Water Maintains the UV-Vis Spectral Features During the Insertion of Anionic Naproxen and Ibuprofen into Model Cell Membranes.

UV-vis spectra of anionic ibuprofen and naproxen in a model lipid bilayer of the cell membrane are investigated using computational techniques in combination with a comparative analysis of drug spectra in purely aqueous environments. The simulations aim at elucidating the intricacies behind the negligible changes in the maximum absorption wavelength in the experimental spectra. A set of configurations of the systems constituted by lipid, water, and drugs or just water and drugs are obtained from classical Molecular Dynamics simulations. UV-vis spectra are computed in the framework of atomistic Quantum Mechanical/Molecular Mechanics (QM/MM) approaches together with Time-Dependent Density Functional Theory (TD-DFT). Our results suggest that the molecular orbitals involved in the electronic transitions are the same, regardless of the chemical environment. A thorough analysis of the contacts between the drug and water molecules reveals that no significant changes in UV-vis spectra are a consequence of ibuprofen and naproxen molecules being permanently microsolvated by water molecules, despite the presence of lipid molecules. Water molecules microsolvate the charged carboxylate group as expected but also microsolvate the aromatic regions of the drugs.

Formation and evolution of C-C, C-O, C[double bond, length as m-dash]O and C-N bonds in chemical reactions of prebiotic interest.

A series of prebiotic chemical reactions yielding the precursor building blocks of amino acids, proteins and carbohydrates, starting solely from HCN and water is studied here. We closely follow the formation and evolution of the pivotal C-C, C-O, C[double bond, length as m-dash]O, and C-N bonds, which dictate the chemistry of the molecules of life. In many cases, formation of these bonds is set in motion by proton transfers in which individual water molecules act as catalysts so that water atoms end up in the products. Our results indicate that the prebiotic formation of carbon dioxide, formaldehyde, formic acid, formaldimine, glycolaldehyde, glycine, glycolonitrile, and oxazole derivatives, among others, are best described as highly nonsynchronous concerted single step processes. Nonetheless, for all reactions involving double proton transfer, the formation and breaking of O-H bonds around a particular O atom occur in a synchronous fashion, apparently independently from other primitive processes. For the most part, the first process to initiate seems to be the double proton transfer in the reactions where they are present, then bond breaking/formation around the reactive carbon in the carbonyl group and finally rupture of the C-N bonds in the appropriate cases, which are the most reluctant to break. Remarkably, within the limitations of our non-dynamical computational model, the wide ranges of temperature and pressure in which these reactions occur, downplay the problematic determination of the exact constraints on the early Earth.

A computational protocol for the calculation of the standard reduction potential of iron complexes: application to Fe2+/3+-Aß model systems relevant to Alzheimer's disease.

Iron complexes play a key role in several biological processes, and they are also related to the development of neurological disorders, such as Alzheimer's and Parkinson's diseases. One of the main properties involved in these processes is the standard reduction potential (SRP) of iron complexes. However, the calculation of this property is challenging, mainly due to problems in the electronic structure description, solvent effects and the thermodynamic cycles used for its calculation. In this work, we proposed a computational protocol for the calculation of SRPs of iron complexes by evaluating a wide range of density functionals for the electronic structure description, two implicit solvent models with varying radii and two thermodynamic cycles. Results show that the M06L density functional in combination with the SMD solvation model and the isodesmic method provides good results compared with SRP experimental values for a set of iron complexes. Finally, this protocol was applied to three Fe2+/3+-Aß model systems involved in the development of Alzheimer's disease and the obtained SRP values are in good agreement with those reported previously by means of MP2 calculations.

Rationalizing the Substituent Effects in Diels-Alder Reactions of Triazolinediones with Anthracene.

