Copper catalysed Ullmann type chemistry: from mechanistic ...
Mechanistic Studies in Copper Catalysis
Transcript of Mechanistic Studies in Copper Catalysis
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Mechanistic Studies in Copper Catalysis
Jen AllevaMay 1st 2013
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Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Glaser, C. Ann. D. Chemie U. Pharm, 1869, 2, 137–171
1869
Glaser
first cross-couplings
General Historical Overview
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Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Ullman, F. Ber. 1903, 36, 2382–2384Goldberg, I. Ber. 1906, 39, 1691–1692
1869
Glaser
first cross-couplings
General Historical Overview
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Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem, 1952, 17, 1630–1634
1923 1952
Reich Gilman
synthesis of first copperorganometallic reagents
1869
Glaser
first cross-couplings
General Historical Overview
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Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Huisgen, R. Proc. Chem Soc., 1961, 357–396
1923 1952
Reich Gilman
synthesis of first copperorganometallic reagents
1869
Glaser
first cross-couplings
Huisgen
1961
2001
Sharpless
"Click" Chemistry
General Historical Overview
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Timeline of Achievements in Copper Chemistry
Ullmann–Goldberg
1903
Huisgen, R. Proc. Chem Soc., 1961, 357–396
1923 1952
Reich Gilman
synthesis of first copperorganometallic reagents
1869
Glaser
first cross-couplings
Huisgen
1961
2001
Sharpless
"Click" Chemistry
General Historical Overview
1998
Chan-Evans-LamCu C–N couplings
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Copper in Cross-Coupling Reactions
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Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
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Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
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Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
■ forms shorter bonds than Pd
■ harder Lewis acidity than Pd
■ higher affinity for O, N ligands
■ smaller coordination shell can notaccomodate large ancillary ligands
Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808
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NNH N
H
R
CuIII
Br
Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
■ forms shorter bonds than Pd
■ harder Lewis acidity than Pd
■ higher affinity for O, N ligands
■ smaller coordination shell can notaccomodate large ancillary ligands
■ highly electrophilic and unstable
■ potent oxidizer
■ requires highly stabilizing ligands
Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808
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Electronic Properties of Copper
CuI CuII CuIIIE1/2= 2.4VE1/2= 0.16V
* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21
d8, metal cationd9d10
isoelectronic withNi(0)
isoelectronic withPd(II)
■ forms shorter bonds than Pd
■ harder Lewis acidity than Pd
■ higher affinity for O, N ligands
■ smaller coordination shell can notaccomodate large ancillary ligands
■ highly electrophilic and unstable
■ potent oxidizer
■ requires highly stabilizing ligands
■ unstable towards the reversereductive elimination
■ can not take part in ligand exchange
■ requires the nucleophile to be in thecoordination sphere prior to oxidativeaddition
Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808
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Cross-Coupling Classifications
R1 XR2
HN
R3B ML X
R2N
R3BH
organic N–Hnucleophile
base
regular cross-coupling: transition metal mediated nucleophilic substitution
electrophile
R1
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Cross-Coupling Classifications
R1 XR2
HN
R3B ML X
R2N
R3BH
organic N–Hnucleophile
base
regular cross-coupling: transition metal mediated nucleophilic substitution
electrophile
R1
Pd0/PdII
Pd0
PdIIR1 X
R1 X R2
HN
R3
B
PdIIR1 N R3
R2
R2N
R3
R1
BH
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Cross-Coupling Classifications
R1 XR2
HN
R3B ML X
R2N
R3BH
organic N–Hnucleophile
