Design Concepts ofNitroxyl Radicals
Literature Seminar
2018/3/10
B4 Katsuya Maruyama
1Contents
1. Introduction
2. TEMPOs and AZADOs
3. Design Concept of Nitroxyl Radicals
4. Summary2

1. Introduction

3

1. Introduction
Nitroxyl radicals (nitroxides, aminoxyl radicals)
Representatives

4

Use of Nitroxyl Radicals••••

Chemical use
Oxidation catalyst
Nitroxide mediated radical
polymerization (NMP)
Radical coupling
Mechanism analysis

Material use
Biological use• Dye-sensitized solar cells• Spin probe• Superoxide dismutase • Organic radical batterymimics• Antioxidant

Tuning design for each purpose can improve the efficacy.
5Property of Nitroxyl Radicals• TEMPO is stabilized both thermodynamically and kinetically.
Thermodynamic stabilization-> Delocalization of unpaired electron

Kinetic stabilization-> 4 α-methyl groups• Four Me shield the radical.
• N-O bond contains three electrons.
• Bond order of N-O is 1.5.
Wertz, S.; Studer, A. Green Chem. 2013, 15 (11), 3116.

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Property of Nitroxyl Radicals
TEMPO• Thermodynamic driving force
for direct H-abstraction is low.

PINO• Stronger H-abstraction
reagent, but unstable.
(generated in situ)• Used in transition-metal
mediated C-Hfunctionalization with Co, Mn.
Wertz, S.; Studer, A. Green Chem. 2013, 15 (11), 3116.

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Oxidation State of Nitroxyl Radicals
Oxidation states of nitroxyl radical• Oxoammonium ion acts as an active
species in oxidation.
• Oxoammonium salt can be isolatedwith proper counteranion. (e.g. BF4-)

Generation of oxoammonium salt
• Acid cause disproportionation.
• Nitroxyl radical and hydroxylamine
are oxidized into oxoammonium salt.
82. TEMPOs and AZADOs

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2-1. TEMPOsTEMPO (2,2,6,6-tetramethylpiperidyl-1-oxyl)• Alcohol oxidation catalyst.
• 1° alcohol > 2° alcohol.
• Terminal oxidant: NaOCl, PhI(OAc)2, oxone, I2, O2, etc..
10Alcohol Oxidation by TEMPO
Oxoammonium as active species
pH < 4Hydride-transfer tooxoammonium cation

Catalytic cycle
pH > 5Cope-type eliminationfrom alcohol adductWertz, S.; Studer, A. Green Chem. 2013, 15 (11), 3116.
Tebben, L.; Studer, A. Angew. Chem. Int. Ed. 2011, 50 (22), 5034.

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Alcohol Oxidation by TEMPO
Aerobic oxidation with Cu

Simplified catalytic cycle

NMI: N-methylimidazole• Cu(II) isn’t sufficiently strongoxidant for the oxidation ofTEMPO to TEMPO+.
• Oxoammonium cation isn’t
generated.
Stahl, S. S. et al. J. Am. Chem. Soc. 2013, 135 (6), 2357.

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2-2. AZADOs
Problems with TEMPO
reactivity

stability
Alcohol oxidationintermediatesteric repulsion between Me and R1, R2-> 1° alcohol > 2° alcohol
Development of AZADOs
AZADO: 2-azaadamantane N-oxyl

Steric hindrance

Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.

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Catalytic Activity

AZADO

1-Me-AZADO

TEMPOIwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197. 14

Redox Property
Cyclic Voltammetry (CV)Oxidation
N-O・→N+=O• Stable for >100 measurement cycles.
Redox Potential (E0 vs Ag/Ag+)

Reduction
N+=O→N-O・

nitroxide

E0a: TEMPO
b: AZADO
c: 1-Me-AZADO
d: 1,3-diMe-AZADO

294236
186
136

Readily
ReducedReadily
Oxidized

Catalytic activity: a: TEMPO ~ d: 1,3-diMe-AZADO << c: 1-Me-AZADO < b: AZADOHigh catalytic activity is mainly due to kinetic factors.
Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.

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Development of ABNO and Nor-AZADO• Nor-AZADO showed higher catalytic activity than AZADO.
Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.