In this work we tackle the problem of the substituent effects in the Diels-Alder cycloadditions between triazolinediones (TADs) and anthracene. Experiments showed that aryl TADs substituted with electron-withdrawing groups (EWG) are more reactive than those substituted with electron-donating (EDG) or alkyl groups. However, the molecular origin of this preference is not yet understood. By a combination of methods including the activation strain model (ASM), energy decomposition analysis (EDA), molecular orbital (MO) theory, and conceptual density functional theory (CDFT), we disclosed the substituent effects of TADs. First, ASM/EDA analysis revealed that the reactivity of alkyl and aryl-substituted TADs is controlled by interaction energies, ΔEint, which are ultimately defined by orbital interactions between frontier molecular orbitals. Moreover, alkyl-TADs are also controlled by the extent of strain at the transition state. The MO analysis suggested that the rate acceleration for EWG-substituted TADs is due to a more favorable orbital interaction between the HOMO of anthracene and the LUMO of the TADs, which is corroborated by calculations of charge transfer at the transition states. From CDFT, the chemical potential of anthracene is higher than those of TADs, indicating a flow of electron density from anthracene to TADs, in agreement with the results from the electrophilicity index.

Alkane C-H activation and ligand exchange on silica supported d0 metal alkylidenes: relevance to alkane metathesis.

In this work, we study the ligand exchange process between an alkane and a series of silica supported metal alkylidenes, which may occur by different pathways: C-H addition, σ-bond metathesis, and α-H abstraction. The results indicate that the α-H abstraction pathway is the preferred one, regardless of the catalyst and ligands. This is in contrast to the expected preference for the C-H addition route. When looking for the origin of this preference, our calculations revealed that the α-H abstraction pathway is driven by entropy, which favors the initial dissociation of the alkyl ligand from the catalyst.

Thermodynamics and Intermolecular Interactions during the Insertion of Anionic Naproxen into Model Cell Membranes.

The insertion process of Naproxen into model dimyristoylphosphatidylcholine (DMPC) membranes is studied by resorting to state-of-the-art classical and quantum mechanical atomistic computational approaches. Molecular dynamics simulations indicate that anionic Naproxen finds an equilibrium position right at the polar/nonpolar interphase when the process takes place in aqueous environments. With respect to the reference aqueous phase, the insertion process faces a small energy barrier of ≈5 kJ mol-1 and yields a net stabilization of also ≈5 kJ mol-1. Entropy changes along the insertion path, mainly due to a growing number of realizable microstates because of structural reorganization, are the main factors driving the insertion. An attractive fluxional wall of noncovalent interactions is characterized by all-quantum descriptors of chemical bonding (natural bond orbitals, quantum theory of atoms in molecules, noncovalent interaction, density differences, and natural charges). This attractive wall originates in the accumulation of tiny transfers of electron densities to the interstitial region between the fragments from a multitude of individual intermolecular contacts stabilizing the tertiary drug/water/membrane system.

Diels-Alder Reactivity of a Chiral Anthracene Template with Symmetrical and Unsymmetrical Dienophiles: A DFT Study.

In this work, we used Density Functional Theory calculations to assess the factors that control the reactivity of a chiral anthracene template with three sets of dienophiles including maleic anhydrides, maleimides and acetoxy lactones in the context of Diels-Alder cycloadditions. The results obtained here (at the M06-2X/6-311++G(d,p) level of theory) suggest that the activation energies for maleic anhydrides and acetoxy lactones are dependent on the nature of the substituent in the dienophile. Among all studied substituents, only -CN reduces the energy barrier of the cycloaddition. For maleimides, the activation energies are independent of the heteroatom of the dienophile and the R group attached to it. The analysis of frontier molecular orbitals, charge transfer and the activation strain model (at the M06-2X/TZVP level based on M06-2X/6-311++G(d,p) geometries) suggest that the activation energies in maleic anhydrides are mainly controlled by the amount of charge transfer from the diene to the dienophile during cycloaddition. For maleimides, there is a dual control of interaction and strain energies on the activation energies, whereas for the acetoxy lactones the activation energies seem to be controlled by the degree of template distortion at the transition state. Finally, calculations show that considering a catalyst on the studied cycloadditions changes the reaction mechanism from concerted to stepwise and proceed with much lower activation energies.

