Design Concepts of Nitroxyl Radicalskanai/seminar/pdf/Lit_K_Maruyama_B4.pdf · Synthesized...
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Design Concepts of Nitroxyl Radicals
Literature Seminar
2018/3/10
B4 Katsuya Maruyama
1
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Contents
2
1. Introduction
2. TEMPOs and AZADOs
3. Design Concept of Nitroxyl Radicals
4. Summary
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3
1. Introduction
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1. Introduction
4
Representatives
Nitroxyl radicals (nitroxides, aminoxyl radicals)
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Use of Nitroxyl Radicals
5
Tuning design for each purpose can improve the efficacy.
Material use
• Dye-sensitized solar cells
• Organic radical battery
Chemical use
• Oxidation catalyst
• Nitroxide mediated radical
polymerization (NMP)
• Radical coupling
• Mechanism analysis
Biological use
• Spin probe
• Superoxide dismutase
mimics
• Antioxidant
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Property of Nitroxyl Radicals
6
Thermodynamic stabilization
-> Delocalization of unpaired electron
• N-O bond contains three electrons.
• Bond order of N-O is 1.5.
• TEMPO is stabilized both thermodynamically and kinetically.
Kinetic stabilization
-> 4 α-methyl groups
• Four Me shield the radical.
Wertz, S.; Studer, A. Green Chem. 2013, 15 (11), 3116.
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Property of Nitroxyl Radicals
7
TEMPO
• Thermodynamic driving force
for direct H-abstraction is low.
PINO:
Wertz, S.; Studer, A. Green Chem. 2013, 15 (11), 3116.
PINO
• Stronger H-abstraction
reagent, but unstable.
(generated in situ)
• Used in transition-metal
mediated C-H
functionalization with Co, Mn.
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Oxidation State of Nitroxyl Radicals
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• Oxoammonium ion acts as an active
species in oxidation.
• Oxoammonium salt can be isolated
with proper counteranion. (e.g. BF4-)
Oxidation states of nitroxyl radical
Generation of oxoammonium salt
• Acid cause disproportionation.
• Nitroxyl radical and hydroxylamine
are oxidized into oxoammonium salt.
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2. TEMPOs and AZADOs
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2-1. TEMPOs
10
TEMPO (2,2,6,6-tetramethylpiperidyl-1-oxyl)
• Alcohol oxidation catalyst.• 1° alcohol > 2° alcohol.
• Terminal oxidant: NaOCl, PhI(OAc)2, oxone, I2, O2, etc..
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Alcohol Oxidation by TEMPO
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Oxoammonium as active species
Tebben, L.; Studer, A. Angew. Chem. Int. Ed. 2011, 50 (22), 5034.
Catalytic cycle
Wertz, S.; Studer, A. Green Chem. 2013, 15 (11), 3116.
pH < 4
pH > 5
Cope-type elimination
from alcohol adduct
Hydride-transfer to
oxoammonium cation
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Alcohol Oxidation by TEMPO
12
Aerobic oxidation with Cu
• Cu(II) isn’t sufficiently strong
oxidant for the oxidation of
TEMPO to TEMPO+.
• Oxoammonium cation isn’t
generated.
NMI: N-methylimidazole
Simplified catalytic cycle
Stahl, S. S. et al. J. Am. Chem. Soc. 2013, 135 (6), 2357.
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2-2. AZADOs
13
Development of AZADOs
Steric hindrance
Problems with TEMPO
AZADO: 2-azaadamantane N-oxyl
Alcohol oxidation
intermediate
steric repulsion between Me and R1, R2 -> 1° alcohol > 2° alcohol
Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.
reactivity stability
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Catalytic Activity
14
AZADO
1-Me-AZADO
TEMPO
Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.
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Redox Property
15
Cyclic Voltammetry (CV)
• Stable for >100 measurement cycles.
a: TEMPO
b: AZADO
c: 1-Me-AZADO
d: 1,3-diMe-AZADO
294
236
186
136
nitroxide E0
Catalytic activity: a: TEMPO ~ d: 1,3-diMe-AZADO << c: 1-Me-AZADO < b: AZADO
High catalytic activity is mainly due to kinetic factors.
