Assessing the Effect of Dopants on the C-H Activation Activity of γ-Al2 O3 using First-Principles Calculations.

In recent years, the high availability of methane in the shale gas reserves has raised significant interest in its conversion to high-value chemicals but this process is still not commercially viable. Metal oxides, due to their surface heterogeneity and the presence of Lewis acidic and basic site pairs are known to facilitate the activation of C-H bonds of methane. In this work, we investigate the C-H bond activation of methane on pristine and doped γ-Al2 O3 clusters using density functional theory (DFT) calculations. Our results demonstrate that the polar pathway is energetically preferred over the radical pathway on these systems. We found that the metal dopants (boron and gallium) not only alter the catalytic activity of dopant sites but this effect is more pronounced on some of the adjacent sites (non-local). Among the selected dopants, gallium greatly improves the catalytic activity on most of the site pairs (including most active and least active) of pristine γ-Al2 O3 . Additionally, we identified a correlation between H2 binding energies and the C-H activation free energies on Ga-doped γ-Al2 O3 .

Opportunities and Challenges in the Development of Layered Positive Electrode Materials for High-Energy Sodium Ion Batteries: A Computational Perspective.

In recent years, high-energy-density sodium ion batteries (SIBs) have attracted enormous attention as a potential replacement for LIBs due to the chemical similarity between Li and Na, high natural abundance, and low cost of Na. Despite the promise of high energy, SIBs with layered cathode materials face several challenges including irreversible capacity loss, voltage hysteresis, voltage decay, irreversible TM migrations that lead to fast capacity fading, and structural degradation. However, their electrochemical performance can be improved by introducing reversible anionic redox along with conventional cationic redox. This Perspective systematically summarizes different factors that trigger the irreversible anionic redox in Na-based cathode materials. Additionally, this Perspective highlights the mechanistic understanding and key challenges for reversible anionic redox and proposes plausible solutions to overcome these limitations. The overview of various existing experimental and theoretical approaches presented here could provide a futuristic pathway to design Na-based cathode materials for high-energy-density SIBs.

Unraveling the Mechanistic Details of Ru-Bis(pyridyl)borate Complex Catalyst for the Dehydrogenation of Ammonia Borane.

Ru-Bis(pyridyl)borate complex (CAT) is an efficient catalyst for ammonia borane (AB) dehydrogenation. Although the mechanistic pathway of this catalyst has been theoretically investigated previously, the gap between the experimental findings and the computational results could not be bridged thus far. In our study, using density functional theory calculations, we elucidate the mechanism of AB dehydrogenation of CAT at a variable degree of ligand hydrogenation. Our results confirm that the acetonitrile ligands get reduced in the presence of AB and remain hydrogenated. Moreover, in line with experiments, we find that AB dehydrogenation on CAT proceeds via a concerted mechanism (with the free energy energetic span between 25.4 and 32.5 kcal/mol). We find that the ligand reduction alters the electronic structure and activity of CAT and the highest activity of the catalyst is expected at the fifth degree of hydrogenation of ligands with an energetic span of 25.4 kcal/mol. Additionally, the mechanism for the removal of molecular H2 from the catalysts also alters with the degree of ligand hydrogenation. Furthermore, our results show that optimal H2 binding free energy calculations can be used as a descriptor to identify the most active sites. Finally, this work demonstrates that ligand reduction improves the activity of the catalyst. These results highlight the importance of ligand hydrogenation in probing the activity and operating mechanism of the Ru-bis(pyridyl)borate complexes for AB dehydrogenation. Further, we identify a plausible dimer structure and rationalized experimental observation that the deactivation chemistry of this catalyst is different from the Shvo's catalyst.

Copper acetate catalysed C-C bond formation en route to the synthesis of spiro indanedione cyclopropylpyrazolones.

This article reports the synthesis of spiro compounds based on an indanedione-cyclopropane-pyrazolone framework. The reaction relied upon the Michael-initiated ring closure strategy and was carried out under Cu(OAc)2 catalysis, assisted by an oxygen atmosphere and the base Et3N. The final compounds were obtained as an inseparable mixture in most cases with modest to good yields using diverse substrates. Among the two plausible routes, computational studies indicated the feasibility of a route which involves a four-membered Cu containing intermediate. Given the generic nature of the developed method, it may be utilised to synthesise other analogous spiro systems.