Diels-Alder reaction mechanisms of substituted chiral anthracene: A theoretical study based on the reaction force and reaction electronic flux.

Quantum chemical calculations were used to study the mechanism of Diels-Alder reactions involving chiral anthracenes as dienes and a series of dienophiles. The reaction force analysis was employed to obtain a detailed scrutiny of the reaction mechanisms, it has been found that thermodynamics and kinetics of the reactions are quite consistent: the lower the activation energy, the lower the reaction energy, thus following the Bell-Evans-Polanyi principle. It has been found that activation energies are mostly due to structural rearrangements that in most cases represented more than 70% of the activation energy. Electronic activity mostly due to changes in σ and π bonding were revealed by the reaction electronic flux (REF), this property helps identify whether changes on σ or π bonding drive the reaction. Additionally, new global indexes describing the behavior of the electronic activity were introduced and then used to classify the reactions in terms of the spontaneity of their electronic activity. Local natural bond order electronic population analysis was used to check consistency with global REF through the characterization of specific changes in the electronic density that might be responsible for the activity already detected by the REF. Results show that reactions involving acetoxy lactones are driven by spontaneous electronic activity coming from bond forming/strengthening processes; in the case of maleic anhydrides and maleimides it appears that both spontaneous and non-spontaneous electronic activity are quite active in driving the reactions.

Mechanistic Insights into Alkane Metathesis Catalyzed by Silica-Supported Tantalum Hydrides: A DFT Study.

Alkane metathesis transforms small alkanes into their higher and lower homologues. The reaction is catalyzed by either supported d0 metal hydrides (M = Ta, W) or d0 alkyl alkylidene complexes (M = Ta, Mo, W, Re). For the silica-supported tantalum hydrides, several reaction mechanisms have been proposed. We performed DFT-D3 calculations to analyze the viability of the proposed pathways and compare them with alkane hydrogenolysis, which is a competitive process observed at the early stages of the reaction. The results show that the reaction mechanisms for alkane metathesis and for alkane hydrogenolysis present similar energetics, and this is consistent with the fact that the process taking place depends on the concentrations of the initial reactants. Overall, a modified version of the so-called one-site mechanism that involves alkyl alkylidene intermediates appears to be more likely and consistent with experiments. According to this proposal, tantalum hydrides are precursors of the alkyl alkylidene active species. During precursor activation, H2 is released and this allows alkane hydrogenolysis to occur. In contrast, the catalytic cycle implies only the reaction with alkane molecules in excess and does not form H2. Thus, the activity for alkane hydrogenolysis decreases. The catalytic cycle proposed here implies three stages: (i) ß-H elimination from the alkyl ligand, liberating ethene, (ii) alkene cross-metathesis, allowing olefin substituent exchange, and (iii) formation of the final products and alkyl alkylidene regeneration by olefin insertion and three successive 1,2-CH insertions to the alkylidene followed by α abstraction. These results relate the reactivity of silica-supported hydrides with that of the alkyl alkylidene complexes, the other common catalyst for alkane metathesis.

Local Structures and Heterogeneity of Silica-Supported M(III) Sites Evidenced by EPR, IR, NMR, and Luminescence Spectroscopies.

