N-Oxy Radical Chemistry- Toward Application for Efficient Catalysis -Literature Seminar
Shogo HASHIZUME (D1)‘12. 7. 2. (Mon.)1

Today’s Contents
1. Fundamentals of N-Oxy Radical Species
2. Aminoxyl Radical-Mediated Reactions
3. Imidoxyl Radical-Mediated Reactions
4. Iminoxyl Radical-Mediated Reactions
5. Perspectives– For exploration of novel & efficient N-oxy radical catalysis

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Today’s Contents
1. Fundamentals of N-Oxy Radical Species
2. Aminoxyl Radical-Mediated Reactions
3. Imidoxyl Radical-Mediated Reactions
4. Iminoxyl Radical-Mediated Reactions
5. Perspectives– For exploration of novel & efficient N-oxy radical catalysis

31. Fundamentals

Why N-OHs Generate Radicals ??
Radical = Subvalent compounds

Hicks, R. G.
Org. Biomol. Chem. 2007, 5, 1321.

one less bond than principle of general valency
Radical states is generally reactive and difficult to generate
But, some radicals are stable to isolate or generatable although transient.
Due to…

- Delocalization of unpaired electron by conjugation- Steric shielding of unpaired electron
Stability of N-oxy radical owes much todelocalization of the unpaired electron over N-O bond.
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1. Fundamentals

What Makes N-Oxy Radical Stable ??
Factors to stabilize the radical state:
1. Enough conjugation with N’s lone pair

- Conformational advantage for conjugation
Conjugation is not reduced
by steric freedom- Varied stabilities depending on N’s electron density51. Fundamentals

What Makes N-Oxy Radical Stable ??
Factors to stabilize the radical state:
2. Structure NOT to cause self-decomposition- More one-electron oxidation to afford nitrone
N-O radical having
a-proton is unstable- Radicalic dimerization

61. Fundamentals

Considering Bond-Dissociation-Energy (BDE)
Bond-Dissociation-Energy (BDE)= Enthalpy change when a bond is cleaved by homolysis

Useful representation of generation & stability of radical
BDEs of some compounds

Blanksby, S. J.; Ellison, G. B.
Acc. Chem. Res. 2003, 36, 255;
and reviews on N-oxy radical

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1. Fundamentals

Classification of N-Oxy Radicals
1. Aminoxyl Radical

2. Imidoxyl/Amidoxyl Radical

3. Iminoxyl Radical

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1. Fundamentals

Aminoxyl Radicals
Bulky/sterically restricted aminoxyl radicals are generally stable & isolable.

TEMPO

Di-tert-butylnitroxylLebedev, Nazarnovskii (1960)

Hoffmann, Hnderson (1960)

One more oxidation of TEMPO affords oxoammonium cation.

Disproportionation occurs under acidic conditions.

91. Fundamentals

Imidoxyl/Amidoxyl Radicals
PINO radical: Not isolated but detected in situ generationaN = 4.36 G : smaller than other N-O
g = 2.0073 : larger than other N-O

These values indicate
strong decrease of spin density on nitrogensmall increase of spin density on oxygen
EWG on N increases BDE = unstable radical state due to decrease of conjugation

Recupero, F. et al. Chem. Rev. 2007, 107, 3800.

101. Fundamentals

Imidoxyl/Amidoxyl Radicals
PINO radical cause self-decomposition
due to its non-persistency (especially high temp.)

PINO often cause H-abstraction because of its unstability.

111. Fundamentals

Iminoxyl Radicals- First identified iminoxyl radicals

Thomas, J. R.
JACS 1964, 86, 1446.

Suggesting generationof oxime radical- Large nitrogen coupling constant
The unpaired e- on N is not in pure 2pz orbital.
(=Having s-radical characteristics?)- cis/trans isomers detected (Fig.1a)Isomerization by conjudation occurs

121. Fundamentals

Iminoxyl Radicals- Isolated stable iminoxyl radicals

Ingold, K. U. et al.
JACS 1971, 93, 5278.

First example ofisolated iminoxyl radical- Carorimetric studies on iminoxyl radicals
Mahoney, L. R.; Ingold, K. U. et al.
JACS 1973, 95, 8610.

Isolablity of stable oxime radical is due to its low BDE.
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1. Fundamentals

What Stabilizes Iminoxyl Radicals ??
Bordwell, F. G.; Zhang, S.-H. et al. JACS 1995, 117, 4858.