Readily
Reduced
Redox Potential (E0 vs Ag/Ag+)
Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.
Oxidation
N-O・→N+=O
Reduction
N+=O→N-O・
Readily
Oxidized
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Development of ABNO and Nor-AZADO
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• Nor-AZADO showed higher catalytic activity than AZADO.
Iwabuchi, Y. Chem. Pharm. Bull. 2013, 61 (12), 1197.
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5-F-AZADO
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e- poor oxoammonium salt
Introduction of electron-withdrawing group
• NOx works as reoxidant.
Iwabuchi, Y. et al. J. Am. Chem. Soc. 2011, 133 (17), 6497.
wider scope of substrate
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Mechanism Analysis with 5-F-AZADO
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5-F-AZADO -> Lower basicity
prevents the formation of IV and V.
Proposed mechanism
Iwabuchi, Y. et al. J. Org. Chem. 2014, 79, 10256.
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General Trend of Redox Property
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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
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Redox 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 is
favorable.)
• Redox potential is an important
factor.
Iwabuchi, Y. et al. Tetrahedron Lett. 2012, 53 (16), 2070.
Readily
Oxidized
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2-3. Steric Effect vs Driving Force
21
Cyclic voltammogram
Increment of oxidation current and disappearance of reduction current
-> electrocatalysis
a: AZADO
b: ABNO
c: TEMPO
d: 4-acetamido-TEMPO
e: 4-oxo-TEMPO
with 1-butanol (50 mM)without 1-butanol
Stahl, S. S. et al. J. Am. Chem. Soc. 2015, 137 (46), 14751.
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Oxidation Under Electrochemical Conditions
22
TOFs of alcohol oxidation
electrode
Electrochemical oxidation
Stahl, S. S. et al. J. Am. Chem. Soc. 2015, 137 (46), 14751.
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Oxidation Under Chemical Conditions
Poor catalytic activity of 4-acetamido-TEMPO
Formation of N-O・->N+=O (reoxidation) is slow.
Chemical oxidation 1-Butanol oxidation with NaClO
Left :
nitroxyl radical
Right :
oxoammonium
Concentration in the presence of NaClO
Stahl, S. S. et al. J. Am. Chem. Soc.
2015, 137 (46), 14751.
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Intrinsic Catalytic Activity of 4-Acetamido-TEMPO
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Chemical conditions vs electrochemical conditions
Oxidation with NaClO
Electrochmical Oxidation
• Intrinsic reactivity can overcome the steric effect.
High reactivity
Low reactivity
Stahl, S. S. et al. J. Am. Chem. Soc. 2015, 137 (46), 14751.
Oxidation of 1-butanol Compared with TEMPO…
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Use of Stoichiometric Amount of Oxoammonium
25
• 1.7-3.2 times faster than 4-acetamido-TEMPO.
Bailey, W. F. et al. J. Org. Chem. 2017, 82 (21), 11440.
Rate of oxidation (k * 104 s-1)
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Short Summary
26
• AZADOs were designed to achieve higher reactivity.
• Steric property and electric property are important for them.
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27
3. Design Concepts
of Nitroxyl Radicals
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3-1. Effect of Direct Conjugation on Redox Property
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2-Pyridyl nitroxyl radicals
Direct conjugation of N-O with Py.
2-Pyridylhydroxylamine isoindoline
σ+
5-NMe2
5-SMe5-Me
H 5-CF3
Piperidine, isoindoline, azaphenalene derivatives
• Over 4 times sensitive to substituent
effect than isoindoline.
->easy to tune the reactivity and stability.
• SOMO is localized on N-O bond.
• Substituent effects: σ-inductive effects.
Schelter, E. J. et al. J. Org. Chem. 2013, 78 (12), 6344.
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SOMOs of 2-Pyridyl nitroxides
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SOMO (calculated)
SOMO delocalizes at 1-, 3-, 5- position.