Mechanistic Studies on the Michael Addition of Amines and Hydrazines To Nitrostyrenes: Nitroalkane Elimination via a Retro-aza-Henry-Type Process.

In this article we report on the mechanistic studies of the Michael addition of amines and hydrazines to nitrostyrenes. Under the present conditions, the corresponding N-alkyl/aryl substituted benzyl imines and N-methyl/phenyl substituted benzyl hydrazones were observed via a retro-aza-Henry-type process. By combining organic synthesis and characterization experiments with computational chemistry calculations, we reveal that this reaction proceeds via a protic solvent-mediated mechanism. Experiments in deuterated methanol CD3OD reveal the synthesis and isolation of the corresponding deuterated intermediated Michael adduct, results that support the proposed slovent-mediated pathway. From the synthetic point of view, the reaction occurs under mild, noncatalytic conditions and can be used as a useful platform to yield the biologically important N-methyl pyrazoles in a one-pot manner, simple starting with the corresponding nitrostyrenes and the methylhydrazine.

A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist.

Extracellular nucleotides can regulate the production/drainage of the aqueous humor via activation of P2 receptors, thus affecting the intraocular pressure (IOP). We evaluated 5-OMe-UDP(α-B), 1A, a potent P2Y6-receptor agonist, for reducing IOP and treating glaucoma. Cell viability in the presence of 1A was measured using [3-(4, 5-dimethyl-thiazol-2-yl) 2, 5-diphenyl-tetrazolium bromide] (MTT) assay in rabbit NPE ciliary non-pigmented and corneal epithelial cells, human retinoblastoma, and liver Huh7 cells. The effect of 1A on IOP was determined in acute glaucomatous rabbit hyaluronate model and phenol-induced chronic glaucomatous rabbit model. The origin of activity of 1A was investigated by generation of a homology model of hP2Y6-R and docking studies. 1A did not exert cytotoxic effects up to 100 mM vs. trusopt and timolol in MTT assay in ocular and liver cells. In normotensive rabbits, 100 µM 1A vs. xalatan, trusopt, and pilocarpine reduced IOP by 45 vs. 20-30%, respectively. In the phenol animal model, 1A (100 µM) showed reduction of IOP by 40 and 20%, following early and late administration, respectively. Docking results suggest that the high activity and selectivity of 1A is due to intramolecular interaction between Pα-BH3 and C5-OMe which positions 1A in a most favorable site inside the receptor. P2Y6-receptor agonist 1A effectively and safely reduces IOP in normotense, acute, and chronic glaucomatous rabbits, and hence may be suggested as a novel approach for the treatment of glaucoma.

Is it True That the Normal Valence-Length Correlation Is Irrelevant for Metal-Metal Bonds?

The most intriguing feature of metal-metal bonds in inorganic compounds is an apparent lack of correlation between the bond order and the bond length. In this study, we combine a variety of literature data obtained by quantum chemistry and our results based on the empirical bond valence model (BVM), to confirm for the first time the existence of a normal exponential correlation between the effective bond order (EBO) and the length of the metal-metal bonds. The difference between the EBO and the formal bond order is attributed to steric conflict between the (TM)n cluster (TM=transition metal) and its environment. This conflict, affected mainly by structural type, should cause high lattice strains, but electron redistribution around TM atoms, evident from the BVM calculations, results in a full or partial strain relaxation.

Nucleoside-2',3'/3',5'-bis(thio)phosphate antioxidants are also capable of disassembly of amyloid beta42-Zn(ii)/Cu(ii) aggregates via Zn(ii)/Cu(ii)-chelation.