base
regular cross-coupling: transition metal mediated nucleophilic substitution
electrophile
R1
Pd0/PdII CuI/CuIII
Pd0
PdIIR1 X
R1 X R2
HN
R3
B
PdIIR1 N R3
R2
R2N
R3
R1
BH
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
nucleophile plays the role of ancillary ligand in CuI/CuIII
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Cross-Coupling Classifications
R1 MR2
HN
R3
ML MR2
NR3
M
organic N–Hnucleophile
oxidative cross-coupling: transition metal mediated coupling of two nucleophiles
nucleophile
R1
–2e–
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Cross-Coupling Classifications
R1 MR2
HN
R3
ML MR2
NR3
M
organic N–Hnucleophile
oxidative cross-coupling: transition metal mediated coupling of two nucleophiles
nucleophile
R1
PdII/PdIV
PdIIR1 M
R1 M R2
HN
R3
PdIIR1 N R3
R2
R2N
R3
R1
–2e–
PdII
PdIVR1 N R3
R2
O2
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Cross-Coupling Classifications
R1 MR2
HN
R3
ML MR2
NR3
M
organic N–Hnucleophile
oxidative cross-coupling: transition metal mediated coupling of two nucleophiles
nucleophile
R1
PdII/PdIV CuI/CuII/CuIII
PdIIR1 M
R1 M R2
HN
R3
PdIIR1 N R3
R2
R2N
R3
R1
CuII
R2
HN
R3
CuIINR3
R2
R1 X
CuIINR3
R2
R1
R2N
R3
R1
–2e–
PdII
CuI
CuII
CuIIINR3
R2
R1
O2
PdIVR1 N R3
R2
O2
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Cross-Coupling Classifications
R1 XR2
NR3
MLLG
R2N
R3
organic N–Helectrophile
inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution
nucleophile
R1LG
nucleofugal leavinggroup
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Cross-Coupling Classifications
R1 XR2
NR3
MLLG
R2N
R3
organic N–Helectrophile
inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution
nucleophile
R1
Pd0/PdII
Pd0
PdIIN LG
R1 X
PdIIR1 N R3
R2
R2N
R3
R1
LG
R2N
R3
LG R3
R2
nucleofugal leavinggroup
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Cross-Coupling Classifications
R1 XR2
NR3
MLLG
R2N
R3
organic N–Helectrophile
inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution
nucleophile
R1
Pd0/PdII CuI/CuIII
Pd0
PdIIN LG
R1 X
PdIIR1 N R3
R2
R2N
R3
R1
CuI
CuIR1 X
CuIIINR3
R2
R1
R2N
R3
R1
LG
R2N
R3
LG R3
R2
nucleofugal leavinggroup
R2N
R3
LGR1 X
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Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
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Mechanistic Studies in Copper Catalysis
Shannon Stahl Xavi Ribas Ted Cohen
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Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
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Chan-Evans-Lam Couplingoxidative cross-coupling
OH
Me
BHO OH
2 equiv. Cu(OAc)2
4Å mol sieves, O2EtOAc
O
Me
heteroatom boronic acid diaryl ether
Chan D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933.Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. T., Combs, A. Tetrahedron Lett. 1998, 39, 2941.
nucleophile
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Chan-Evans-Lam Couplingoxidative cross-coupling
OH
Me
BHO OH
2 equiv. Cu(OAc)2
4Å mol sieves, O2EtOAc
O
Me
heteroatom boronic acid diaryl ethernucleophile
CuI/CuII/CuIIICuII
R2
HN
R3
CuIINR3
R2
R1 X
CuIINR3
R2
R1
R2N
R3
R1
CuI
CuII
CuIIINR3
R2
R1
O2
CEL is stoichiometric in CuII
can be made catalytic with anadded oxidant
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Chan-Evans-Lam Couplingselect catalytic methods
BHO OH
N
HN 20 mol% [Cu(OH)•TMEDA]2Cl2
CH2Cl2, O2, r.t.
NN 72%
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236
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Chan-Evans-Lam Couplingselect catalytic methods
NNH2
O
Si(OMe)31.1 equiv Cu(OAc)2
TBAF, DMF, O2, r.t.N
HN
O
61%
Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429
BHO OH
N
HN 20 mol% [Cu(OH)•TMEDA]2Cl2
CH2Cl2, O2, r.t.
NN 72%
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236
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Chan-Evans-Lam Couplingselect catalytic methods
NNH2
O
Si(OMe)31.1 equiv Cu(OAc)2
TBAF, DMF, O2, r.t.N
HN
O
61%
Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429
BHO OH
N
HN 20 mol% [Cu(OH)•TMEDA]2Cl2
CH2Cl2, O2, r.t.
NN 72%
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236
5 mol% Cu(OAc)2
2,6-lutidine, PhMe, r.t.
