mechanistic studies in copper catalysis

Mechanistic Studies in Copper Catalysis

Jen AllevaMay 1st 2013

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


Ullmann–Goldberg

1903

Ullman, F. Ber. 1903, 36, 2382–2384Goldberg, I. Ber. 1906, 39, 1691–1692

1869

Glaser




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




Ullmann–Goldberg

1903

Huisgen, R. Proc. Chem Soc., 1961, 357–396

1923 1952

Reich Gilman


1869

Glaser


Huisgen

1961

2001

Sharpless

"Click" Chemistry



Ullmann–Goldberg

1903

Huisgen, R. Proc. Chem Soc., 1961, 357–396

1923 1952

Reich Gilman


1869

Glaser


Huisgen

1961

2001

Sharpless

"Click" Chemistry


1998

Chan-Evans-LamCu C–N couplings

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

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

NNH N

H

R

CuIII

Br











■ highly electrophilic and unstable

■ potent oxidizer

■ requires highly stabilizing 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


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


R1 XR2

HN

R3B ML X

R2N

R3BH


base


electrophile

R1

Pd0/PdII

Pd0

PdIIR1 X

R1 X R2

HN

R3

B

PdIIR1 N R3

R2

R2N

R3

R1

BH


R1 XR2

HN

R3B ML X

R2N

R3BH


base


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


R1 MR2

HN

R3

ML MR2

NR3

M


oxidative cross-coupling: transition metal mediated coupling of two nucleophiles

nucleophile

R1

–2e–


R1 MR2

HN

R3

ML MR2

NR3

M



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


R1 MR2

HN

R3

ML MR2

NR3

M



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


R1 XR2

NR3

MLLG

R2N

R3

organic N–Helectrophile

inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution

nucleophile

R1LG

nucleofugal leavinggroup


R1 XR2

NR3

MLLG

R2N

R3



nucleophile

R1

Pd0/PdII

Pd0

PdIIN LG

R1 X

PdIIR1 N R3

R2

R2N

R3

R1

LG

R2N

R3

LG R3

R2



R1 XR2

NR3

MLLG

R2N

R3



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


R2N

R3

LGR1 X


BRO OR

X

X = N, O, S

X

oxidative coupling

Chan-Evans-Lam

X

X = halide

Nu


Ullmann-Goldberg

X

X = halide

X

oxidative coupling


Nu

HN O

O

nucleophile

Mechanistic Studies in Copper Catalysis

Shannon Stahl Xavi Ribas Ted Cohen


BRO OR

X

X = N, O, S

X

oxidative coupling

Chan-Evans-Lam

X

X = halide

Nu


Ullmann-Goldberg

X

X = halide

X

oxidative coupling


Nu

HN O

O

nucleophile

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

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

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


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


CH2Cl2, O2, r.t.

NN 72%



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


CH2Cl2, O2, r.t.

NN 72%


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

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


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%


Cu and O2 stoichiometry determined from anaerobic single-turnover experiment

CuII/product ratio is 2:1


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%


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

Chan-Evans-Lam Couplinginitial rates experiment reveals turnover-limiting step

BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%


Initial rates experiment: suggest transmetalation as turnover-limiting


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%



■ 1st order dependence on Cu(OAc)2

■ saturation dependence on boronic ester


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%



■ 1st order dependence on Cu(OAc)2

■ saturation dependence on boronic ester

■ 0 order dependence on O2

CuI oxidation is relativelyfast compared totransmetalation

Electron Paramagnetic Resonance Spectroscopy

dx2–y2

dxy

dz2

dyz dxz

CuII: d9, square planar

ground state


dx2–y2

dxy

dz2

dyz dxz


dx2–y2

dxy

dz2

dyz dxz

ground state coupling excited state


dx2–y2

dxy

dz2

dyz dxz


dx2–y2

dxy

dz2

dyz dxz

dx2–y2

dxy

dz2

dyz dxz

ground state coupling excited state dz2 does not coupleorbitals have incorrect symmetry