Currently, there is an urgent need for biocompatible metal-ion chelators capable of antioxidant activity and disassembly of amyloid beta (Aß)-aggregates as potential therapeutics for Alzheimer's disease (AD). We recently demonstrated the promising antioxidant activity of adenine/guanine 2',3' or 3',5'-bis(thio)phosphate analogues, 2'-dA/G3'5'PO/S and A2'3'PO/S, and their affinity to Zn(ii)-ions. These findings encouraged us to evaluate them as agents for the dissolution of Aß42-Zn(ii)/Cu(ii) aggregates. Specifically, we explored their ability to bind Cu(ii)/Zn(ii)-ions, the geometry and stoichiometry of these complexes, Cu(ii)/Zn(ii)-binding-sites and binding mode, and the ability of these analogues to dissolve Aß42-Zn(ii)/Cu(ii) aggregates, as well as their effect on the secondary structure of those aggregates. Finally, we identified the most promising agents for dissolution of Aß42-Zn(ii)/Cu(ii) aggregates. Specifically, we observed the formation of a 1 : 1 complex between 2'-dG3'5'PO and Cu(ii), involving O4 ligands. Zn(ii) was coordinated by both thiophosphate groups of 2'-dA3'5'PS and A2'3'PS involving O2S2 ligands in a 1 : 1 stoichiometry. A2'3'PS dissolves Aß42-Zn(ii) and Aß42-Cu(ii) aggregates as effectively as, and 2.5-fold more effectively than EDTA, respectively. Furthermore, 2'-dG3'5'PS and A2'3'PS reverted the Aß42-M(ii) structure, back to that of the free Aß42. Finally, cryo-TEM and TEM images confirmed the disassembly of Aß42 and Aß42-M(ii) aggregates by A2'3'PS. Hence, 2'-dG3'5'PS and A2'3'PS may serve as promising scaffolds for new AD therapeutics, acting as both effective antioxidants and agents for solubilization of Aß42-Cu(ii)/Zn(ii) aggregates.

First principles model calculations of the biosynthetic pathway in selinadiene synthase.

Terpenes comprise the largest class of natural products currently known. These ubiquitous molecules are synthesized by terpene synthases via complex carbocationic reactions, incorporating highly reactive intermediates. In the current study, we present a mechanistic investigation of the biosynthetic pathway for the formation of selina-4(15),7(11)-diene. We employ density functional theory to study a model carbocation system in the gas-phase, and delineate the energetic feasibility of a plausible reaction path. Our results suggests that during formation of selina-4(15),7(11)-diene, the substrate is likely folded in a conformation conducive to sequential cyclizations. We propose that a required proton transfer cannot occur intramolecularly in the gas-phase due to a high free energy barrier, and that enzyme assistance is essential for this step. Hybrid quantum mechanics-molecular mechanics docking studies suggest that enzyme intervention could be realized through electrostatic guidance.

Thermodynamic and kinetic studies of LiNi0.5Co0.2Mn0.3O2 as a positive electrode material for Li-ion batteries using first principles.

Ni-rich Li-based layered Ni, Co, and Mn (NCM) materials have shown tremendous promise in recent years as positive electrode materials for Li-ion batteries. This is evident as companies developing batteries for electrical vehicles are currently commercializing these materials. Despite the considerable research performed on LiNiαCoßMnγO2 systems, we do not yet have a complete atomic level understanding of these materials. In this work we study the cationic ordering, thermodynamics, and diffusion kinetics of LiNi0.5Co0.2Mn0.3O2 (NCM-523). Initially, we show that cationic ordering can be predicted employing cheap atomistic simulations, instead of using expensive first-principles methods. Subsequently, we investigate the electrochemical, thermodynamic and kinetic properties of NCM-523 using density functional theory (DFT). Our results demonstrate the importance of including dispersion corrections to standard first principles functionals in order to correctly predict the lattice parameters of layered cathode materials. We also demonstrate that a careful choice of computational protocol is essential to reproduce the experimental intercalation potential trends observed in the LiNi0.5Co0.2Mn0.3O2 electrodes. Analysis of the electronic structure confirms an active role of Ni in the electrochemical redox process. Moreover, we confirm the experimental finding that on complete delithiation, this material remains in an O3 phase, unlike LiCoO2 and NCM-333. Finally, we study various pathways for the Li-ion diffusion in NCM-523, and pinpoint the preferred diffusion channel based on first principles simulations. Interestingly, we observe that the Li diffusion barrier in NCM-523 is lower than that in LiCoO2.