Grafting molecular precursors on partially dehydroxylated silica followed by a thermal treatment yields silica-supported M(III) sites for a broad range of metals. They display unique properties such as high activity in olefin polymerization and alkane dehydrogenation (M = Cr) or efficient luminescence properties (M = Yb and Eu) essential for bioimaging. Here, we interrogate the local structure of the M(III) surface sites obtained from two molecular precursors, amides M(N(SiMe3)2)3 vs siloxides (M(OSi(OtBu)3)3·L with L = (THF)2 or HOSi(OtBu)3 for M = Cr, Yb, Eu, and Y, by a combination of advanced spectroscopic techniques (EPR, IR, XAS, UV-vis, NMR, luminescence spectroscopies). For paramagnetic Cr(III), EPR (HYSCORE) spectroscopy shows hyperfine coupling to nitrogen only when the amide precursor is used, consistent with the presence of nitrogen neighbors. This changes their specific reactivity compared to Cr(III) sites in oxygen environments obtained from siloxide precursors: no coordination of CO and oligomer formation during the polymerization of ethylene due to the presence of a N-donor ligand. The presence of the N-ligand also affects the photophysical properties of Yb and Eu by decreasing their lifetime, probably due to nonradiative deactivation of excited states by N-H bonds. Both types of precursors lead to a distribution of surface sites according to reactivity for Cr, luminescence spectroscopy for Yb and Eu, and dynamic nuclear polarization surface-enhanced 89Y NMR spectroscopy (DNP SENS). In particular, DNP SENS provides molecular-level information about the structure of surface sites by evidencing the presence of tri-, tetra-, and pentacoordinated Y-surface sites. This study provides unprecedented evidence and tools to assess the local structure of metal surface sites in relation to their chemical and physical properties.

The Effect of the Electronic Nature of Spectator Ligands in the C-H Bond Activation of Ethylene by Cr(III) Silicates: An ab initio Study.

The Phillips catalyst, chromium oxides supported on silica, is one of the most widely used catalysts for the industrial production of polyethylene (PE). We recently synthesized a well-defined mononuclear Cr(III) silicate as active site model of the Phillips catalyst. The catalytic activity of this well-defined catalyst was similar to the industrial Phillips catalyst. We proposed that C-H bond activation of ethylene over a Cr-O bond initiates polymerization in this Cr(III) catalyst. Our results also showed that the presence of a second ethylene olefin in the coordination sphere of Cr decreases the intrinsic energy barrier of the C-H activation of ethylene. In order to understand the effect of this additional ligand in the C-H activation of ethylene by the Cr(III) catalyst, we evaluated the energetics of this step with different spectator ligands (C2H4, C2F4, N2 and CO) coordinated to the Cr center. The Charge Decomposition Analysis (CDA) of the bonding interactions between the Cr(III) catalyst and the ligands showed that the intrinsic energy barrier for the C-H activation of ethylene decreases with the increasing electron-donor properties of the spectator ligand.

Heterolytic Activation of C-H Bonds on Cr(III)-O Surface Sites Is a Key Step in Catalytic Polymerization of Ethylene and Dehydrogenation of Propane.

We describe the reactivity of well-defined chromium silicates toward ethylene and propane. The initial motivation for this study was to obtain a molecular understanding of the Phillips polymerization catalyst. The Phillips catalyst contains reduced chromium sites on silica and catalyzes the polymerization of ethylene without activators or a preformed Cr-C bond. Cr(II) sites are commonly proposed active sites in this catalyst. We synthesized and characterized well-defined chromium(II) silicates and found that these materials, slightly contaminated with a minor amount of Cr(III) sites, have poor polymerization activity and few active sites. In contrast, chromium(III) silicates have 1 order of magnitude higher activity. The chromium(III) silicates initiate polymerization by the activation of a C-H bond of ethylene. Density functional theory analysis of this process showed that the C-H bond activation step is heterolytic and corresponds to a σ-bond metathesis type process. The same well-defined chromium(III) silicate catalyzes the dehydrogenation of propane at elevated temperatures with activities similar to those of a related industrial chromium-based catalyst. This reaction also involves a key heterolytic C-H bond activation step similar to that described for ethylene but with a significantly higher energy barrier. The higher energy barrier is consistent with the higher pKa of the C-H bond in propane compared to the C-H bond in ethylene. In both cases, the rate-determining step is the heterolytic C-H bond activation.

NMR signatures of the active sites in Sn-ß zeolite.

Dynamic nuclear polarization surface enhanced NMR (DNP-SENS), Mössbauer spectroscopy, and computational chemistry were combined to obtain structural information on the active-site speciation in Sn-ß zeolite. This approach unambiguously shows the presence of framework Sn(IV)-active sites in an octahedral environment, which probably correspond to so-called open and closed sites, respectively (namely, tin bound to three or four siloxy groups of the zeolite framework).