dx2–y2

dxy

dz2

dyz dxz


dx2–y2

dxy

dz2

dyz dxz

dx2–y2

dxy

dz2

dyz dxz


gobs = ge – xλΔE


dx2–y2

dxy

dz2

dyz dxz


dx2–y2

dxy

dz2

dyz dxz

dx2–y2

dxy

dz2

dyz dxz



gobs: empirical value from spectrum

ge: energy of free electron (2.00023)


dx2–y2

dxy

dz2

dyz dxz


dx2–y2

dxy

dz2

dyz dxz

dx2–y2

dxy

dz2

dyz dxz





x: modification factor of the free electron based on orbital mixing


dx2–y2

dxy

dz2

dyz dxz


dx2–y2

dxy

dz2

dyz dxz

dx2–y2

dxy

dz2

dyz dxz





x: modification factor of the free electron based on orbital mixing

λ: spin orbit coupling constant

ΔE: energy between two orbitals


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%


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

Chan-Evans-Lam Couplingequilibrium prior to transmetalation

BMeO OMe

Me

5 mol% Cu(OAc)2


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.


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%


deviation from standard conditions effect on efficiency

added acetate

added acetic acid

Cu(ClO4)2 instead of Cu(OAc)2

inhibition

inhibition

no reactivity


BMeO OMe

Me

5 mol% Cu(OAc)2


Me Me

OHOMe

B(OMe)2(OH)

88% 12%


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

Chan-Evans-Lam CouplingEPR spectroscopy




EPR signals appears after addition of boronic ester



EPR signals appears after addition of boronic esterexhibits a saturation depedence on

concentration of ester



acetic acid additive sodium acetate additive

both display an inhibitory effect on EPR signalsuggesting that paddlewheel structure is stabilized



EPR signal obtained immediately after mixingCu(OAc)2 and boronic ester displays two species



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

Chan-Evans-Lam Couplingmechanism of transmetalation


BMeO OMe

1/2[Cu(OAc)2]2Me

O

O

CuII(OAc)

BOMe

OMeMe

O

O

CuII

BOMe

OMe

–OAc

inhibitory effect of addedacetate



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



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

Chan-Evans-Lam Couplingmechanism of oxidative coupling


OH

Me

Cu(II)

OCu(II)

Menucleophile coordination

Copper Oxidasemechanism

lowersCuII/CuIII redox potential



OHB

HO OH

Me

Cu(II)

OCu(II)

O Cu(II)

Me

Me

nucleophile coordination

transmetalation



irreversible and turnover-limiting



OHB

HO OH

Me

Cu(II)

OCu(II)

Cu(II)

Cu(I)

O Cu(II)

Me

Me

O Cu(III)

Me


transmetalation


Oxidation to Cu(III)



stoichiometry determinedfrom single turnover

experiment



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)


transmetalation


reductive eliminationOxidation to Cu(III)




experiment



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


transmetalation


reductive eliminationOxidation to Cu(III)




experiment


experiment


BRO OR

X

X = N, O, S

X

oxidative coupling

Chan-Evans-Lam

X

X = halide

Nu


Ullmann-Goldberg

X

X = halide

X

oxidative coupling


Nu

HN O

O

nucleophile

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

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

Ullmann-Goldberg Reactioncross-coupling reaction mediated by CuI/CuIII redox cycle

CuI

nucleophile coordination/deprotonation

CuI

R1

HN

R2

NR2

R1

proposedmechanism


CuI


CuI

R1

HN

R2

NR2

R1

X

NCuIIIR1

R2

oxidative additionreversible

proposedmechanism


CuI


CuI

R1

HN

R2

NR2

R1

X

NCuIIIR1

R2

oxidative addition

reductive elimination

NR2

R1

reversible

proposedmechanism


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


NCuIIIR1

R2

putative aryl CuIII

NNH N

H

R

X

utilization of constrainingmacrocyclic ligands

UV-Vis spectroscopy (NMR, CV, X-ray) kinetics

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

CuOTf, aq. NH3

acetone

NO2

O2N

NO2


formation of 2, 2'-dinitro-biphenyl:

NO2

BrCuOTf

2nd order dependence 1st order

formation of nitrobenzene:

NO2

BrCuOTf

1st order1st order


NO2

Br

CuOTf, aq. NH3

acetone

NO2

O2N

NO2


NO2

Br

Cu OTf CuIIIBr

NO2k1

k–1

CuIIIBr

NO2NO2

Br

k2

NO2

O2N

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



NNH N

H

R

H


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



NNH N

H

R

X


NNH N

H

R

CuIII

xX CuI

NH

O



NNH N

H

R

X


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

Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex


NNH N

H

R

H NNH N

H

R

CuIII

xCuCl2 or CuBr2CuCl or CuBr



NNH N

H

R

H NNH N

H

R

CuIII


electronic spectra (LMCT): agrees with ligand field strengths of the halides

369 and 521 nm 399 and 550 nm 422 and 635 nm



NNH N

H

R

H NNH N

H

R

CuIII


cyclic voltammetry: values for CuIII/CuII redox couple

–330mV –310mV –300mV

Ullmann-type Coupling Reactionreductive elimination


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

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



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

Ullmann-type Coupling Reactionrelationship of this study to the Ullmann reaction


NNH N

H

R

N-pyrNNH N

H

R

Br NH


CD3CN, 298K

CuI/CuIII

CuI

R2

HN

R3

CuINR3

R2

R1 X

CuIIINR3

R2

R1

R2N

R3

R1



NNH N

H

R

N-pyrNNH N

H

R

Br NH


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



NNH N

H

R

N-pyrNNH N

H

R

Br NH


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


BRO OR

X

X = N, O, S

X

oxidative coupling

Chan-Evans-Lam

X

X = halide

Nu


Ullmann-Goldberg

X

X = halide

X

oxidative coupling


Nu

HN O

O

nucleophile

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


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


CuII

R RCuIII CuI




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




RCu

O2R

HLiX X

X= Cl, Br

MeO

2 equiv. CuX2

AcOH MeO

O Me

O

OMeOMe



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



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

Glaser-Hay Type Couplingspreliminary investigations


RCu

O2R

HLiX X

X= Cl, Br

MeO

25 mol% CuBr2

AcOH, 60°C

OMe

MeO

OMeBr

LiBr



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.



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



RCu

O2R

HLiX X

X= Cl, Br

CuBr2 2 CuBr Br2


Δ


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



RCu

O2R

HLiX X

X= Cl, Br

CuBr2 2 CuBr Br2


Δ


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%




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


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

H NNH N

H

R

CuIII

Br

CuBr2

–HBr

MeCNN

NH N

H

R

CuI



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

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

Glaser-Hay Type Couplingskinetics of methoxylation reaction using the method of intial rates


NNH N

H

R

CuIII

Br

MeCN

MeOHN

NH N

H

R

OMe

kinetics determined by O2 consumption



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



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



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



NNH N

H

R

CuIII

Br

MeCN

MeOHN

NH N

H

R

OMe

CuIII

CuII

Glaser-Hay Type Couplingsproposed mechanism of Aromatic Glaser-Hay coupling


NNH N

H

R

CuII

NNH N

H

R

H

CuII



NNH N

H

R

CuII

NNH N

H

R

H

CuII

NNH N

H

R

CuIII

Br

NNH N

H

R

CuI



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



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


BRO OR

X

X = N, O, S

X

oxidative coupling

Chan-Evans-Lam

X

X = halide

Nu


Ullmann-Goldberg

X

X = halide

X

oxidative coupling


Nu

HN O

O

nucleophile

mechanistic studies in copper catalysis

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