Valence Tautomerism in a High-Valent Manganese-Oxo Porphyrinoid Complex Induced by a Lewis Acid
ABSTRACT Addition of the Lewis acid Zn(2+) to (TBP(8)Cz)Mn(V)(O) induces valence tautomerization, resulting in the formation of [(TBP(8)Cz(+•))Mn(IV)(O)-Zn(2+)]. This new species was characterized by UV-vis, EPR, the Evans method, and (1)H NMR and supported by DFT calculations. Removal of Zn(2+) quantitatively restores the starting material. Electron-transfer and hydrogen-atom-transfer reactions are strongly influenced by the presence of Zn(2+).
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- "Although these QM-cluster calculations in many cases were able to reproduce experimentally determined product distributions, kinetic isotope effects and rate constants as well as spectroscopic features of key stable intermediates (Kumar et al., 2005; Vardhaman et al., 2011, 2013a,b), we cannot be certain that the methodology will also work on an enzyme such as a cysteine protease. In particular, QM/MM studies on these enzymatic systems showed that in many cases the active features were sufficient to describe the enzyme accurately (Godfrey et al., 2008; Porro et al., 2009; Kumar et al., 2011b), but in cases where the active species has close lying electronic states environmental perturbations were shown to change the electronic properties of the reactant and consequently the reactivity patterns (Ogliaro et al., 2000; de Visser et al., 2002; Leeladee et al., 2012). We anticipated similar problems in the current system, where strong polar interactions influenced the reaction kinetics, therefore, a combined DFT and QM/MM approach was applied. "
ABSTRACT: Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density functional theory and quantum mechanics/molecular mechanics study on the reaction of a nitrile-based inhibitor with the enzyme active site amino acids. We show here that small perturbations to the inhibitor structure can have dramatic effects on the catalysis and inhibition processes. Thus, we investigated a range of inhibitor templates and show that specific structural changes reduce the inhibitory efficiency by several orders of magnitude. Moreover, as the reaction takes place on a polar surface, we find strong differences between the DFT and QM/MM calculated energetics. In particular, the DFT model led to dramatic distortions from the starting structure and the convergence to a structure that would not fit the enzyme active site. In the subsequent QM/MM study we investigated the use of mechanical vs. electronic embedding on the kinetics, thermodynamics and geometries along the reaction mechanism. We find minor effects on the kinetics of the reaction but large geometric and thermodynamics differences as a result of inclusion of electronic embedding corrections. The work here highlights the importance of model choice in the investigation of this biochemical reaction mechanism.Frontiers in Chemistry 12/2013; 1:39. DOI:10.3389/fchem.2013.00039
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ABSTRACT: Multiple transition metal functional groups including metaloxo, hydroxo, and hydroperoxide groups play significant roles in various biological and chemical oxidations such as electron transfer, oxygen transfer, and hydrogen abstraction. Further studies that clarify their oxidative relationships and the relationship between their reactivity and their physicochemical properties will expand our ability to predict the reactivity of the intermediate in different oxidative events. As a result researchers will be able to provide rational explanations of poorly understood oxidative phenomena and design selective oxidation catalysts. This Account summarizes results from recent studies of oxidative relationships among manganese(IV) molecules that include pairs of hydroxo/oxo ligands. Changes in the protonation state may simultaneously affect the net charge, the redox potential, the metal-oxygen bond order (M-O vs M═O), and the reactivity of the metal ion. In the manganese(IV) model system, [Mn(IV)(Me(2)EBC)(OH)(2)](PF(6))(2), the Mn(IV)-OH and Mn(IV)═O moieties have similar hydrogen abstraction capabilities, but Mn(IV)═O abstracts hydrogen at a more than 40-fold faster rate than the corresponding Mn(IV)-OH. However, after the first hydrogen abstraction, the reduction product, Mn(III)-OH(2) from the Mn(IV)-OH moiety, cannot transfer a subsequent OH group to the substrate radical. Instead the Mn(III)-OH from the Mn(IV)═O moiety reforms the OH group, generating the hydroxylated product. In the oxygenation of substrates such as triarylphosphines, the reaction with the Mn(IV)═O moiety proceeds by concerted oxygen atom transfer, but the reaction with the Mn(IV)-OH functional group proceeds by electron transfer. In addition, the manganese(IV) species with a Mn(IV)-OH group has a higher redox potential and demonstrates much more facile electron transfer than the one that has the Mn(IV)═O group. Furthermore, an increase in the net charge of the Mn(IV)-OH further accelerates its electron transfer rate. But its influence on hydrogen abstraction is minor because charge-promoted electron transfer does not enhance hydrogen abstraction remarkably. The Mn(IV)-OOH moiety with an identical coordination environment is a more powerful oxidant than the corresponding Mn(IV)-OH and Mn(IV)═O moieties in both hydrogen abstraction and oxygen atom transfer. With this full understanding of the oxidative reactivity of the Mn(IV)-OH and Mn(IV)═O moieties, we have clarified the correlation between the physicochemical properties of these active intermediates, including net charge, redox potential, and metal-oxygen bond order, and their reactivities. The reactivity differences between the metal oxo and hydroxo moieties on these manganese(IV) functional groups after the first hydrogen abstraction have provided clues for understanding their occurrence and functions in metalloenzymes. The P450 enzymes require an iron(IV) oxo form rather than an iron(IV) hydroxo form to perform substrate hydroxylation. However, the lipoxygenases use an iron(III) hydroxo group to dioxygenate unsaturated fatty acids rather than an iron(III) oxo species, a moiety that could facilitate hydroxylation reactions. These distinctly different physicochemical properties and reactivities of the metal oxo and hydroxo moieties could provide clues to understand these elusive oxidation phenomena and provide the foundation for the rational design of novel oxidation catalysts.Accounts of Chemical Research 11/2012; 46(2). DOI:10.1021/ar300208z · 24.35 Impact Factor
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ABSTRACT: Redox-inactive metal ions play pivotal roles in regulating reactivities of high-valent metal-oxo species in a variety of enzymatic and chemical reactions. A mononuclear nonheme manganese(IV)-oxo complex bearing a pentadentate N5 ligand has been synthesized and used in the synthesis of a Mn(IV)-oxo complex binding scandium ions. The Mn(IV)-oxo complexes are characterized with various spectroscopic methods. The reactivities of the Mn(IV)-oxo complex are markedly influenced by binding Sc3+ ions in oxidation reactions, such as ~2500-fold increase in the oxidation of thioanisole (i.e., oxygen atom transfer) but ~180-fold decrease in the C-H bond activation of 1,4-cyclohexadiene (i.e., hydrogen atom transfer). The present results provide the first example of a nonheme Mn(IV)-oxo complex binding redox-inactive metal ions that shows a contrasting effect of redox-inactive metal ions on the reactivities of metal-oxo species in the oxygen atom transfer and hydrogen atom transfer reactions.Journal of the American Chemical Society 01/2013; 135(17). DOI:10.1021/ja312113p · 11.44 Impact Factor