Chemistry

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Molecular fluorophores based on N,C-chelate, four-coordinate organoborons exhibit tunable solid-state emission colors that cover the whole visible region from blue to red. The emission color can be tuned through the substituents on either quinolines or the boron center. © The Royal Society of Chemistry 2015.

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Chemical Communications

Highly emissive organic solids with remarkably broad color tunability based on N,C-chelate, four-coordinate organoborons

In biological oxidations, the intermediate FeV(O)(OH) has been proposed to be the active species for catalyzing the epoxidation of alkenes by nonheme iron complexes. However, no study has been reported yet that elucidates the mechanism of direct O-atom transfer during the reaction of FeV(O) with alkenes to form the corresponding epoxide. For the first time, we study the mechanism of O-atom transfer to alkenes using the FeV(O) complex of biuret-modified Fe-TAML at room temperature. The second-order rate constant (k2) for the reaction of different alkenes with FeV(O) was determined under single-turnover conditions. An 8000-fold rate difference was found between electron-rich (4-methoxystyrene; k2 = 216 M-1 s-1) and electron-deficient (methyl trans-cinnamate; k2 = 0.03 M-1 s-1) substrates. This rate difference indicates the electrophilic character of FeV(O). The use of cis-stilbene as a mechanistic probe leads to the formation of both cis- and trans-stilbene epoxides (73:27). This suggests the formation of a radical intermediate, which would allow C-C bond rotation to yield both stereoisomers of stilbene-epoxide. Additionally, a Hammett ρ value of -0.56 was obtained for the para-substituted styrene derivatives. Detailed DFT calculations show that the reaction proceeds via a two-step process through a doublet spin surface. Finally, using biuret-modified Fe-TAML as the catalyst and NaOCl as the oxidant under catalytic conditions epoxide was formed with modest yields and turnover numbers. (Graph Presented). © 2015 American Chemical Society.

Inorganic Chemistry

Mechanism of Oxygen Atom Transfer from FeV(O) to Olefins at Room Temperature

The presence of an FeV(O) species has been postulated as the active intermediate for the oxidation of both C-H and C=C bonds in the Rieske dioxygenase family of enzymes. Understanding the reactivity of these high valent iron-oxo intermediates, especially in an aqueous medium, would provide a better understanding of these enzymatic reaction mechanisms. The formation of an FeV(O) complex at room temperature in an aqueous CH3CN mixture that contains up to 90% water using NaOCl as the oxidant is reported here. The stability of FeV(O) decreases with increasing water concentration. We show that the reactivity of FeV(O) toward the oxidation of C-H bonds, such as those in toluene, can be tuned by varying the amount of water in the H2O/CH3CN mixture. Rate acceleration of up to 60 times is observed for the oxidation of toluene upon increasing the water concentration. The role of water in accelerating the rate of the reaction has been studied using kinetic measurements, isotope labeling experiments, and density functional theory (DFT) calculations. A kinetic isotope effect of ∼13 was observed for the oxidation of toluene and d8-toluene showing that C-H abstraction was involved in the rate-determining step. Activation parameters determined for toluene oxidation in H2O/CH3CN mixtures on the basis of Eyring plots for the rate constants show a gain in enthalpy with a concomitant loss in entropy. This points to the formation of a more-ordered transition state involving water molecules. To further understand the role of water, we performed a careful DFT study, concentrating mostly on the rate-determining hydrogen abstraction step. The DFT-optimized structure of the starting FeV(O) and the transition state indicates that the rate enhancement is due to the transition states favored stabilization over the reactant due to enhanced hydrogen bonding with water. © 2015 American Chemical Society.

Tuning the reactivity of FeV(O) toward C-H bonds at room temperature: Effect of water

The concept of encapsulation of ultra small clusters within silica evolved as a means to address the sintering of active metal nanoparticles and subsequent deactivation observed in supported noble metal catalysts. It is hypothesised that sintering, which mainly occurs due to mobility of metal species on the support surfaces, can be minimised if the growth and movement of metal nanoparticles are constrained. First, nanoparticles are isolated inside 1D channels in 2D mesoporous compounds and the idea develops to complete encapsulation of thiol protected ultra small nanoclusters in silica spheres. Sintering is better controlled in the latter due to the confined space for growth of nanoparticles. Access of reactant molecules to the active metal surfaces also is ensured by porosity created in the silica matrix forming the basis of the concept of nanoreactors. In this paper, we elaborate on the evolution of this concept from our earlier work on highly sinter resistant silica encapsulated Au, Pd and Au-Pd alloys to the present system of Ag-Pd alloy encapsulated in silica. Silver, with the lowest Tammann temperature among noble metals, is highly prone to sintering which is adequately controlled by alloying with Pd as well as encapsulation in silica. Its enhanced activity in paranitrophenol reduction in comparison with pure metals indicates the advantageous effect of alloying. © 2014 Elsevier B.V. All rights reserved.

Catalysis Today

Encapsulation of ultra small metal clusters in silica: Evolution of the concept of nanoreactors and the case of Ag-Pd@SiO2 alloy catalyst

Potassium tert-butoxide acts as a nucleophilic oxygen source during the hydration of nitriles to give the corresponding amides under anhydrous conditions. The reaction proceeds smoothly for a broad range of substrates under mild conditions, providing an efficient and economically affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an ionic mechanism have been proposed for the hydration process.

