Bio-Inspired Metal-Oxo Catalysts for C–H Bond Functionalization A.S. Borovik and Sarah Cook University of California-Irvine

Metal-Oxo Centers: Bonding Fundamentals Overview: Metal-oxo complexes are important species in the activation of strong C–H bonds in biological systems. The high reactivity of metal-oxo complexes results from the way their valence electrons are arranged, and this arrangement depends strongly on the geometry around the metal center. All metal-oxo species contain multiple bonds: one σ bond and at least one π bond that comes from donation of electrons on the oxygen atom into empty orbitals on the metal center. This donation causes the oxo ligand to be electrophilic. Geometric Configurations Octahedral Tetrahedral Trigonal Bipryamidal d-Orbital Arrangements σ anti-bonding π anti-bonding σ anti-bonding σ anti-bonding non-bonding Energy π anti-bonding non bonding non bonding π anti-bonding Bond order = 3 Bond order = 3 Bond order = 2 Bond order = (# electrons in bonding orbitals – # electrons in anti-bonding orbitals) / 2 Wiki Pages: https://en.wikipedia.org/wiki/Oxo_ligand Other References: Borovik, A.S. Chem. Soc. Rev. 2011, 40, 1870-1874. Gunay, A., K. H. Theopold Chem. Rev. 2010, 110, 1060-1081.

Metal-Oxo Centers in Biology: Cytochrome P450 The electrophilicity of the oxo ligand increases as the metal center loses electrons. As a result, the active oxidizing species in many biological enzymes often contain metal centers in the +4 or +5 oxidation state. This increased electrophilicity allows the metal-oxo species to react with thermodynamically strong C–H bonds via abstraction of an H-atom (H•) to generate a radical on the organic substrate. Proposed mechanism for C–H bond functionalization by cytochrome P450 enzymes. Structure of the iron-oxo complex in the active site of cytochrome P450. Selective hydroxylation of progesterone by cytochrome P450 17A1 during the biosynthesis of steroid hormones. R. R. Ortiz de Montellano, Chem. Rev. 2010, 110, 932–948; J. Rittle and M. T. Green, Science, 2010, 330, 933-937. Haider S, Patel J, Poojari C, Neidle S, J. Mol. Biol. 2010, 400, 1078-1098.

Metal-Oxo Centers in Biology: Non-Heme Enzymes Bicyclization reaction perfomed by isopenicillin-N synthase. Hydroxylation of proline by prolyl-4-hydroxylase in the post-translational modification of proteins. Baggaley, K. H., Brown A. G., Schofield C. J., Nat. Prod.Rep., 1997, 14, 309–333.; Baldwin, J. E., Bradley, M. Chem. Rev. 1990, 90, 1079-1088.; Gorres, K. L., Raines, R. T., Crit. Rev. Biochem. Mol. Biol. 2010, 45, 106-124.

Metal-Oxo Centers in Synthetic Chemistry The high reactivity of the metal-oxo species in biological enzymes with strong C–H bonds provides motivation for synthetic inorganic chemists to develop systems that allow similar metal-oxo complexes to be generated σ* Energy π* nb [FeIV(O)(N4Py)]2+ σ* nb Energy C–H bond activation reactions performed by the Fe(IV)–oxo complex [FeIV(O)(N4Py)]2+. π* [MnVH3buea(O)]– Kaizer, J. et al. J. Am. Chem. Soc. 2004, 126, 472-473. Taguchi, T. et al. J. Am. Chem. Soc. 2012, 134, 1996-1999.

Problems Determine the bond order for an octahedral metal-oxo complex whose d-orbital arrangement is shown below and that contains: 0 d-electrons 4 d-electrons 6 d-electrons If all metal-oxo compounds must contain multiple bonds (have a bond order of 2 or more), could a metal- oxo complex be prepared for the above electron counts in octahedral symmetry? σ anti-bonding Energy π anti-bonding non bonding

Problems 2. Draw an arrow-pushing mechanism for how the iron(IV)-oxo compound in the enzyme ten-eleven translocation dioxygenase reacts with 5-methylcytosine to form 5-hydroxymethylcytosine during the repair of damaged DNA. Hashimoto, H. et al, Nature 2014, 506, 391-395.

Metal-Oxo Centers in Biology: α-Ketoglutarate dependent dioxygenases The electrophilicity of the oxo ligand increases as the metal center loses electrons. As a result, the active oxidizing species in many biological enzymes often contain metal centers in the +4 or +5 oxidation state. This allows the metal-oxo species to react with strong C–H bonds via abstraction of an H atom (H•) to generate a radical on the organic substrate. Reaction of the Fe(IV)–oxo species in taurine dioxygenase with the substrate taurine. 5-methylcytosine is hydroxylated by ten-eleven translocation dioxygenase in a step of the repair of damaged DNA. Structure of the iron complex in the active site of taurine dioxygenase before formation of the reactive Fe(IV)–oxo species. Biochemistry 2003, 42, 7497-7508. Hashimoto, H. et. al, Nature 2014, 506, 391-395.

Contributed by: A.S. Borovik and Sarah Cook University of California-Irvine, 2014