Mechanistic Studies in Copper Catalysis

Jen AllevaMay 1st 2013

Timeline of Achievements in Copper Chemistry

Ullmann–Goldberg

Glaser, C. Ann. D. Chemie U. Pharm, 1869, 2, 137–171

Glaser

first cross-couplings

General Historical Overview

Ullmann–Goldberg

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

Glaser

Ullmann–Goldberg

Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem, 1952, 17, 1630–1634

1923 1952

Reich Gilman

synthesis of first copperorganometallic reagents

Glaser

Ullmann–Goldberg

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

1923 1952

Reich Gilman

Glaser

Huisgen

Sharpless

"Click" Chemistry

Ullmann–Goldberg

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

1923 1952

Reich Gilman

Glaser

Huisgen

Sharpless

"Click" Chemistry

Chan-Evans-LamCu C–N couplings

Copper in Cross-Coupling Reactions

BRO OR

X = N, O, S

oxidative coupling

Chan-Evans-Lam

X = halide

standard cross-coupling

Ullmann-Goldberg

X = halide

oxidative coupling

"Aromatic Glaser-Hay"

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

■ 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

R3B ML X

organic N–Hnucleophile

regular cross-coupling: transition metal mediated nucleophilic substitution

electrophile

R1 XR2

R3B ML X

electrophile

Pd0/PdII

PdIIR1 X

R1 X R2

PdIIR1 N R3

R1 XR2

R3B ML X

electrophile

Pd0/PdII CuI/CuIII

PdIIR1 X

R1 X R2

PdIIR1 N R3

CuINR3

CuIIINR3

nucleophile plays the role of ancillary ligand in CuI/CuIII

R1 MR2

ML MR2

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

nucleophile

–2e–

R1 MR2

ML MR2

nucleophile

PdII/PdIV

PdIIR1 M

R1 M R2

PdIIR1 N R3

–2e–

PdIVR1 N R3

R1 MR2

ML MR2

nucleophile

PdII/PdIV CuI/CuII/CuIII

PdIIR1 M

R1 M R2

PdIIR1 N R3

CuIINR3

–2e–

CuIIINR3

PdIVR1 N R3

R1 XR2

organic N–Helectrophile

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

nucleophile

nucleofugal leavinggroup

R1 XR2

nucleophile

Pd0/PdII

PdIIN LG

PdIIR1 N R3

R1 XR2

nucleophile

Pd0/PdII CuI/CuIII

PdIIN LG

PdIIR1 N R3

CuIR1 X

CuIIINR3

LGR1 X

BRO OR

X = N, O, S

oxidative coupling

Chan-Evans-Lam

X = halide

Ullmann-Goldberg

X = halide

oxidative coupling

nucleophile

Mechanistic Studies in Copper Catalysis

Shannon Stahl Xavi Ribas Ted Cohen

BRO OR

X = N, O, S

oxidative coupling

Chan-Evans-Lam

X = halide

Ullmann-Goldberg

X = halide

oxidative coupling

nucleophile

Chan-Evans-Lam Couplingoxidative cross-coupling

BHO OH

2 equiv. Cu(OAc)2

4Å mol sieves, O2EtOAc

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

BHO OH

2 equiv. Cu(OAc)2

4Å mol sieves, O2EtOAc

heteroatom boronic acid diaryl ethernucleophile

CuI/CuII/CuIIICuII

CuIINR3

CuIIINR3

CEL is stoichiometric in CuII

can be made catalytic with anadded oxidant

Chan-Evans-Lam Couplingselect catalytic methods

BHO OH

HN 20 mol% [Cu(OH)•TMEDA]2Cl2

CH2Cl2, O2, r.t.

NN 72%

Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236

Si(OMe)31.1 equiv Cu(OAc)2

TBAF, DMF, O2, r.t.N

Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429

BHO OH

CH2Cl2, O2, r.t.

NN 72%

Si(OMe)31.1 equiv Cu(OAc)2

TBAF, DMF, O2, r.t.N

Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429

BHO OH

CH2Cl2, O2, r.t.

NN 72%

5 mol% Cu(OAc)2

2,6-lutidine, PhMe, r.t.