Proton transfers are key elementary steps in ethylene polymerization on isolated chromium(III) silicates.

Mononuclear Cr(III) surface sites were synthesized from grafting [Cr(OSi(O(t)Bu)3)3(tetrahydrofurano)2] on silica partially dehydroxylated at 700 °C, followed by a thermal treatment under vacuum, and characterized by infrared, ultraviolet-visible, electron paramagnetic resonance (EPR), and X-ray absorption spectroscopy (XAS). These sites are highly active in ethylene polymerization to yield polyethylene with a broad molecular weight distribution, similar to that typically obtained from the Phillips catalyst. CO binding, EPR spectroscopy, and poisoning studies indicate that two different types of Cr(III) sites are present on the surface, one of which is active in polymerization. Density functional theory (DFT) calculations using cluster models show that active sites are tricoordinated Cr(III) centers and that the presence of an additional siloxane bridge coordinated to Cr leads to inactive species. From IR spectroscopy and DFT calculations, these tricoordinated Cr(III) sites initiate and regulate the polymer chain length via unique proton transfer steps in polymerization catalysis.

DFT study on the recovery of Hoveyda-grubbs-type catalyst precursors in enyne and diene ring-closing metathesis.

DFT (B3LYP-D) calculations have been used to better understand the origin of the recovered Hoveyda-Grubbs derivative catalysts after ring-closing diene or enyne metathesis reactions. For that, we have considered the activation process of five different Hoveyda-Grubbs precursors in the reaction with models of usual diene and enyne reactants as well as the potential precursor regeneration through the release/return mechanism. The results show that, regardless of the nature of the initial precursor, the activation process needs to overcome relatively high energy barriers, which is in agreement with a relatively slow process. The precursor regeneration process is in all cases exergonic and it presents low energy barriers, particularly when compared to those of the activation process. This indicates that the precursor regeneration should always be feasible, unlike the moderate recoveries sometimes observed experimentally, which suggests that other competitive processes that hinder recovery should take place. Indeed, calculations presented in this work show that the reactions between the more abundant olefinic products and the active carbenes usually require lower energy barriers than those that regenerate the initial precatalyst, which could prevent precursor regeneration. On the other hand, varying the precursor concentration with time obtained from the computed energy barriers shows that, under the reaction conditions, the precursor activation is incomplete, thereby suggesting that the origin of the recovered catalyst probably arises from incomplete precursor activation.

Mechanistic insights into ring-closing enyne metathesis with the second-generation Grubbs-Hoveyda catalyst: a DFT study.

The full catalytic process (precatalyst activation, propagating cycle and active-species interconversion) of the ring-closing enyne metathesis (RCEYM) reaction of 1-allyloxy-2-propyne with the Grubbs-Hoveyda complex as catalyst was studied by B3LYP density functional theory. Both the ene-then-yne and yne-then-ene pathways are considered and, for the productive catalytic cycle, the feasibility of the endo-yne-then-ene route is also explored. Calculations predict that the ene-then-yne and yne-then-ene pathways proceed through equivalent steps, the only major difference being the order in which they take place. In this way, all alkene metathesis processes studied here involve four steps: olefin coordination, cycloaddition, cycloreversion and olefin decoordination. Among them, the two more energetically demanding ones are the olefin coordination and decoordination steps. The reaction of the alkyne fragment consists of two steps: alkyne coordination and alkyne skeletal reorganization, the latter of which has the highest Gibbs energy barrier. Comparison between the ene-then-yne and yne-then-ene pathways shows that there is no clear energetic preference for either of the two processes, and thus both should be operative when unsubstituted enynes are involved. In addition, although the endo orientation is computed to be slightly disfavored, it is not ruled out for 1-allyloxy-2-propyne, and thus calculations seem to indicate that the exo versus endo selectivity is strongly influenced by the presence of substituents in the reagent.