Magnetism in olivine-type LiCo(1-x)Fe(x)PO4 cathode materials: bridging theory and experiment.

In the current paper, we present a non-aqueous sol-gel synthesis of olivine type LiCo1-xFexPO4 compounds (x = 0.00, 0.25, 0.50, 0.75, 1.00). The magnetic properties of the olivines are measured experimentally and calculated using first-principles theory. Specifically, the electronic and magnetic properties are studied in detail with standard density functional theory (DFT), as well as by including spin-orbit coupling (SOC), which couples the spin to the crystal structure. We find that the Co(2+) ions exhibit strong orbital moment in the pure LiCoPO4 system, which is partially quenched upon substitution of Co(2+) by Fe(2+). Interestingly, we also observe a non-negligible orbital moment on the Fe(2+) ion. We underscore that the inclusion of SOC in the calculations is essential to obtain qualitative agreement with the observed effective magnetic moments. Additionally, Wannier functions were used to understand the experimentally observed rising trend in the Néel temperature, which is directly related to the magnetic exchange interaction paths in the materials. We suggest that out of layer M-O-P-O-M magnetic interactions (J⊥) are present in the studied materials. The current findings shed light on important differences observed in the electrochemistry of the cathode material LiCoPO4 compared to the already mature olivine material LiFePO4.

Side-Chain Modification in Conjugated Polymer Frameworks for the Electrocatalytic Oxygen Evolution Reaction.

Conjugated polymer frameworks (CPFs) have recently sparked tremendous research interest due to their broad potentials in various frontline application areas such as photocatalysis, sensing, gas storage, energy storage, etc. These framework materials, without sidechains or functional groups on their backbone, are generally insoluble in common organic solvents and less solution processable for further device applications. There are few reports on metal-free electrocatalysis, especially oxygen evolution reaction (OER) using CPF. Herein, we have developed two triazine-based donor-acceptor conjugated polymer frameworks by coupling a 3-substituted thiophene (donor) unit with a triazine ring (acceptor) through a phenyl ring spacer. Two different sidechains, alkyl and oligoethylene glycol, were rationally introduced into the 3-position of thiophene in the polymer framework to investigate the effect of side-chain functionality on the electrocatalytic property. Both the CPFs demonstrated superior electrocatalytic OER activity and long-term durability. The electrocatalytic performance of CPF2, which achieved a current density of 10 mA/cm2 at an overpotential (η) of 328 mV, is much superior to CPF1, which reached the same current density at an overpotential of 488 mV. The porous and interconnected nanostructure of the conjugated organic building blocks, which allowed for fast charge and mass transport processes, could be attributed to the higher electrocatalytic activity of both CPFs. However, the superior activity of CPF2 compared to CPF1 may be due to the presence of a more polar oxygen-containing ethylene glycol side chain, which enhances the surface hydrophilicity, promotes better ion/charge and mass transfer, and increases the accessibility of the active sites toward adsorption through lower π-π stacking compared to hexyl side chain present in CPF1. The DFT study also supports the plausible better performance toward OER for CPF2. This study confirms the promising potentiality of metal-free CPF electrocatalysts for OER and further sidechain modification to improve their electrocatalytic property.

A terpyridine based hydrogel system for reversible transmissive-to-dark electrochromism and bright-to-quenched electrofluorochromism.

A carboxylic acid-containing terpyridine-based hydrogelator (TPPCA) is synthesized to afford a self-assembly induced TPPCA hydrogel, which was used as an all-in-one electrochrome in electrochromic devices (ECDs) to demonstrate reversible transparent-to-black electrochromism with fast darkening and bleaching time of 8.3 s and 9.5 s, respectively, high photopic coloration efficiency of 65.8 cm2 C-1 and high optical memory. The ECD also revealed bluish-white to quenched emission simultaneously under the -3.5 V to 0 V voltage range.

Solvent manipulation of the pre-reduction metal-ligand complex and particle-ligand binding for controlled synthesis of Pd nanoparticles.