BHO OHNH2
10 mol% myristic acid
HN
91%
Antilla, J. C.; Buchwald, S. L. Org Lett, 2001, 3, 2077–2079
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Chan-Evans-Lam Couplingdetermining reaction stoichiometry
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
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Chan-Evans-Lam Couplingdetermining reaction stoichiometry
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Cu and O2 stoichiometry determined from anaerobic single-turnover experiment
CuII/product ratio is 2:1
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Chan-Evans-Lam Couplingdetermining reaction stoichiometry
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Cu and O2 stoichiometry determined from anaerobic single-turnover experiment
CuII/product ratio is 2:1 CuI/O2 ratio is 4:1
result consistent withCu oxidase mechanism
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Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Initial rates experiment: suggest transmetalation as turnover-limiting
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Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Initial rates experiment: suggest transmetalation as turnover-limiting
■ 1st order dependence on Cu(OAc)2
■ saturation dependence on boronic ester
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Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
Initial rates experiment: suggest transmetalation as turnover-limiting
■ 1st order dependence on Cu(OAc)2
■ saturation dependence on boronic ester
■ 0 order dependence on O2
CuI oxidation is relativelyfast compared totransmetalation
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
ground state
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
gobs: empirical value from spectrum
ge: energy of free electron (2.00023)
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
gobs: empirical value from spectrum
ge: energy of free electron (2.00023)
x: modification factor of the free electron based on orbital mixing
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Electron Paramagnetic Resonance Spectroscopy
dx2–y2
dxy
dz2
dyz dxz
CuII: d9, square planar
dx2–y2
dxy
dz2
dyz dxz
dx2–y2
dxy
dz2
dyz dxz
ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry
gobs = ge – xλΔE
gobs: empirical value from spectrum
ge: energy of free electron (2.00023)
x: modification factor of the free electron based on orbital mixing
λ: spin orbit coupling constant
ΔE: energy between two orbitals
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Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045
EPR spectroscopy shows catalyst resting state as CuII
no strong field aryl ligand evidentconsistent with transmetalation being as
turnover-limiting
reaction progress correlated withEPR spectra
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Chan-Evans-Lam Couplingequilibrium prior to transmetalation
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
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Chan-Evans-Lam Couplingequilibrium prior to transmetalation
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
deviation from standard conditions effect on efficiency
added acetate
added acetic acid
Cu(ClO4)2 instead of Cu(OAc)2
inhibition
inhibition
no reactivity
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Chan-Evans-Lam Couplingequilibrium prior to transmetalation
BMeO OMe
Me
5 mol% Cu(OAc)2
1 atm O2, MeOH27°C, 6h
Me Me
OHOMe
B(OMe)2(OH)
88% 12%
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
deviation from standard conditions effect on efficiency
added acetate
added acetic acid
Cu(ClO4)2 instead of Cu(OAc)2
Cu(ClO4)2 + 1 equiv NaOAc
Cu(ClO4)2 + 1 equiv NaOMe
inhibition
inhibition
no reactivity
rate acceleration
rate acceleration
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Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
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Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signals appears after addition of boronic ester
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Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signals appears after addition of boronic esterexhibits a saturation depedence on
concentration of ester
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Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
acetic acid additive sodium acetate additive
both display an inhibitory effect on EPR signalsuggesting that paddlewheel structure is stabilized
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Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signal obtained immediately after mixingCu(OAc)2 and boronic ester displays two species
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Chan-Evans-Lam CouplingEPR spectroscopy
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
EPR signal obtained immediately after mixingCu(OAc)2 and boronic ester displays two species
relative concentrations of the two species are alteredby the addition of additives
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Chan-Evans-Lam Couplingmechanism of transmetalation
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
BMeO OMe
1/2[Cu(OAc)2]2Me
O
O
CuII(OAc)
BOMe
OMeMe
O
O
CuII
BOMe
OMe
–OAc
inhibitory effect of addedacetate