Decreasing BDE parallels
increasing the steric hinderance.
Bulkier alkyl group increase
relief of steric strain by loss of H-atom

The steric hinderance effects

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Today’s Contents
1. Fundamentals of N-Oxy Radical Species
2. Aminoxyl Radical-Mediated Reactions
3. Imidoxyl Radical-Mediated Reactions
4. Iminoxyl Radical-Mediated Reactions
5. Perspectives– For exploration of novel & efficient N-oxy radical catalysis

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2. Aminoxyl Radical-Mediated Reactions

Aminoxyl Radical-Mediated Reactions
TEMPO : most popular aminoxyl radical

Stability of the radical state = easy to be oxidized

Useful mediator for redox reaction ??
Main topic = Alcohol oxidation

2-1. Copper-TEMPO catalysis
2-2. Ruthenium-TEMPO catalysis
2-3. Metal-free catalysis
162-0. Early Works of TEMPO Oxidation

Early Works on TEMPO-Mediated Oxidation- With stoichiometric oxoammonium cation- With stoichiometric TEMPO

Golubev, V. A. et al.
Bull. Acad. Sci. USSR, Chem. Ser.
1965, 14, 1898.

Bobbitt, J. M. et al. JOC 1991, 56, 6110.

Oxidation proceed by in situ disproportionation of TEMPO(TEMPO is known to disproportionate at acidic pH.)

Sheldon, R. A. et al.
Adv. Synth. Catal. 2004, 346, 1051.
172-0. Early Works of TEMPO Oxidation

Mechanism of TEMPO-Mediated Oxidation ??
Semmelhack et al. TL 1986, 27, 1119.

Considerable mechanism

Hammet study

Only slight positive charge
at benzylic carbon in RDS

Path b unfavorable

Cyclopropyl carbinol
Path aunfavorable

Via intermediate 4
Path cfavorable??

Which is actual mechanism ??
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2-0. Early Works of TEMPO Oxidation

Mechanism of TEMPO-Mediated Oxidation ??
Semmelhack et al. TL 1986, 27, 1119.

Considerable mechanism

Hammet study

Only slight positive charge
at benzylic carbon in RDS

Path b unfavorable

Cyclopropyl carbinol
Path aunfavorable

Via intermediate 4
Path cfavorable??

Possible pathway(Although cannot rule out d)19

2-1. Cu-TEMPO Catalysis

Copper-TEMPO Catalysis with O2- Cu(II)-phen.-tBu2nitroxide catalysis

Brackman W.; Gaasbeek, C. J.
Recl. Trav. Chim. Pays-Bas
1966, 85, 257.

Mechanism proposed by themOxidation proceeds by cooperation of Cu(II) and N-O radical ??
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2-1. Cu-TEMPO Catalysis

Copper-TEMPO Catalysis with O2- Cu(I)-TEMPO catalysis

Semmelhack, M. F. et al.
JACS 1984, 106, 3374.

Mechanism proposed by them

Actual oxidant ??
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2-1. Cu-TEMPO Catalysis

What’s The Correct Mechanism??
- Mechanistic study- Cu(I) is oxidized by TEMPO

Sheldon, R. A. et al. Org. Biomol. Chem. 2003, 1, 3232.

- Cu(I)-catalyzed reaction
using stoichiometric TEMPO

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2-1. Cu-TEMPO Catalysis

What’s The Correct Mechanism??
- Mechanistic study

Sheldon, R. A. et al. Org. Biomol. Chem. 2003, 1, 3232.

- KIE and Hammet correlation study

Similar to GO/GO-mimics rather than oxoammonium salt23

2-1. Cu-TEMPO Catalysis

What’s The Correct Mechanism??
- Plausible mechanism

Sheldon, R. A. et al. Org. Biomol. Chem. 2003, 1, 3232.

Cu(II)-TEMPO

Cu(I)-TEMPOH

Key step occurs via
alkoxycopper(II)-TEMPO complex

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2-1. Cu-TEMPO Catalysis

Selective Copper-TEMPO Oxidation
Sheldon, R. A. et al.
Chem. Commun. 2003, 2414.

Rationalization of the selectivity

Remarkable selectivity
for primary over secondary25

2-2. Ru-TEMPO Catalysis

Ruthenium-TEMPO Catalysis with O2Sheldon, R. A. et al.
JACS 2001, 123, 6826.
Plat. Metals Rev. 2001, 45, 15.

Although these substrates are unreactive(deactivating catalyst by chelating??)26

2-2. Ru-TEMPO Catalysis

Mechanism of Ruthenium-TEMPO Catalysis- Mechanistic study

Sheldon, R. A. et al. JACS 2001, 123, 6826.

Reaction proceeds even in inert atmosphere with stoichiometric TEMPOKIEs are same in the absence/presence of O2
Under stoichiometric TEMPO & inert
atmosphere condition…
5.1
3.4

The same active species with/without oxygen
Dehydrogenation by RuCl2(PPh3)3 andTEMPO regenerates RuX2 from RuH2 ??

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2-2. Ru-TEMPO Catalysis

Mechanism of Ruthenium-TEMPO Catalysis- Mechanistic study

Sheldon, R. A. et al. JACS 2001, 123, 6826.

