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

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

2. Metal-Oxo Centers: Bonding Fundamentals
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.
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 Trigonal BipryamidalTetrahedral
d-Orbital Arrangements
σ anti-bonding
π anti-bonding
non bonding
π anti-bonding
σ anti-bonding
non bonding
σ anti-bonding
non-bonding
π anti-bonding
Energy
Bond order = (# electrons in bonding orbitals – # electrons in anti-bonding orbitals) / 2
Bond order = 3 Bond order = 3 Bond order = 2

3. Metal-Oxo Centers in Biology: Cytochrome P450
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.
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.
Structure of the iron-oxo complex in the
active site of cytochrome P450.
Proposed mechanism for C–H bond functionalization
by cytochrome P450 enzymes.
Selective hydroxylation of progesterone by cytochrome
P450 17A1 during the biosynthesis of steroid hormones.

4. Metal-Oxo Centers in Biology: Non-Heme Enzymes
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.
Bicyclization reaction perfomed
by isopenicillin-N synthase.
Hydroxylation of proline by prolyl-4-hydroxylase
in the post-translational modification of proteins.

5. Metal-Oxo Centers in Synthetic Chemistry
Kaizer, J. et al. J. Am. Chem. Soc. 2004, 126, 472-473.
Taguchi, T. et al. J. Am. Chem. Soc. 2012, 134, 1996-1999.
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
[MnVH3buea(O)]–
[FeIV(O)(N4Py)]2+
EnergyEnergy
σ*
π*
nb
nb
π*
σ*
C–H bond activation reactions performed by
the Fe(IV)–oxo complex [FeIV(O)(N4Py)]2+.

6. Problems
1. Determine the bond order for an octahedral metal-oxo complex whose d-orbital arrangement is shown
below and that contains:
a) 0 d-electrons
b) 4 d-electrons
c) 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?
Energy
π anti-bonding
σ anti-bonding
non bonding

7. Problems
Hashimoto, H. et al, Nature 2014, 506, 391-395.
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.

8. Metal-Oxo Centers in Biology: α-Ketoglutarate dependent dioxygenases
Biochemistry 2003, 42, 7497-7508. Hashimoto, H. et. al, Nature 2014, 506, 391-395.
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.
Structure of the iron complex in the active
site of taurine dioxygenase before formation
of the reactive Fe(IV)–oxo species.
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.

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