1Literature Seminar

Bio-inspired C-H functionalization
by metal-oxo complexes

2016. 7. 23.
Nagashima Nozomu

2C-H functionalization by enzymes

Enzymes enable aliphatic C-H functionalization

3P450 oxidation mechanism

Cytochrome P450

Reactive Oxygen Cytochrome P450 makes reactive oxygen species.
 P450 can activate aliphatic C-H Bond.
Dawson, J. H. et al. Chem. Rev. 1996, 96, 2841.

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These enzymes functions can be mimicked?

Today’s topic: Make enzyme-like reaction by metal catalysts

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1. Why nature uses Fe for
C-H functionalization?

6Spin chemistry and reactivity
 Exchange interactions
Interactions between two electrons whose spins are parallel.

EnergyMetal’s spin state depends on1) Orbital energies2) Exchange interaction

7Exchange Interaction
 Table of metal’s exchange interaction

 As the atom size shrinks, the average electron-electron distancedecreases and the exchange interaction increases.
 Cr, Mn, Fe, Co, and Ni show high exchange interaction and theyshow high reactivity.

Shaik, S. et al. Nat. Chem. 2011, 3, 19.

8Non-heam Fe = O species spin state Interaction of d orbitals in tetra-coordinated metal

dxy < dxz, yz < dx2-y2 < dz2Energy

 Triplet and quintet state of iron-oxo species

Fe can make two states, S = 1 triplet and S = 2 quintet.
Both states are related to the high reactivity of iron-oxo species.
Shaik, S. et al. Acc. Chem. Res. 2007, 40, 532.

9C-H abstraction by non-heam ironExchange interaction stabilizes transition state of S = 2.
S = 2 can cleave C-H bonds easily.

Shaik, S. et al. J. Am. Chem. Soc. 2006, 128, 8590.
Shaik, S. et al. Nat. Chem. 2011, 3, 19.

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C-H abstraction by ruthenium

1. The exchange interaction of ruthenium is lower than that of iron
2. Ruthenium binds to ligand more strongly than iron
→ d orbitals are more delocalized and raise S = 2 state.
Han, K. et al. J. Biol. Inorg. Chem. 2010, 351.
Shaik, S. et al. Nat. Chem. 2011, 3, 19.

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2. Oxygen atom transfer by iron-oxo species

12Target reaction by metal catalysts

Epoxidation and hydroxylation should be achieved by using
tetra-coordinated or tri-coordinated metal catalysts

13Alkene epoxidation by Fe(mep)(CH3CN)2

mep: N,N’-dimethyl-N,N’-bis(2-pyridylmethyl)-ethane,1,2-diamine
Jacobsen, E. N. et al. J. Am. Chem. Soc. 2001, 123, 7194.

14Fe(mep)(CH3CN)2 activation by acetic acid1) The addition of acid promotes O-O bond cleavage.
2) Ligand structure enables both generation of FeV=O
species and activation of Fe.
3) Pyridine ring also interacts with H2O2 and promotes
O-O bond cleavage.

Jacobsen, E. N. et al. J. Am. Chem. Soc. 2001, 123, 7194.
Que-Jr. L. et al. J. Am. Chem. Soc. 2007, 129, 15964.
Nishida, Y. et al. Dalton Trans. 1997, 3547.

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Ligand structure of Iron for C-H functionalization

mep: Jacobsen’s iron ligand

Most reactive

They showed the rigidity and the stabilization of cis-a (twist) complex
were important in C-H functionalization
White, A. J. P. et al. Inorg. Chem. 2007, 46, 3752.

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C-H hydroxylation by Iron catalyst White’s new iron catalyst enabled C-H hydroxylation highly selectively.
 Selectivity increased by the inhibition of decomposition of catalysts.
White, M. C. et al. Science. 2007, 318, 783.

17C-H hydroxylation of tertiary alcohols

Fe(S,S-PDP)(CH3CN)2 promoted C-H oxidation 1) electron-richor 2) sterically accessible site selectively.

