Application of QM simulations and multivariate analysis in the study of alkene reactivity in the zeolite H‐ZSM5

Reported herein are the results of an investigation into the effect of the extended framework of the zeolite ZSM‐5 on the reaction energetics and structures of (a) the physisorbed complex formed between the zeolite and six alkenes, (b) the corresponding chemisorbed alkoxide intermediate and (c) the transition states (TS) connecting the two. For this, quantum mechanical (QM) simulations of ZSM‐5 in the presence and absence of the zeolite framework have been employed. A 46T density functional theory (DFT) cluster model and a 3T:46T DFT:UFF ONIOM model are used to represent the former scenario and a simple 3T DFT cluster model for the latter. The structural implications of neglecting the zeolite framework have been rigorously compared using the multivariate statistical method principal components analysis (PCA). This method allows one to assess the correlated nature of the changes in structure along the reaction coordinate, for multiple different alkenes, in a facile, reliable way. Copyright © 2008 John Wiley & Sons, Ltd.     

Probing the structural and electronic factors affecting the adsorption and reactivity of alkenes in acidic zeolites using DFT calculations and multivariate statistical methods

Quantum mechanical (QM) cluster calculations have been performed on a model of ZSM-5 at DFT and MP2 levels. We investigated how the adsorption energies and the energetics of alkoxide intermediate formation of six different alkene substrates, ethene, propene, 1-butene, cis/trans butene, and isobutene, vary in this zeolite model. An analysis of the DFT geometric, electronic, and energetic parameters of the zeolite-substrate complexes, transition states, and alkoxide intermediates is performed using principal components analysis (PCA) and partial least squares (PLS). These deliver an insight into the correlated changes that occur between molecular structure and energy along the reaction coordinate between the physisorbed and chemisorbed species within the zeolite. To the best of our knowledge, this is the first occasion multivariate techniques such as PCA or PLS have been employed to profile the changes in electronics, distances, and angles in QM calculations of catalytic systems such as zeolites. We find the calculated adsorption and the alkoxide intermediate energies correlate strongly with the absolute charge on the substrate and the length of the substrate double bond. The transition states' energies are not affected by the zeolite framework as modeled, which explains why they correlate strongly with the gas-phase substrate protonation energy. Our cluster results show that for ethene, propene, 1-butene, and isobutene, the relative energetics associated with the formation of the alkoxide intermediate in ZSM-5 follow the same trends as calculations where the effects of the framework are included.     

A theoretical study of <Emphasis Type="Italic">cis</Emphasis>–<Emphasis Type="Italic">trans</Emphasis> isomerisation in H-ZSM5: probing the impact of cluster size and zeolite framework on energetics and structure

In this study the results from a series of calculations are reported that probe the influence of the QM cluster size and the extended framework treatment in ONIOM calculations. This is done by comparing the differences in the structures and energetics obtained during simulations of cis–trans isomerisation of butene in H-ZSM-5 at varying level of accuracy. Seven different models have been employed; 3T, 5T and 10T DFT cluster models, and to more effectively encode the extended framework of ZSM-5; 3T:46T, 5T:46T, 10T:46T DFT:MM ONIOM models, and a 46T DFT cluster model. The results show that irrespective of the exact QM cluster size, relatively small gasphase clusters show clear limitations due to the neglect of the extended framework. In particular, the structural and electronic implications of using the different zeolite models have been rigorously assessed using the multivariate statistical method principal components analysis (PCA). Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Confining the Sol-Gel Reaction at the Water/Oil Interface: Creating Compartmentalized Enzymatic Nano-Organelles for Artificial Cells

Living organisms compartmentalize their catalytic reactions in membranes for increased efficiency and selectivity. To mimic the organelles of eukaryotic cells, we develop a mild approach for in situ encapsulating enzymes in aqueous-core silica nanocapsules. In order to confine the sol-gel reaction at the water/oil interface of miniemulsion, we introduce an aminosilane to the silica precursors, which serves as both catalyst and an amphiphilic anchor that electrostatically assembles with negatively charged hydrolyzed alkoxysilanes at the interface. The semi-permeable shell protects enzymes from proteolytic attack, and allows the transport of reactants and products. The enzyme-carrying nanocapsules, as synthetic nano-organelles, are able to perform cascade reactions when enveloped in a polymer vesicle, mimicking the hierarchically compartmentalized reactions in eukaryotic cells. This in situ encapsulation approach provides a versatile platform for the delivery of biomacromolecules.     