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Chan-Evans-Lam Couplingmechanism of transmetalation
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
BMeO OMe
1/2[Cu(OAc)2]2Me
O
O
CuII(OAc)
BOMe
OMeMe
O
O
CuII
BOMe
OMe
–OAc
MeO
O
CuII
BOMe
OMe MeOH OB
CuII
MeOMe
OMe
–HOAc
inhibitory effect of addedacetic acid
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Chan-Evans-Lam Couplingmechanism of transmetalation
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
BMeO OMe
1/2[Cu(OAc)2]2Me
O
O
CuII(OAc)
BOMe
OMeMe
O
O
CuII
BOMe
OMe
–OAc
MeO
O
CuII
BOMe
OMe MeOH OB
CuII
MeOMe
OMe
–HOAc
inhibitory effect of addedacetic acid
BOMe
OMe
MeO
irreversibletransmetalation
aryl Cu(II)
CuII
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Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OH
Me
Cu(II)
OCu(II)
Menucleophile coordination
Copper Oxidasemechanism
lowersCuII/CuIII redox potential
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Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
O Cu(II)
Me
Me
nucleophile coordination
transmetalation
Copper Oxidasemechanism
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
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Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
Cu(II)
Cu(I)
O Cu(II)
Me
Me
O Cu(III)
Me
nucleophile coordination
transmetalation
Copper Oxidasemechanism
Oxidation to Cu(III)
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
stoichiometry determinedfrom single turnover
experiment
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Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
Cu(II)
Cu(I)
O Cu(II)
Me
Me
O Cu(III)
Me
O
Me
Cu(I)
nucleophile coordination
transmetalation
Copper Oxidasemechanism
reductive eliminationOxidation to Cu(III)
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
stoichiometry determinedfrom single turnover
experiment
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Chan-Evans-Lam Couplingmechanism of oxidative coupling
King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.
OHB
HO OH
Me
Cu(II)
OCu(II)
Cu(II)
Cu(I)
O Cu(II)
Me
Me
O Cu(III)
Me
O
Me
Cu(I)
O2
H2O
nucleophile coordination
transmetalation
Copper Oxidasemechanism
reductive eliminationOxidation to Cu(III)
lowersCuII/CuIII redox potential
irreversible and turnover-limiting
stoichiometry determinedfrom single turnover
experiment
stoichiometry determinedfrom single turnover
experiment
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Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
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Ullmann-Goldberg Reaction
Classic Ullmann-Goldberg reaction
cross-coupling reaction mediated by CuI/CuIII redox cycle
X
X = Br, Cl, I2 equiv.
2 equiv. CuIL
symmetric biaryl bond
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Ullmann-Goldberg Reaction
X
H NuCuIL
Nu
X H
Classic Ullmann-Goldberg reaction
Ullmann-type coupling
cross-coupling reaction mediated by CuI/CuIII redox cycle
X
X = Br, Cl, I
X = Br, Cl, I2 equiv.
2 equiv. CuIL
symmetric biaryl bond
C–heteroatom bond
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Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
CuI
nucleophile coordination/deprotonation
CuI
R1
HN
R2
NR2
R1
proposedmechanism
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Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
CuI
nucleophile coordination/deprotonation
CuI
R1
HN
R2
NR2
R1
X
NCuIIIR1
R2
oxidative additionreversible
proposedmechanism
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Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
CuI
nucleophile coordination/deprotonation
CuI
R1
HN
R2
NR2
R1
X
NCuIIIR1
R2
oxidative addition
reductive elimination
NR2
R1
reversible
proposedmechanism
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Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
NCuIIIR1
R2
putative aryl CuIII
■ CuIII has been widely proposed as an intermediate
■ oxidative addition product has never been observed
■ oxidative addition to Cu has no precedent
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Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle
NCuIIIR1
R2
putative aryl CuIII
NNH N
H
R
X
utilization of constrainingmacrocyclic ligands
UV-Vis spectroscopy (NMR, CV, X-ray) kinetics
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Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition
NO2
Br
CuOTf, aq. NH3
acetone
NO2
O2N
NO2
Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753
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Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition
NO2
Br
CuOTf, aq. NH3
acetone
NO2
O2N
NO2
Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753
formation of 2, 2'-dinitro-biphenyl:
NO2
BrCuOTf
2nd order dependence 1st order
formation of nitrobenzene:
NO2
BrCuOTf
1st order1st order
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Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition
NO2
Br
CuOTf, aq. NH3
acetone
NO2
O2N
NO2
Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753
NO2
Br
Cu OTf CuIIIBr
NO2k1
k–1
CuIIIBr
NO2NO2
Br
k2
NO2
O2N
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Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H
Ribas and Stahl's strategy:
X Cu X NNH N
H
R
CuIII
x
X CuI
highly constrained and stabilizedaryl CuIII species
macrocyclic ligand shown toundergo C–H insertion with Cu