Journal of Organic Chemistry

Transition-metal-free hydration of nitriles using potassium tert -butoxide under anhydrous conditions

Selective oxidation of alcohol to its corresponding carbonyl compound is an important chemical process in biological as well as industrial reactions. The heme containing enzyme CytP450 has been known to selectively oxidize alcohols to their corresponding carbonyl compounds. The mechanism of this reaction, which involves high-valent FeIV(O)-porphyrin•+ intermediate with alcohol, has been well-studied extensively both with the native enzyme and with model complexes. In this paper, we report for the first time the mechanistic insight of alcohol oxidation with FeV(O) complex of biuret TAML (bTAML), which is isoelectronic with FeIV(O)-porphyrin•+ intermediate form in CytP450. The oxidations displayed saturation kinetics, which allowed us to determine both the binding constants and first-order rate constants for the reaction. The K and k values observed for the oxidation of benzyl alcohol by FeV(O) at room temperature (K = 300 M-1, k = 0.35 s-1) is very similar to that obtained by CytP450 compound I at -50 °C (K = 214 M-1, k = 0.48 s-1). Thermodynamic parameters determined from van't Hoff's plot (ΔH∼ -4 kcal/mol) suggest hydrogen bonding interaction between substrate and bTAML ligand framework of the FeV(O) complex. Analysis of H/D KIE (kH/kD ∼ 19 at 303 K), Hammett correlation and linearity in Bell-Evans-Polyanski plot points to the C-H abstraction as the rate determination step. Finally, experiments using FeV(O18) for benzyl alcohol oxidation and use of the "radical clock" cyclobutanol as a substrate shows the absence of a rebound mechanism as is observed for CytP450. Instead, an ET/PT process is proposed after C-H abstraction leading to formation of the aldehyde, similar to what has been proposed for the heme and nonheme model compounds. © 2015 American Chemical Society.

Mechanism of Alcohol Oxidation by FeV(O) at Room Temperature

Examination of protein structure at the subatomic level is required to improve the understanding of enzymatic function. For this purpose, X-ray diffraction data have been collected at 100K from cholesterol oxidase crystals using synchrotron radiation to an optical resolution of 0.94Å. After refinement using the spherical atom model, nonmodelled bonding peaks were detected in the Fourier residual electron density on some of the individual bonds. Well defined bond density was observed in the peptide plane after averaging maps on the residues with the lowest thermal motion. The multipolar electron density of the protein-cofactor complex was modelled by transfer of the ELMAM2 charge-density database, and the topology of the intermolecular interactions between the protein and the flavin adenine dinucleotide (FAD) cofactor was subsequently investigated. Taking advantage of the high resolution of the structure, the stereochemistry of main-chain bond lengths and of C=O⋯H - N hydrogen bonds was analyzed with respect to the different secondary-structure elements.

Acta Crystallographica Section D: Biological Crystallography

Cholesterol oxidase: Ultrahigh-resolution crystal structure and multipolar atom model-based analysis

Malaria a global pandemic has engulfed nearly 0.63 million people globally. It is high time that a cure for malaria is required to stop its ever increasing menace. Our commentary discusses the advent and contribution of diversity oriented synthesis (DOS) in the drug discovery efforts towards developing cure for malaria. DOS based on chemical genetics focusses on design and synthesis of molecular libraries which covers large tracts of biologically relevant chemical space. Herein we will discuss the applications, advantages, disadvantages and future directions of DOS with respect to malaria. © 2015, Springer Science+Business Media Dordrecht.

Systems and Synthetic Biology

Diversity oriented synthesis for novel anti-malarials

Abstract Herein we have reported design, synthesis and in vitro biological evaluation of a library of bicyclic lactams that led to the discovery of compounds 6 and 7 as a novel class of α-glucosidase inhibitors. They inhibited α-glucosidase (yeast origin) in a mixed type of inhibition with an IC50 of ∼150 nM. Molecular docking studies further substantiated screening results. Interestingly phenotypic screening of this library against the human malaria parasite revealed 7 as a potent antiplasmodial agent. © 2015 Elsevier Masson SAS.

Life Sciences

European Journal of Medicinal Chemistry

Design, synthesis and biological evaluation of small molecules as potent glucosidase inhibitors

The global preponderance of diabetes mellitus has prompted the medical community to opt for various therapeutic solutions to curb this menace. One of the means involved controlling the post prandial hyperglycemia. α-Glucosidase inhibitors are known to be excellent agents for controlling postprandial hyperglycemia. Different classes of α-glucosidase inhibitors have been discovered. In this context, a diverse library of substituted furopyridinediones (12a-v) was designed as potential inhibitors of α-glucosidase, using an intuitive scaffold hopping approach (which was further rationalized by molecular docking). They were synthesized in one step via an aldol condensation reaction of the furopyridinedione scaffold and appropriate aldehydes. The compounds were screened against α-glucosidase using acarbose as the reference inhibitor. Among the screened compounds, 12p transpired to be the lead candidate with an IC50 of 0.24 μM. Lineweaver-Burke analysis of 12p indicated that it is a mixed inhibitor. X-ray crystallography of 12p further confirmed its structure. Molecular modelling studies and molecular dynamic simulation experiments were performed against a homology model of α-glucosidase to observe the binding interaction of 12p with the enzymes. © The Royal Society of Chemistry 2015.