White, M. C. et al. Science. 2007, 318, 783.

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Methylene oxidation by White’s catalysts

White, M. C. et al. Science. 2010, 327, 566.

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C-H bond oxidations of terpenoids

 It enabled C-H oxidation sterically accessible and electron-rich position selectively.
 Methylene selectivity was sometimes not perfect because it depended on thesubstrate structures.
White, M. C. et al. Science. 2010, 327, 566.

20Bulky catalyst controlled site-selective oxidation

Bulky catalyst enabled
the activation of lesshindered methylene bondselectively.

White, M. C. et al. J. Am. Chem. Soc.
2013, 135, 14052.

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C-H functionalization by iron catalyst

They enabled C-H epoxidation and hydroxylation

How about other functionalization by metal-oxo species??

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3. Various C-H functionalization
by manganese-oxo complexes

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C-H abstraction and oxygen transfer to toluene by heam manganese Hydrogen atom abstraction
starts from S = 1 state, butboth S=1 and S=2 showhigh reactivity in oxygen
atom transfer.
Eisenstein, O. et al. Chem. Commun. 2008, 744.

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C-H halogenation by metal-oxo species

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C-H halogenation by metal-oxo species

By trapping R・ radical, C-H halogenation should be achieved.

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C-H chlorination by heam manganese

Groves, J. T. et al. J. Am. Chem. Soc. 2010, 132, 12847.

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Reaction mechanism

Groves, J. T. et al. J. Am. Chem. Soc. 2010, 132, 12847.
dioxo Mn(V): Groves, J. T. et al. J. Am. Chem. Soc. 2007, 129, 12416.

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Axial ligands effect Electron-donating axial ligand leads to radicalrearranged products.

Groves, J. T. et al. Acc. Chem. Res. 2015, 48, 1727.

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EnergyAxial ligands effect for radical character

Decreasing axial donation
Ray, K. et al. Angew. Chem. Int. Ed. 2016, 55, 7632.

 OH- and OCl- made long-lived radical intermediate30

Methylene selectivity of chlorination

Mn catalyst which has bulky substituents showed the selective chlorination to lesshindered methylene position.

Groves, J. T. et al. J. Am. Chem. Soc. 2010, 132, 12847.

31Strategy for fluorination

 Strategy 1 failed (The reason was not mentioned in paper.) By using long-lived radical intermediate, strategy 2 should be achieved.

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C-H fluorination by heam manganese

Groves, J. T. et al. Science 2012, 337, 1322.

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Reaction mechanism of fluorination
 Catalytic cycle

 Axial ligand controlled thereactivity of Mn-porphyrin.

 Energy landscape for F rebound The axial ligand of F makes the Frebound barrier lower.
Groves, J. T. et al. Science 2012, 337, 1322.

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C-H azidation by Mn-catalysts

Groves, J. T. et al. J. Am. Chem. Soc. 2015, 137, 5300.

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4. Summary

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Summary
1. C-H hydroxylation by iron catalyst

2. C-H functionalization by manganese catalyst

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Future prospects

Use as radical initiator through C-H activation.
White, M. C. et al. Nat. Chem. 2011, 3, 216.

These various catalyst can activate different C-Hbond and can be used as different radical initiator.

38Appendix

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C-H abstraction by heam iron

Iron shows high reactivity.

Shaik, S. et al. J. Am. Chem. Soc. 2006, 128, 8590.
Shaik, S. et al. Nat. Chem. 2011, 3, 19.

40Axial ligand and HAA, OAT

Ray, K. et al. Angew. Chem. Int. Ed. 2016, 55, 7632.

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Manganese reactivity

Wonwoo, N. et al. Chem. Eur. J. 2009, 15, 11482.

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Radical feature

Rearranged products indicated a long-lived radical intermediate.

43Rieske non-heam Iron species