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Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H
Ribas and Stahl's strategy:
X Cu X NNH N
H
R
CuIII
x
X CuI
highly constrained and stabilizedaryl CuIII species
macrocyclic ligand shown toundergo C–H insertion with Cu
■ allows for characterization by 1H NMR, CV and UV-Vis
■ allows for study of reductive elmination
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Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
X
Ribas and Stahl's strategy:
NNH N
H
R
CuIII
xX CuI
NH
O
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Ullmann-type Coupling Reactiondirection observation of CuI/CuIII redox steps
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
X
Ribas and Stahl's strategy:
NNH N
H
R
CuIII
xX CuI
■ allows for study of oxidative addition
■ allows for study of mechanism of C–N bond formation
NH
O
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Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
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Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
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Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
electronic spectra (LMCT): agrees with ligand field strengths of the halides
369 and 521 nm 399 and 550 nm 422 and 635 nm
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Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xCuCl2 or CuBr2CuCl or CuBr
cyclic voltammetry: values for CuIII/CuII redox couple
–330mV –310mV –300mV
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Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xN
NH N
H
R
Cl
CuCl2 HOTf (1.5-10 equiv)
MeCN, 298K<1hr
quantitative
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Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xN
NH N
H
R
Cl
CuCl2 HOTf (1.5-10 equiv)
MeCN, 298K<1hr
quantitative
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Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
H NNH N
H
R
CuIII
xN
NH N
H
R
Cl
CuCl2 HOTf (1.5-10 equiv)
MeCN, 298K<1hr
quantitative
NNH N
H
R
CuIII
x
complexX R E1/2 (mV) kobs(S–1) (298K)
Cl
Br
Cl
H
H
Me
–330
–300
–400
7.12(6)x10-2
4.08(5)x10-4
5.05(5)x10-3
rate of reductive elimination controlled by C–halogen bond strength
C–X reductive elimination rates do not correlate with E1/2 values
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Ullmann-type Coupling Reactionreductive elimination
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
BrNNH N
H
R
CuIII
Br
NNH N
H
R
N-pyr
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
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Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
CuI/CuIII
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
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Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
CuI/CuIII
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
■ macrocyclic ligand lowers barrier to oxidative addition
■ macrocyclic ligand stabilizes CuIII
*effectively inverts the relative rates of both redoxsteps
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Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction
Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330
NNH N
H
R
N-pyrNNH N
H
R
Br NH
O3.3 mol% Cu(MeCN)4PF6
CD3CN, 298K
CuI/CuIII
CuI
R2
HN
R3
CuINR3
R2
R1 X
CuIIINR3
R2
R1
R2N
R3
R1
■ macrocyclic ligand lowers barrier to oxidative addition
■ macrocyclic ligand stabilizes CuIII
*effectively inverts the relative rates of both redoxsteps
■ mechanism of Ullmann-Goldberg can vary
*use of less coordinating nucleophiles or higher coordinateligands can affect key redox steps
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Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
![Page 88: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/88.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835
RR2
HN
Z
Cu
O2R N
Z
R2
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
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Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
CuII
R RCuIII CuI
![Page 90: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/90.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
![Page 91: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/91.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
![Page 92: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/92.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
2 equiv. CuX2
AcOH MeO
O Me
O
OMeOMe
![Page 93: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/93.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
2 equiv. CuX2
AcOH MeO
O Me
O
OMeOMe
Cu(OAc)2
Cu(OTf)2
Cu(ClO4)2
CuF2
CuCl2CuBr2
X
![Page 94: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/94.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
2 equiv. CuX2
AcOH MeO
O Me
O
OMeOMe
MeO
OMe
MeO
OMe
Cl Cl
Cl
70% 7%Cu(OAc)2
Cu(OTf)2
Cu(ClO4)2
CuF2
CuCl2
CuBr2
![Page 95: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/95.jpg)
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
25 mol% CuBr2
AcOH, 60°C
OMe
MeO
OMeBr
LiBr
![Page 96: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/96.jpg)
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
25 mol% CuBr2
AcOH, 60°C
OMe
MeO
OMeBr
MeO
25 mol% CuCl2
AcOH, 100°C
OMe
MeO
OMeCl
LiBr
LiCl
6 equiv.
