Oxidative Aliphatic Carbon-Carbon Bond Cleavage Reactions

The work presented in this dissertation has focused on synthesizing complexes of relevance to dioxygenase enzymes that oxidatively cleave aliphatic carbon-carbon bonds. The goal of this research was to elucidate mechanistic aspects of the activation of aliphatic carbon-carbon bonds towards cleavage by reaction with oxygen, and also investigate the regioselectivity of these reactions. The oxidative cleavage of a variety of enolizable substrates has been explored by utilizing several transition metal complexes supported by an aryl-appended tris(pyridylmethyl)amine ligand. In order to probe the widely-accepted “chelate hypothesis” for how changes in regiospecificity are achieved as a function of metal ion, we synthesized the compound [(6Ph2TPA)Fe(PhC(O)COHC(O)Ph)]OTf. Based on UV-vis and IR spectroscopy, the acireductone enolate was found to bind via a six-membered chelate ring. By comparison with the reactivity of [(6Ph2TPA)Ni(PhC(O)COHC(O)Ph)]ClO4, we determined that the chelate hypothesis was an insufficient explanation of the observed regioselectivity. Rather, ferrous ion-mediated hydration of a vicinal triketone intermediate was the key factor in determining the regioselectivity of the C-C cleavage reaction. We have developed a high-yielding synthetic route to protected precursors of C(1)H acireductones. Preparation of the complexes [(6Ph2TPA)M(PhC(O)COCHOC(O)CH3)]ClO4 (M = Fe, Ni) followed by judicious choice of deprotecting conditions allowed us to investigate the oxygen reactivity of a mono-nuclear complex with a dianionic acireductone substrate for the first time. This provides a promising strategy to continue investigations of complexes of relevance to the enzyme- substrate adduct of the acireductone dioxygenases. Divalent late first-row transition metal complexes have been used to investigate some new strategies for the activation of dioxygen and subsequent cleavage of C-C bonds. We have utilized photoreduction of a Ni(II) center to generate a highly O2-reactive Ni(I) fragment that leads to cleavage of a chloro-diketonate substrate. Additionally, we have found a Cu(II)-mediated thermal cleavage of chloro-diketonate substrates at room temperature. This reaction is interestingly accelerated by the addition of a catalytic amount of chloride ion

Regioselective Aliphatic Carbon–Carbon Bond Cleavage by a Model System of Relevance to Iron-Containing Acireductone Dioxygenase

Mononuclear Fe­(II) complexes ([(6-Ph₂TPA)­Fe­(PhC­(O)­C­(R)­C­(O)­Ph)]­X (<b>3-X</b>: R = OH, X = ClO₄ or OTf; <b>4</b>: R = H, X = ClO₄)) supported by the 6-Ph₂TPA chelate ligand (6-Ph₂TPA = <i>N</i>,<i>N</i>-bis­((6-phenyl-2-pyridyl)­methyl)-<i>N</i>-(2-pyridylmethyl)­amine) and containing a β-diketonate ligand bound via a six-membered chelate ring have been synthesized. The complexes have all been characterized by ¹H NMR, UV–vis, and infrared spectroscopy and variably by elemental analysis, mass spectrometry, and X-ray crystallography. Treatment of dry CH₃CN solutions of <b>3-OTf</b> with O₂ leads to oxidative cleavage of the C(1)–C(2) and C(2)–C(3) bonds of the acireductone via a dioxygenase reaction, leading to formation of carbon monoxide and 2 equiv of benzoic acid as well as two other products not derived from dioxygenase reactivity: 2-oxo-2-phenylethylbenzoate and benzil. Treatment of CH₃CN/H₂O solutions of <b>3-X</b> with O₂ leads to the formation of an additional product, benzoylformic acid, indicative of the operation of a new reaction pathway in which only the C(1)–C(2) bond is cleaved. Mechanistic studies show that the change in regioselectivity is due to the hydration of a vicinal triketone intermediate in the presence of both an iron center and water. This is the first structural and functional model of relevance to iron-containing acireductone dioxygenase (Fe-ARD′), an enzyme in the methionine salvage pathway that catalyzes the regiospecific oxidation of 1,2-dihydroxy-3-oxo-(<i>S</i>)-methylthiopentene to form 2-oxo-4-methylthiobutyrate. Importantly, this model system is found to control the regioselectivity of aliphatic carbon–carbon bond cleavage by changes involving an intermediate in the reaction pathway, rather than by the binding mode of the substrate, as had been proposed in studies of acireductone enzymes

CCDC 866629: Experimental Crystal Structure Determination

Related Article: K.Grubel, A.R.Marts, S.M.Greer, D.L.Tierney, C.J.Allpress, B.J.Laughlin, R.C.Smith, A.M.Arif, L.M.Berreau|2012|Eur.J.Inorg.Chem.||4750|doi:10.1002/ejic.201200212,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

High-Energy-Resolution Fluorescence-Detected X‑ray Absorption of the Q Intermediate of Soluble Methane Monooxygenase

Kα high-energy-resolution fluorescence detected X-ray absorption spectroscopy (HERFD XAS) provides a powerful tool for overcoming the limitations of conventional XAS to identify the electronic structure and coordination environment of metalloprotein active sites. Herein, Fe Kα HERFD XAS is applied to the diiron active site of soluble methane monooxygenase (sMMO) and to a series of high-valent diiron model complexes, including diamond-core [Fe^IV₂(μ-O)₂(L)₂]­(ClO₄)₄] (<b>3</b>) and open-core [(OFe^IV–O–Fe^IV(OH)­(L)₂]­(ClO₄)₃ (<b>4</b>) models (where, L = tris­(3,5-dimethyl-4-methoxypyridyl-2-methyl)­amine) (TPA*)). Pronounced differences in the HERFD XAS pre-edge energies and intensities are observed for the open versus closed Fe₂O₂ cores in the model compounds. These differences are reproduced by time-dependent density functional theory (TDDFT) calculations and allow for the pre-edge energies and intensity to be directly correlated with the local active site geometric and electronic structure. A comparison of the model complex HERFD XAS data to that of MMOH_Q (the key intermediate in methane oxidation) is supportive of an open-core structure. Specifically, the large pre-edge area observed for MMOH_Q may be rationalized by invoking an open-core structure with a terminal Fe^IVO motif, though further modulations of the core structure due to the protein environment cannot be ruled out. The present study thus motivates the need for additional experimental and theoretical studies to unambiguously assess the active site conformation of MMOH_Q

Halide-Promoted Dioxygenolysis of a Carbon–Carbon Bond by a Copper(II) Diketonate Complex

A mononuclear Cu­(II) chlorodiketonate complex was prepared, characterized, and found to undergo oxidative aliphatic carbon–carbon bond cleavage within the diketonate unit upon exposure to O₂ at ambient temperature. Mechanistic studies provide evidence for a dioxygenase-type C–C bond cleavage reaction pathway involving trione and hypochlorite intermediates. Significantly, the presence of a catalytic amount of chloride ion accelerates the oxygen activation step via the formation of a Cu–Cl species, which facilitates monodentate diketonate formation and lowers the barrier for O₂ activation. The observed reactivity and chloride catalysis is relevant to Cu­(II) halide-catalyzed reactions in which diketonates are oxidatively cleaved using O₂ as the terminal oxidant. The results of this study suggest that anion coordination can play a significant role in influencing copper-mediated oxygen activation in such systems