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5-F-AZADOIntroduction of electron-withdrawing groupe- poor oxoammonium salt

wider scope of substrate• NOx works as reoxidant.
Iwabuchi, Y. et al. J. Am. Chem. Soc. 2011, 133 (17), 6497.

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Mechanism Analysis with 5-F-AZADOProposed mechanism

5-F-AZADO -> Lower basicity
prevents the formation of IV and V.
Iwabuchi, Y. et al. J. Org. Chem. 2014, 79, 10256.

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General Trend of Redox Property
Redox potential E0 (vs Ag/Ag+)

EWG-> destabilization of N+=O-> higher redox potential
EDG-> stabilization of N+=O-> lower redox potential
Iwabuchi, Y. et al. Tetrahedron Lett. 2012, 53 (16), 2070.

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Catalytic Activity vs Redox Potential
Readily
OxidizedRedox potential
AZADO 236 mV
5-F-AZADO 412mV
5,7-diF-AZADO 591 mV• The lower the redox potential,
the higher the catalytic activity.
(Probably because reoxidation
into oxoammonium species isfavorable.)• Redox potential is an importantfactor.
Iwabuchi, Y. et al. Tetrahedron Lett. 2012, 53 (16), 2070.

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2-3. Steric Effect vs Driving Force
Cyclic voltammogram
without 1-butanolwith 1-butanol (50 mM)

a: AZADO
b: ABNO
c: TEMPO
d: 4-acetamido-TEMPO
e: 4-oxo-TEMPO

Increment of oxidation current and disappearance of reduction current-> electrocatalysis
Stahl, S. S. et al. J. Am. Chem. Soc. 2015, 137 (46), 14751. 21

Oxidation Under Electrochemical Conditions
Electrochemical oxidation

TOFs of alcohol oxidationelectrodeStahl, S. S. et al. J. Am. Chem. Soc. 2015, 137 (46), 14751.

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Oxidation Under Chemical Conditions
Chemical oxidation

1-Butanol oxidation with NaClO

Concentration in the presence of NaClO
Left :
nitroxyl radical
Right :
oxoammonium

Stahl, S. S. et al. J. Am. Chem. Soc.
2015, 137 (46), 14751.

Poor catalytic activity of 4-acetamido-TEMPOFormation of N-O・->N+=O (reoxidation) is slow.

Intrinsic Catalytic Activity of 4-Acetamido-TEMPO
Chemical conditions vs electrochemical conditions
Oxidation of 1-butanol

Compared with TEMPO…
High reactivity

Oxidation with NaClO

Electrochmical Oxidation

Low reactivity• Intrinsic reactivity can overcome the steric effect.
Stahl, S. S. et al. J. Am. Chem. Soc. 2015, 137 (46), 14751.

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Use of Stoichiometric Amount of Oxoammonium

Rate of oxidation (k * 104 s-1)

• 1.7-3.2 times faster than 4-acetamido-TEMPO.
Bailey, W. F. et al. J. Org. Chem. 2017, 82 (21), 11440.

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Short Summary• AZADOs were designed to achieve higher reactivity.
• Steric property and electric property are important for them.

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3. Design Conceptsof Nitroxyl Radicals

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3-1. Effect of Direct Conjugation on Redox Property
Piperidine, isoindoline, azaphenalene derivatives 2-Pyridyl nitroxyl radicals
Direct conjugation of N-O with Py.
• SOMO is localized on N-O bond.
• Substituent effects: σ-inductive effects.

H5-CF35-Me
5-SMe

2-Pyridylhydroxylamine

isoindoline• Over 4 times sensitive to substituent
effect than isoindoline.
->easy to tune the reactivity and stability.

5-NMe2σ+Schelter, E. J. et al. J. Org. Chem. 2013, 78 (12), 6344.

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SOMOs of 2-Pyridyl nitroxides
SOMO (calculated)

SOMO delocalizes at 1-, 3-, 5- position.
-> Substituent at 1-, 3- and 5- position can affect the energy of SOMO andenables redox property tuning.
Schelter, E. J. et al. J. Org. Chem. 2013, 78 (12), 6344.