![Page 97: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/97.jpg)
Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
MeO
25 mol% CuBr2
AcOH, 60°C
OMe
MeO
OMeBr
LiBr
CuBr2 2 CuBr Br2
Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448
Δ
regioselectivity follows that of electrophilic aromatic bromination
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Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
CuBr2 2 CuBr Br2
Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448
Δ
regioselectivity follows that of electrophilic aromatic bromination
OMe
OMe
Br
20 mol% NaNO2
1.3 equiv HBr
Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866
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Glaser-Hay Type Couplingspreliminary investigations
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RCu
O2R
HLiX X
X= Cl, Br
CuBr2 2 CuBr Br2
Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448
Δ
regioselectivity follows that of electrophilic aromatic bromination
25 mol% CuBr2
Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866
Br
BrAcOH, O2, LiBr
75%
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Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
![Page 101: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/101.jpg)
Glaser-Hay Type Couplingsoxidative cross-coupling
Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934
Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462
RR2
HN
Z
Cu
O2R N
Z
R2
HN
H
Ar
XR
X= N, O
Cu
O2R
X
NAr
RCu
O2R
HLiX X
X= Cl, Br
Oxidative coupling of a Cu-bound nucleophile and a C–H bond
![Page 102: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/102.jpg)
Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H
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Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H NNH N
H
R
CuIII
Br
CuBr2
–HBr
MeCNN
NH N
H
R
CuI
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Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H NNH N
H
R
CuIII
Br
CuBr2
–HBr
MeCNN
NH N
H
R
CuI
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
![Page 105: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/105.jpg)
Glaser-Hay Type Couplingsevidence for an aryl-CuIII
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
H NNH N
H
R
CuIII
Br
CuBr2
–HBr
MeCNN
NH N
H
R
CuI
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
NNH N
H
R
CuIII
Br
MeCNN
NH N
H
R
NpyrHN
O
![Page 106: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/106.jpg)
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
kinetics determined by O2 consumption
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Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
arene ligand (mM) CuII (mM) pO2 (torr)
1st order dependence 1st order dependence 0 order dependence
![Page 108: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/108.jpg)
Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
arene ligand (mM) CuII (mM) pO2 (torr)
1st order dependence 1st order dependence 0 order dependence
catalytic steps involving O2 are comparatively fastCu reoxidation is not rate-determining
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Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
1H NMR complicated due to paramagnetic line broadeningindicates that CuII is formed during reaction
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Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
CuIII
CuII
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Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuIII
Br
MeCN
MeOHN
NH N
H
R
OMe
CuIII
CuII
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Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
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Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
NNH N
H
R
CuIII
Br
NNH N
H
R
CuI
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Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
MeOH
NNH N
H
R
CuIII
Br
CuI
NNH N
H
R
OMe
NNH N
H
R
CuI
O2
H2O
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Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling
King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169
NNH N
H
R
CuII
NNH N
H
R
H
CuII
MeOH
NNH N
H
R
CuIII
Br
CuI
NNH N
H
R
OMe
NNH N
H
R
CuI
O2
H2O
accounts for apparentbuild-up of CuII during
reaction
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Copper in Cross-Coupling Reactions
BRO OR
X
X = N, O, S
X
oxidative coupling
Chan-Evans-Lam
X
X = halide
Nu
standard cross-coupling
Ullmann-Goldberg
X
X = halide
X
oxidative coupling
"Aromatic Glaser-Hay"
Nu
HN O
O
nucleophile
![Page 117: Mechanistic Studies in Copper Catalysis](https://reader036.fdocuments.us/reader036/viewer/2022082214/586a2c551a28abdf0a8b8885/html5/thumbnails/117.jpg)
Copper in Cross-Coupling Reactions