Flavylium-Based Hypoxia-Responsive Probe for Cancer Cell Imaging

A hypoxia-responsive probe based on a flavylium dye containing an azo group (AZO-Flav) was synthesized to detect hypoxic conditions via a reductase-catalyzed reaction in cancer cells. In in vitro enzymatic investigation, the azo group of AZO-Flav was reduced by a reductase in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) followed by fragmentation to generate a fluorescent molecule, Flav-NH₂. The response of AZO-Flav to the reductase was as fast as 2 min with a limit of detection (LOD) of 0.4 μM. Moreover, AZO-Flav displayed high enzyme specificity even in the presence of high concentrations of biological interferences, such as reducing agents and biothiols. Therefore, AZO-Flav was tested to detect hypoxic and normoxic environments in cancer cells (HepG2). Compared to the normal condition, the fluorescence intensity in hypoxic conditions increased about 10-fold after 15 min. Prolonged incubation showed a 26-fold higher fluorescent intensity after 60 min. In addition, the fluorescence signal under hypoxia can be suppressed by an electron transport process inhibitor, diphenyliodonium chloride (DPIC), suggesting that reductases take part in the azo group reduction of AZO-Flav in a hypoxic environment. Therefore, this probe showed great potential application toward in vivo hypoxia detection.     

The catalytic conversion of acetonitrile to acrylonitrile in zeolitic systems: Rationalization of experimental observations using theoretical simulations

Quantum mechanical calculations have been performed on faujasite and silicalite models to investigate reported experimental differences in yields of two key catalytic products (propionitrile and acrylonitrile) formed from the reaction of acetonitrile with either methanol or formaldehyde, respectively.

The calculations were performed using 12T and 10T cluster representations of faujasite and silicalite, respectively, and the results are in good overall agreement with experimental observations. Both reactions are predicted to proceed in a concerted manner, with the transfer of a proton to the basic zeolite oxygen atom in conjunction with the methyl group migration to form a reaction intermediate.

The stationary points found on the reaction surface in both zeolites have been systematically assessed using principal components analysis to give us an insight into the correlated nature of the structural/electronic changes that occur on the reaction surfaces.     

Evaluating the enthalpic contribution to ligand binding using QM calculations: effect of methodology on geometries and interaction energies

As a result of research on ligand efficiency in the pharmaceutical industry, there is greater focus on optimizing the strength of polar interactions within receptors, so that the contribution of overall size and lipophilicity to binding can be decreased. A number of quantum mechanical (QM) methods involving simple probes are available to assess the H-bonding potential of different heterocycles or functional groups. However, in most receptors, multiple features are present, and these have distinct directionality, meaning very minimalist models may not be so ideal to describe the interactions. We describe how the use of gas phase QM models of kinase protein-ligand complex, which can more closely mimic the polar features of the active site region, can prove useful in assessing alterations to a core template, or different substituents. We investigate some practical issues surrounding the use of QM cluster models in structure based design (SBD). These include the choice of the method; semi-empirical, density functional theory or ab-initio, the choice of the basis set, whether to include implicit or explicit solvation, whether BSSE should be included, etc. We find a combination of the M06-2X method and the 6-31G* basis set is sufficiently rapid, and accurate, for the computation of structural and energetic parameters for this system.     

Microwave Heating Outperforms Conventional Heating for a Thermal Reaction that Produces a Thermally Labile Product: Observations Consistent with Selective Microwave Heating

Microwave (MW) heating is more effective than conventional (CONV) heating for promoting a high‐temperature oxidative cycloisomerization reaction that was previously reported as a key step in a total synthesis of the natural product illudinine. The thermal reaction pathway as envisioned is an inverse electron‐demand dehydro‐Diels–Alder reaction with in situ oxidation to generate a substituted isoquinoline, which itself is unstable to the reaction conditions. Observed reaction yields were higher at a measured bulk temperature of 200 °C than at 180 °C or 220 °C; at 24 hours than at earlier or later time points; and when the reaction solution was heated using MW energy as opposed to CONV heating with a metal heat block. Selective MW heating of polar solute aggregates is postulated to explain these observations.     

Theoretical studies to estimate the skin sensitization potential of chemicals of the Schiff base domain

Skin sensitization occurs when an exogenous chemical substance forms a covalent adduct with a dermal protein electrophile or nucleophile. This instigates an immune response which leads to inflammation. The local lymph node assay is an in vivo model used in the assessment of relative skin sensitizing potency of chemicals. The method is time consuming and expensive, as well as poses ethical questions given that a number of mice must be sacrificed for each compound assessed. In this work, we investigate the use of an inexpensive, rapid, and ethical method to predict the skin sensitization potential of Schiff base chemicals. We employ quantum chemical methods to rationalize the sensitization potential of 22 compounds with a diverse range of activities. To this end, we have evaluated the mechanistic profile associated with this type of reaction using gas-phase models. We subsequently use the predicted rate determining barriers and key physico-chemical parameters (such as logP) to establish stucture activity relationship (SAR) guidelines to predict the skin sensitization potential for new chemicals. We find that the predicted rate determining barriers for aldehydes, ketone, and 1,2 and 1,3 diones generally decrease in the given order, which concurs with the overall trends in sensitization. We find that lipophilicity also plays a role, with those chemicals displaying both low barriers to reaction, and lower lipophilicity (ie, diones), being more likely to display undesirable skin sensitization effects. These findings are in line with experiment-based observations in the literature and point to the value 3D quantum chemical calculations could have if combined with other orthogonal approaches to estimate skin sensitization potential of chemicals.