement with geometric data as well as calculated NMR parameters. Therefore, visualization of the through-space NMR shieldings of trinuclear metal-carbonyl compounds of group 8 is able to reflect the distinct arrangements of the carbonyl groups in these organometallic compounds.

Short stereoselective syntheses of both 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones from natural α-amino acids are described.

Semi-empirical (AM1 and PM3) and DFT (B3LYP/6-31G(d)) calculations were employed to study the tautomeric equilibrium between the aminequinone A and hydroxylquinoneimine B forms of 4-(4-R-phenylamino)naphthalene-1,2-diones. Substituent effects on the tautomeric equilibrium as well as on geometric and electronic parameters were also determined. In the gas phase the hydroxylquinoneimine B form is the most stable, whereas in water the aminequinone A form becomes more stable. The substituents do not modify the relative energies of the two tautomers. These results are in accordance with experimental data reported in the literature.

Malaria is an infectious disease caused by the unicellular parasite Plasmodium sp. Currently, the malaria parasite is becoming resistant to the traditional pharmacological alternatives, which are ineffective. Artemisinin is the most recent advance in the chemotherapy of malaria. Since it has been proven that artemisinin may act on intracellular heme, we have undertaken a systematic study of several interactions and arrangements between artemisinin and heme. Density Functional Theory calculations were employed to calculate interaction energies, electronic states, and geometrical arrangements for the complex between the heme group and artemisinin. The results show that the interaction between the heme group and artemisinin at long distances occurs through a complex where the iron atom of the heme group retains its electronic features, leading to a quintet state as the most stable one. However, for interaction at short distances, due to artemisinin reduction by the heme group, the most stable complex has a septet spin state. These results suggest that a thermodynamically favorable interaction between artemisinin and heme may happen.

Artemisinin is a sesquiterpene lactone with an endoperoxide function that is essential for its antimalarial activity. The DFT B3LYP method, together with the 6-31G(d) and 6-31+G(d,p) basis set, is employed to calculate a set of radical anions and neutral species supposed to be formed during the rearrangement of artemisinin from the two radicals (C-centered and O-centered) that are supposed to play a relevant role in the mechanism of action. The B3LYP results show that the primary and the secondary radicals centered on C 4 , generated by homolytic break of the C 3 –C 4 bond and by 1,5 hydrogen shift, respectively, are more stable than radicals centered on oxygen. The calculations show that the activation barriers for rearrangements are low, leading to a thermodynamically favorable process. These results reinforce our previous conclusions based on semi-empirical calculations but also give additional information on the reductive decomposition of artemisinin.

Several molecular parameters for 2,3,5-substituted 1,4-naphthoquinones including 2-aziridinyl and 2,3-aziridinyl-1,4-naphthoquinones with antimalarial activities were obtained with the semi-empirical PM3 method. The descriptor related to the Gibbs free energy of an isodesmic equation defining the reduction of the naphthoquinones was found to have high correlation with activity. The quantitative models reported clearly show a dependence of activity on the redox potential for reduction of the naphthoquinones. Compounds with lower values of DeltaG for reduction are more active than those with higher values of DeltaG.

Two series of flexible dicyanomethylene compounds, specifically, class 1 and class 2 compounds, have been designed and synthesised. In class 1 compounds, the dicyanomethylene groups are separated by glycol chain spacers of different lengths, whereas, in class 2 compounds, the spacers are alkyl linkers of different lengths. The notion underlying the design of these compounds is that in class 1 molecules, the spacers contain donor oxygen atoms that could not only form hydrogen bonds during the course of crystal packing but also promote withdrawing effects that modify the photophysical and electrochemical properties of these molecules in solution; in contrast, these effects would be absent for class 2 molecules. However, this study revealed that, with respect to crystal packing, the size of the spacers and their even and odd numbers of atoms are more important than their chemical nature. All of the synthesised compounds exhibited blue emission in the solid state and in CH2Cl2 solutions. The photophysical and electrochemical properties of these compounds in solution were not significantly affected by the type and length of the spacer that was used in each molecule. In the solid state, however, the compound with the shortest spacer showed the highest Stokes shift. The electronic transitions for the synthesized compounds in solution were explained by density functional theory and time-dependent density functional theory calculations, which indicated that the methylene moieties control the properties of both classes of compounds and that the spacers do not conjugate with the end groups. These two series of flexible dicyanomethylene compounds could be utilised as molecular building blocks for the development of new solids with novel properties.