-> Substituent at 1-, 3- and 5- position can affect the energy of SOMO and
enables 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
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11
• Normally unstable due to spin delocalization on Ar.
Diaryl-Nitroxyl radical
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.
Magdesieva, T. V. et al. Eur. J. Org. Chem. 2017, 2017 (32), 4726.
Decomposition pathway
• Substituent at p-position can prevent this pathway.
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Calculated Structure and SOMO
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• One ring with o-substituent is out of conjugation due to its bulkiness.
-> Spin delocalization over the ring is prevented.
twisted diaryl-nitroxyl radical
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.
TEMPO
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Redox Property
• Oxidation into oxoammonium cation is less favorable than TEMPO.
Redox potential E0 (vs Ag/Ag+)
Oxidation (N-O・ <-> N+=O) : E0ox Reduction (N-O・ <-> N-O-) : E0
red
Effect of twist
Effect of twistMagdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.
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• ΔE = E0ox - E0
red increases when twist exists.
<-> Inductive substituent normally shifts E0ox and E0
red to the same direction.
Interesting Property
33
E0red = -866 mVE0
ox = 952 mV E0ox = 808 mVE0
red = -919 mV
1: twisted 5: non-twisted
ΔE = 1871 mV ΔE = 1674 mV
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.
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Torsion Angle
34
O-N-C-C torsion angle (θ)
Torsion angle θ depends on
• Position of substituents
• Electronic property of substituents
: θ is larger. -> conjugation is less.
Magdesieva, T. V. et al. Electrochim. Acta 2018, 260, 459.
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Relationship Between θ and Redox Potential
35
• Plotted E0ox+E0
red 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
36
• Only acyclic and bicyclic system had
been reported.
• The examples aren’t abundant.
• Stable but highly encumbered.
Nitroxyl radicals with tertiary alkyl group
Conventional α-hydrogen nitroxyl radicals
Replacing Me with H for higher reactivity
New design concept Amar, M. et al. Nat. Commun. 2015, 6, 1.
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Disproportionation of α-Hydrogen Nitroxyl Radicals
37
Disproportionation of α-hydrogen nitroxyl radicals
• Bridgehead H inhibit the formation of nitrone.
(Bredt’s rule)
• bridgehead H strategy isn’t
necessarily effective.
Amar, M. et al. Nat. Commun. 2015, 6, 1.
But...
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Design Concept of α-Hydrogen Nitroxyl Radicals
38
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.
New α-hydrogen
nitroxyl radicals
Design concept
Amar, M. et al. Nat. Commun. 2015, 6, 1.
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Design Concept of α-Hydrogen Nitroxyl Radicals
39
3: H-C-N-O angle (Φ)
This case:
Ideal angle for C-H abstraction:
• C-H bond overlaps SOMO.
-> H abstraction is favored.
• C-H bond is orthogonal to
SOMO.
-> 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
40
Stable for months.
Synthesized molecules DFT calculation
calculated reaction free energies (ΔG298, sol ,kcal mol-1)
• Disproportionation is thermodynamically favored.
-> Stability of the nitroxyl radicals is due to kinetic factors.
(H abstraction)
Amar, M. et al. Nat. Commun. 2015, 6, 1.
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Potential as Catalyst
41
Stahl’s conditions(TEMPO)
• In some Nitroxides, catalytic activity is
better than TEMPO.
Aerobic alcohol oxidation
23
Further investigation
• Nitroxide 35 shows 2~3 times higher catalytic activity than TEMPO.
Amar, M. et al. Nat. Commun. 2015, 6, 1–9.
Szpilman, A. M. et al. ChemCatChem 2015, 7 (7), 1129.
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4. Summary
42
• Reactivity and stability of nitroxyl radical can be tuned by the
parameters 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
43Dempsey, J. L. et al. J. Chem. Educ. 2018, 95 (2), 197.
Caution
<- The direction of x
(potential) and y (current)
axis is inversed with the
figures in this seminar.