RuH2 reacts with TEMPO (observed in situ IR)*Ru-H vibration of RuH2(PPh3)3 at 2150 cm-1

Conclusive mechanism28

2-3. Metal-Free Catalysis

Metal-Free N-Oxy Radical Catalysis- TEMPO + stoichiometric oxidant
Many reports…

- The first non-metal aerobic oxidation catalyzed by TEMPO
all catalytic amount

Liang, X.- M.; Hu, X.-Q. et al.
JACS 2004, 126, 4112.

But multiple components…
= Difficult application for complex molecule??

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2-3. Metal-Free Catalysis

Metal-Free N-Oxy Radical Catalysis- Novel N-oxy radical AZADO for high efficiency
TEMPO: inefficient for hindered secondary alcohol

Iwabuchi, Y. et al.
JACS 2006, 128, 8412.

Concept of their catalyst design:

AZADO exhibits great reactivity for alcohol oxidation30

2-3. Metal-Free Catalysis

Metal-Free N-Oxy Radical Catalysis- Novel N-oxy radical AZADO for high efficiency
And various hindered alcohols can be oxidized.

Iwabuchi, Y. et al.
JACS 2006, 128, 8412.

312-3. Metal-Free Catalysis

Metal-Free N-Oxy Radical Catalysis- Aerobic version with more efficient catalyst
Introduction of F at C5 position

Iwabuchi, Y. et al.
JACS 2011, 133, 6497.

Also wide substrate scope including hindered alcohol32

2-3. Metal-Free Catalysis

Metal-Free N-Oxy Radical Catalysis- Aerobic version with more efficient catalyst
Proposed mechanism

Iwabuchi, Y. et al.
JACS 2011, 133, 6497.

I think oxoammonium cation is generated through disproportionation…
(Because solvent is AcOH)

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Today’s Contents
1. Fundamentals of N-Oxy Radical Species
2. Aminoxyl Radical-Mediated Reactions
3. Imidoxyl Radical-Mediated Reactions
4. Iminoxyl Radical-Mediated Reactions
5. Perspectives– For exploration of novel & efficient N-oxy radical catalysis

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3. Imidoxyl Radical-Mediated Reactions

Imidoxyl Radical-Mediated Reactions
Imidoxyl radical : High BDE makes the radical state unstable
Enables radicalic cleaveage of various C-H bonds

Reactions introduced today:

3-1. Alkane oxidation to alcohols/carboxylic acids
3-2. Ethers/Acetals oxidation
3-3. Application to C-C bond formation35

3-0. Early Works

Early Works on NHPI-Mediated Reactions- Coupling between ethers and DEAD

Grochowski, E. et al.
Synthesis 1977, 718.

Initiation occurred by homolysis of N=N bond ?

- Electrochemical oxidation of alcohols

Masui, M. et al.
Chem. Commun. 1983, 479.

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3-1. Alkane Oxidation

Alkane C(sp3)-H Oxidation – Focusing on Prof. Ishii’s Work
Key person: Prof. Ishii
Alkane oxidation using O2
Green oxidation of bulk chemicals ??

(Adv. Synth. Catal. 2001, 343, 393.)

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3-1. Alkane Oxidation

Alkane C(sp3)-H Oxidation – Focusing on Prof. Ishii’s Work
- Oxidation catalyzed by NHPI

Ishii, Y. et al.
JOC 1995, 60, 3934.

But conversions of simple alkanes are low…

- Co-NHPI combined catalysis

Ishii, Y. et al.
JOC 1996, 61, 4520.

With broad substrate scope of simple alkane38

3-1. Alkane Oxidation

Alkane C(sp3)-H Oxidation – Focusing on Prof. Ishii’s Work- Co-NHPI catalysis at room temp.

Ishii, Y. et al. JOC 1997, 62, 6810.

First example of catalytic aerobic oxidation of toluene at rt.

- THICA catalysis

Ishii, Y. et al. JOC 2003, 68, 6587.

THICA allows low cat. loading due to stability of its radical(PINO is subject to the decomposition)

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3. Imidoxyl Radical-Mediated Reactions

What’s The Mechanism of NHPI Catalysis ??
- O2 uptake experiment

Ishii, Y. et al. JOC 1996, 61, 4520.

CoII + NHPICoIII + NHPICoII is the active catalyst ??
(CoIII somehow reduced in situ.)- ESR measurement

Ishii, Y. et al. JOC 1997, 62, 6810.
PINO’s ESR spectra

CoII accelerates generation of PINO

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3. Imidoxyl Radical-Mediated Reactions

What’s The Mechanism of NHPI Catalysis ??
- General mechanism of free radical chain aerobic oxidation
CoII acts as the initiator ??