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3-2. Twisted Diaryl-Nitroxyl Radical
Diaryl-Nitroxyl radical• Normally unstable due to spin delocalization on Ar.
Decomposition pathway• Substituent at p-position can prevent this pathway.
Magdesieva, T. V. et al. Eur. J. Org. Chem. 2017, 2017 (32), 4726.
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.

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Calculated Structure and SOMO

TEMPO

twisted diaryl-nitroxyl radical• One ring with o-substituent is out of conjugation due to its bulkiness.
-> Spin delocalization over the ring is prevented.
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.

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Redox Property
Redox potential E0(vs Ag/Ag+)

Oxidation (N-O・ <-> N+=O) : E0oxReduction (N-O・ <-> N-O-) : E0red

Effect of twist

Effect of twist

Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.

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Interesting Property
1: twisted

5: non-twisted

ΔE = 1871 mV

ΔE = 1674 mV

E0red = -919 mV

E0ox = 952 mV

E0red = -866 mV

E0ox = 808 mV• ΔE = E0ox - E0red increases when twist exists.
<-> Inductive substituent normally shifts E0ox and E0red to the same direction.
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.

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Torsion Angle
O-N-C-C torsion angle (θ) : θ is larger. -> conjugation is less.

Torsion angle θ depends on• Position of substituents• Electronic property of substituents
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.

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Relationship Between θ and Redox Potential• Plotted E0ox+E0red vs Σ(σp+σocosθ)• Such σo was determined that makes R2 minimum.
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.

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3-3. α-Hydrogen Nitroxyl Radicals
Nitroxyl radicals with tertiary alkyl group• Stable but highly encumbered.
Replacing Me with H for higher reactivity

Conventional α-hydrogen nitroxyl radicals• Only acyclic and bicyclic system had
been reported.
• The examples aren’t abundant.

New design concept

Amar, M. et al. Nat. Commun. 2015, 6, 1.

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Disproportionation of α-Hydrogen Nitroxyl Radicals
Disproportionation of α-hydrogen nitroxyl radicals• Bridgehead H inhibit the formation of nitrone.
(Bredt’s rule)
But...

• bridgehead H strategy isn’t
necessarily effective.
Amar, M. et al. Nat. Commun. 2015, 6, 1.

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Design Concept of α-Hydrogen Nitroxyl Radicals
New α-hydrogennitroxyl radicals

Design concept

1: pushing out the substituent• R6 push R5 away from the plane.
-> H abstraction by another molecule is inhibited.
2: 1,3-allylic strain• Nitrone formation is disfavored due to A(1,3) strain.
Amar, M. et al. Nat. Commun. 2015, 6, 1.

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Design Concept of α-Hydrogen Nitroxyl Radicals
3: H-C-N-O angle (Φ)
Ideal angle for C-H abstraction:• C-H bond overlaps SOMO.
-> H abstraction is favored.

This case:• C-H bond is orthogonal toSOMO.
-> H abstraction is disfavored.

Based on these concepts, improved stability of was expected.

Amar, M. et al. Nat. Commun. 2015, 6, 1.

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Results
Synthesized molecules

DFT calculation

calculated reaction free energies (ΔG298, sol ,kcal mol-1)(H abstraction)

Stable for months.

• Disproportionation is thermodynamically favored.
-> Stability of the nitroxyl radicals is due to kinetic factors.
Amar, M. et al. Nat. Commun. 2015, 6, 1. 40

Potential as Catalyst
Aerobic alcohol oxidation
Stahl’s conditions(TEMPO)• In some Nitroxides, catalytic activity isbetter than TEMPO.

Amar, M. et al. Nat. Commun. 2015, 6, 1–9.

Further investigation• Nitroxide 35 shows 2~3 times higher catalytic activity than TEMPO.
Szpilman, A. M. et al. ChemCatChem 2015, 7 (7), 1129.

2341

4. Summary• Reactivity and stability of nitroxyl radical can be tuned by theparameters here and maybe by other parameters.
• The examples of the use of fine-tuned nitroxyl radicals aren’t many,so the best design of nitroxyl radicals for the purpose could
improve the efficiency.

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Appendix: Cyclic Voltammetry

Caution<- The direction of x(potential) and y (current)
axis is inversed with thefigures in this seminar.

Dempsey, J. L. et al. J. Chem. Educ. 2018, 95 (2), 197.

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