Understanding how to control the nucleation and growth rates is crucial for designing nanoparticles with specific sizes and shapes. In this study, we show that the nucleation and growth rates are correlated with the thermodynamics of metal-ligand/solvent binding for the pre-reduction complex and the surface of the nanoparticle, respectively. To obtain these correlations, we measured the nucleation and growth rates by in situ small angle X-ray scattering during the synthesis of colloidal Pd nanoparticles in the presence of trioctylphosphine in solvents of varying coordinating ability. The results show that the nucleation rate decreased, while the growth rate increased in the following order, toluene, piperidine, 3,4-lutidine and pyridine, leading to a large increase in the final nanoparticle size (from 1.4 nm in toluene to 5.0 nm in pyridine). Using density functional theory (DFT), complemented by 31P nuclear magnetic resonance and X-ray absorption spectroscopy, we calculated the reduction Gibbs free energies of the solvent-dependent dominant pre-reduction complex and the solvent-nanoparticle binding energy. The results indicate that lower nucleation rates originate from solvent coordination which stabilizes the pre-reduction complex and increases its reduction free energy. At the same time, DFT calculations suggest that the solvent coordination affects the effective capping of the surface where stronger binding solvents slow the nanoparticle growth by lowering the number of active sites (not already bound by trioctylphosphine). The findings represent a promising advancement towards understanding the microscopic connection between the metal-ligand thermodynamic interactions and the kinetics of nucleation and growth to control the size of colloidal metal nanoparticles.

The role of nanoparticle size and ligand coverage in size focusing of colloidal metal nanoparticles.

Controlling the size distribution of nanoparticles is important for many applications and typically involves the use of ligands during synthesis. In this study, we show that the mechanism of size focusing involves a dependence of the growth rate on the size of the nanoparticles and the ligand coverage on the surface of the nanoparticles. To demonstrate these effects, we used in situ small angle X-ray scattering (SAXS) and population balance kinetic modeling (PBM) to investigate the evolution of size distribution during the synthesis of colloidal Pd metal nanoparticles. Despite temporal overlap of nucleation and growth, our in situ SAXS show size focusing of the distribution under different synthetic conditions (different concentrations of metal and ligand as well as solvent type). To understand the mechanism of size focusing using PBM, we systematically studied how the evolution of the nanoparticle size distribution is affected by nucleation rate, and dependence of the growth rate constant on ligand surface coverage, and size of the nanoparticles. We show that continuous nucleation contributes to size defocusing. However, continuous nucleation results in different reaction times for the nanoparticle population leading to time and size-dependent ligand surface coverage. Using density functional theory (DFT) calculations and Brønsted-Evans-Polanyi relations, we show that as the population grows, larger nanoparticles grow more slowly than smaller ones due to lower intrinsic activity and higher ligand coverage on the surface. Therefore, despite continuous nucleation, the faster growth of smaller nanoparticles in the population leads to size focusing. The size focusing behaviour (due to faster growth of smaller nanoparticles) was found to be model independent and similar results were demonstrated under different nucleation and growth pathways (e.g. growth via ion reduction on the surface and/or monomer addition). Our results provide a microscopic connection between kinetics and thermodynamics of nanoparticle growth and metal-ligand binding, and their effect on the size distribution of colloidal nanoparticles.

Computational Study of Methane Activation on γ-Al2O3.

The C-H activation of methane remains a longstanding challenge in the chemical industry. Metal oxides are attractive catalysts for the C-H activation of methane due to their surface Lewis acid-base properties. In this work, we applied density functional theory calculations to investigate the C-H activation mechanism of methane on various sites of low-index facets of γ-Al2O3. The feasibility of C-H activation on different metal-oxygen (acid-base) site pairs was assessed through two potential mechanisms, namely, the radical and polar. The effect of surface hydroxylation on C-H activation was also investigated to examine the activity of γ-Al2O3 under realistic catalytic surface conditions (hydration). On the basis of our calculations, it was demonstrated that the C-H activation barriers for polar pathways are significantly lower than those of the radical pathways on γ-Al2O3. We showed that the electronic structure (s- and p-band center) for unoccupied and occupied bands can be used to probe site-dependent Lewis acidity and basicity and the associated catalytic behavior. We identified the dissociated H2 binding and final state energy as C-H activation energy descriptors for the preferred polar pathway. Finally, we developed structure-activity relationships for the C-H activation of methane on γ-Al2O3 that account for surface Lewis acid-base properties and can be utilized to accelerate the discovery of catalysts for methane (and shale gas) upgrade.