Key to efficient catalytic cycle:
1. Increase of the propagation rate
2. Decreasing of the termination rate

NHPI mediates radical propagation cycle ??

3. Imidoxyl Radical-Mediated Reactions

What’s The Mechanism of NHPI Catalysis ??
- Plausible mechanism (for toluene oxidation)

initiation

Ishii, Y. et al.
JOC 1997, 62, 6810.

But
some questionable points remain…
How is alcohol product generated ??
Reduction by CoII ??

propagation

Peroxide really oxidized by CoIII ??
Not via formation of aldehyde ??
etc.

3-2. Ethers/Acetals Oxidation

Ethers/Acetals Oxidation
BDE of a-C-H bond of ethers/acetals is weak (xx kcal/mol)
Facile radicalic C-H cleavage by PINO
Masui, M. et al.
JCS, Chem. Commun.
1985, 1484.

Karimi. B. et al.
Synthesis 2003, 2373.

Oxidation affords
cation equivalent43

3-3. Application for C-C Bond Formation

Application for C-C Bond Formation- Radicalic C-C bond formation
Trap the formed carbon radical by carbon electrophile (e.g. Michael acceptor)
before trapped by oxygen
Radicalic C-C bond formation ??
Ishii, Y. et al. Chem. Commun. 2000, 613;
Chem. Commun. 2000, 2457; JOC 2001, 66, 6425.

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3-3. Application for C-C Bond Formation

Application for C-C Bond Formation- Cross-dehydrogenative coupling (CDC)
Li, C.-J. et al. Synlett 2009, 138.

Li, C.-J. et al. TL 2010, 51, 1172.

Reaction proceeds via formation of cation intermediate ??

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Today’s Contents
1. Fundamentals of N-Oxy Radical Species
2. Aminoxyl Radical-Mediated Reactions
3. Imidoxyl Radical-Mediated Reactions
4. Iminoxyl Radical-Mediated Reactions
5. Perspectives– For exploration of novel & efficient N-oxy radical catalysis

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4. Iminoxyl Radical-Mediated Reactions

Iminoxyl Radical-Mediated Reactions- Amine oxidation with stoichiometric iminoxyl radical
Mendenhall, G. D. et al.
JOC 1985, 50, 5382.

- Phenol oxidation with stoichiometric iminoxyl radical
Mendenhall, G. D. et al.
JOC 1986, 51, 5390.

No reports on use of iminoxyl radical as catalyst. Why…??
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Today’s Contents
1. Fundamentals of N-Oxy Radical Species
2. Aminoxyl Radical-Mediated Reactions
3. Imidoxyl Radical-Mediated Reactions
4. Iminoxyl Radical-Mediated Reactions
5. Perspectives– For exploration of novel & efficient N-oxy radical catalysis

485. Perspectives

Toward C-H Bond Functionalization
Inner-sphere C-H functionalization

Outer-sphere C-H functionalization

Advantages

Advantages- Many catalysis & reaction mode
- Selectivity
Disadvantages- Cheap metal/organocatalysts- Applicable for hindered C-H bondDisadvantages- Harsh conditions- Harsh conditions- Directing group- Selectivity- Noble metal catalysts- Only limited examples- Only unhindered C-H bond

Can we realize efficient outer-sphere C-H functionalizationby overcoming current disadvantages ??

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5. Perspectives

How to Overcome Disadvantages ??
For utilization of N-oxy radical toward outer-sphere C-H functionalization…

- Harsh condition is often necessary- Chemoselectivity between several C-Hs
New N-oxy radical having more suitable BDE

New catalyst design based on strict strategy(e.g. BDE theory) is important…??
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5. Perspectives

Future Potentiality 1 – Sequential C-H Oxidation
In highly oxidized, complex molecule synthesis…
Introduction of FGs at the late stage is ideal.
Concept:

Each C-H has each BDE

Related work:

Selectively cleaved by N-O catalyst having
similar BDE in kinetically controlled reaction ??
White, M. C. et al. Science, 2007, 318, 783

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5. Perspectives

Future Potentiality 2 – Photoredox N-Oxy Radical Catalyst
Activation of unreactive C-H bonds= thermodinamically unfavorable processThis is the cause of need of harsh conditions…??
Can we use photoenergy as energy source ??
Concept:Ref.) Mr.Kojima’s lit. seminar (2012)52

References (Reviews)“What’s new in stable radical chemisty?”
Hicks, R. G. Org. Biomol. Chem. 2007, 5, 1321.
“Organocatalytic Oxidations Mediated by Nitroxyl Radicals”
Sheldon, R. A. et al. Adv. Synth. Catal. 2004, 346, 1051.
“Free Radical Functionalization of Organic Compounds Catalyzed by N-Hydroxyphtalimide”
Recupero, F. et al. Chem. Rev. 2007, 107, 3800.

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