Comment on "Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity".

Wang et al. recently reported an in silico study of the trichodiene synthase (TDS) conversion of farnesyl diphosphate (FPP) to trichodiene (TD) (Wang et al., ACS Catal. 2017, 7, 5841-5846). Although the methods and level of theory used in that work are nearly identical to our own recent work on this system (Dixit et al., ACS Catal. 2017, 7, 812-818), Wang et al. reach rather different conclusions. The authors claimed to obtain a "very credible" mechanism for the biosynthesis of TD and optimized the optimal folding mode of FPP in the 1,6-ring closure in TDS. However, the folding mode of the FPP substrate that was presented contradicts well-established NMR and mass spectrometry data. Moreover, the authors make numerous incorrect statements regarding our earlier work.

Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase.

Terpene cyclases catalyze the highly stereospecific molding of polyisoprenes into terpenes, which are precursors to most known natural compounds. The isoprenoids are formed via intricate chemical cascades employing rich, yet highly erratic, carbocation chemistry. It is currently not well understood how these biocatalysts achieve chemical control. Here, we illustrate the catalytic control exerted by trichodiene synthase, and in particular, we discover two features that could be general catalytic tools adopted by other terpenoid cyclases. First, to avoid formation of byproducts, the enzyme raises the energy of bisabolyl carbocation, which is a general mechanistic branching point in many sesquiterpene cyclases, resulting in an essentially concerted cyclization cascade. Second, we identify a sulfur-carbocation dative bonding interaction that anchors the bisabolyl cation in a reactive conformation, avoiding tumbling and premature deprotonation. Specifically, Met73 acts as a chameleon, shifting from an initial sulfur-π interaction in the Michaelis complex to a sulfur-carbocation complex during catalysis.

Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5'-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action.

With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 µM for ADP. Furthermore, 7A rescued primary neurons subjected to oxidation, EC50 of 0.04 vs 19 µM for ADP. 7A is a most potent P2Y1-R agonist, EC50 of 0.0026 µM. Activity of 7A in cells involved P2Y1/12-R as indicated by blocking P2Y12-R or P2Y1-R. Compound 7A inhibited Fenton reaction better than EDTA, IC50 of 37 vs 54 µM, due to radical scavenging, IC50 of 12.5 vs 30 µM for ADP, and Fe(II)-chelation, IC50 of 80 vs >200 µM for ADP (ferrozine assay). In addition, 7A was stable in human blood serum, t1/2 of 15 vs 1.5 h for ADP, and resisted hydrolysis by NPP1/3, 2-fold vs ADP. Hence, we propose 7A as a highly promising neuroprotectant.

Atomistic details of effect of disulfide bond reduction on active site of Phytase B from Aspergillus niger: A MD Study.

UNLABELLED: The molecular integrity of the active site of phytases from fungi is critical for maintaining phytase function as efficient catalytic machines. In this study, the molecular dynamics (MD) of two monomers of phytase B from Aspergillus niger, the disulfide intact monomer (NAP) and a monomer with broken disulfide bonds (RAP), were simulated to explore the conformational basis of the loss of catalytic activity when disulfide bonds are broken. The simulations indicated that the overall secondary and tertiary structures of the two monomers were nearly identical but differed in some crucial secondary-structural elements in the vicinity of the disulfide bonds and catalytic site. Disulfide bonds stabilize the ß-sheet that contains residue Arg66 of the active site and destabilize the α-helix that contains the catalytic residue Asp319. This stabilization and destabilization lead to changes in the shape of the active-site pocket. Functionally important hydrogen bonds and atomic fluctuations in the catalytic pocket change during the RAP simulation. None of the disulfide bonds are in or near the catalytic pocket but are most likely essential for maintaining the native conformation of the catalytic site. ABBREVIATIONS: PhyB - 2.5 pH acid phophatese from Aspergillus niger, NAP - disulphide intact monomer of Phytase B, RAP - disulphide reduced monomer of Phytase B, Rg - radius of gyration, RMSD - root mean square deviation, MD - molecular dynamics.