BHO OHNH2

10 mol% myristic acid

Antilla, J. C.; Buchwald, S. L. Org Lett, 2001, 3, 2077–2079

Chan-Evans-Lam Couplingdetermining reaction stoichiometry

BMeO OMe

5 mol% Cu(OAc)2

1 atm O2, MeOH27°C, 6h

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

5 mol% Cu(OAc)2

B(OMe)2(OH)

88% 12%

Cu and O2 stoichiometry determined from anaerobic single-turnover experiment

CuII/product ratio is 2:1

BMeO OMe

5 mol% Cu(OAc)2

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

5 mol% Cu(OAc)2

B(OMe)2(OH)

88% 12%

Initial rates experiment: suggest transmetalation as turnover-limiting

BMeO OMe

5 mol% Cu(OAc)2

B(OMe)2(OH)

88% 12%

■ 1st order dependence on Cu(OAc)2

■ saturation dependence on boronic ester

BMeO OMe

5 mol% Cu(OAc)2

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

dyz dxz

CuII: d9, square planar

ground state

dx2–y2

dyz dxz

dx2–y2

dyz dxz

ground state coupling excited state

dx2–y2

dyz dxz

dx2–y2

dyz dxz

dx2–y2

dyz dxz

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

dx2–y2

dyz dxz

dx2–y2

dyz dxz

dx2–y2

dyz dxz

gobs = ge – xλΔE

dx2–y2

dyz dxz

dx2–y2

dyz dxz

dx2–y2

dyz dxz

gobs: empirical value from spectrum

ge: energy of free electron (2.00023)

dx2–y2

dyz dxz

dx2–y2

dyz dxz

dx2–y2

dyz dxz

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

dx2–y2

dyz dxz

dx2–y2

dyz dxz

dx2–y2

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

5 mol% Cu(OAc)2

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

5 mol% Cu(OAc)2

B(OMe)2(OH)

88% 12%

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948.

BMeO OMe

5 mol% Cu(OAc)2

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

no reactivity

BMeO OMe

5 mol% Cu(OAc)2

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

no reactivity

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

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

CuII(OAc)

–OAc

inhibitory effect of addedacetate

BMeO OMe

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

CuII(OAc)

–OAc

OMe MeOH OB

–HOAc

inhibitory effect of addedacetic acid

BMeO OMe

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

CuII(OAc)

–OAc

OMe MeOH OB

–HOAc

inhibitory effect of addedacetic acid

irreversibletransmetalation

aryl Cu(II)

Chan-Evans-Lam Couplingmechanism of oxidative coupling

Cu(II)

OCu(II)

Menucleophile coordination

Copper Oxidasemechanism

lowersCuII/CuIII redox potential

Cu(II)

OCu(II)

O Cu(II)

nucleophile coordination

transmetalation

irreversible and turnover-limiting

Cu(II)

OCu(II)

Cu(II)

O Cu(II)

O Cu(III)

transmetalation

Oxidation to Cu(III)

stoichiometry determinedfrom single turnover

experiment

Cu(II)

OCu(II)

Cu(II)

O Cu(II)

O Cu(III)

transmetalation

reductive eliminationOxidation to Cu(III)

experiment

Cu(II)

OCu(II)

Cu(II)

O Cu(II)

O Cu(III)

transmetalation

reductive eliminationOxidation to Cu(III)

experiment

BRO OR

X = N, O, S

oxidative coupling

Chan-Evans-Lam

X = halide

Ullmann-Goldberg

X = halide

oxidative coupling

nucleophile

Ullmann-Goldberg Reaction

Classic Ullmann-Goldberg reaction

cross-coupling reaction mediated by CuI/CuIII redox cycle

X = Br, Cl, I2 equiv.

2 equiv. CuIL

symmetric biaryl bond

Ullmann-Goldberg Reaction

H NuCuIL

Classic Ullmann-Goldberg reaction

Ullmann-type coupling

cross-coupling reaction mediated by CuI/CuIII redox cycle

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

nucleophile coordination/deprotonation

proposedmechanism

NCuIIIR1

oxidative additionreversible

proposedmechanism

NCuIIIR1

oxidative addition

reductive elimination

reversible

proposedmechanism

NCuIIIR1

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

putative aryl CuIII

utilization of constrainingmacrocyclic ligands

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

Ullmann-Goldberg Reactionkinetics reveal reversible oxidative addition

CuOTf, aq. NH3

acetone

Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753

CuOTf, aq. NH3

acetone

formation of 2, 2'-dinitro-biphenyl:

BrCuOTf

2nd order dependence 1st order

formation of nitrobenzene:

BrCuOTf

1st order1st order

CuOTf, aq. NH3

acetone

Cu OTf CuIIIBr

CuIIIBr

NO2NO2

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

Ribas and Stahl's strategy:

X Cu X NNH N

highly constrained and stabilizedaryl CuIII species

macrocyclic ligand shown toundergo C–H insertion with Cu

X Cu X NNH N

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

xX CuI

■ allows for study of oxidative addition

■ allows for study of mechanism of C–N bond formation

Ullmann-type Coupling Reactioncharacterization of aryl-CuIII complex

H NNH N

xCuCl2 or CuBr2CuCl or CuBr

H NNH N

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

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

H NNH N

cyclic voltammetry: values for CuIII/CuII redox couple

–330mV –310mV –300mV

Ullmann-type Coupling Reactionreductive elimination

H NNH N

CuCl2 HOTf (1.5-10 equiv)

MeCN, 298K<1hr

quantitative

H NNH N

MeCN, 298K<1hr

quantitative

H NNH N

MeCN, 298K<1hr

quantitative

complexX R E1/2 (mV) kobs(S–1) (298K)

–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

BrNNH N

N-pyrNNH N

O3.3 mol% Cu(MeCN)4PF6

CD3CN, 298K

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

N-pyrNNH N

CD3CN, 298K

CuI/CuIII

CuINR3

CuIIINR3

N-pyrNNH N

CD3CN, 298K

CuI/CuIII

CuINR3

CuIIINR3

■ macrocyclic ligand lowers barrier to oxidative addition

■ macrocyclic ligand stabilizes CuIII

*effectively inverts the relative rates of both redoxsteps

N-pyrNNH N

CD3CN, 298K

CuI/CuIII

CuINR3

CuIIINR3

■ 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 = N, O, S

oxidative coupling

Chan-Evans-Lam

X = halide

Ullmann-Goldberg

X = halide

oxidative coupling

nucleophile

Glaser-Hay Type Couplingsoxidative cross-coupling

Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835

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

R RCuIII CuI

X= N, O

HLiX X

X= Cl, Br

X= N, O

HLiX X

X= Cl, Br

HLiX X

X= Cl, Br

2 equiv. CuX2

AcOH MeO

OMeOMe

HLiX X

X= Cl, Br

2 equiv. CuX2

AcOH MeO

OMeOMe

Cu(OAc)2

Cu(OTf)2

Cu(ClO4)2

CuCl2CuBr2

HLiX X

X= Cl, Br

2 equiv. CuX2

AcOH MeO

OMeOMe

70% 7%Cu(OAc)2

Cu(OTf)2

Cu(ClO4)2

Glaser-Hay Type Couplingspreliminary investigations

HLiX X

X= Cl, Br

25 mol% CuBr2

AcOH, 60°C

HLiX X

X= Cl, Br

25 mol% CuBr2

AcOH, 60°C

25 mol% CuCl2

AcOH, 100°C

6 equiv.

HLiX X

X= Cl, Br

25 mol% CuBr2

AcOH, 60°C

CuBr2 2 CuBr Br2

Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448

regioselectivity follows that of electrophilic aromatic bromination

HLiX X

X= Cl, Br

CuBr2 2 CuBr Br2

20 mol% NaNO2

1.3 equiv HBr

Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866

HLiX X

X= Cl, Br

CuBr2 2 CuBr Br2

25 mol% CuBr2

Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866

BrAcOH, O2, LiBr

X= N, O

HLiX X

X= Cl, Br

X= N, O

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

H NNH N

–HBr

H NNH N

–HBr

H NNH N

–HBr

NpyrHN

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

kinetics determined by O2 consumption

arene ligand (mM) CuII (mM) pO2 (torr)

1st order dependence 1st order dependence 0 order dependence

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

1H NMR complicated due to paramagnetic line broadeningindicates that CuII is formed during reaction

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

accounts for apparentbuild-up of CuII during

reaction

BRO OR

X = N, O, S

oxidative coupling

Chan-Evans-Lam

X = halide

Ullmann-Goldberg

X = halide

oxidative coupling

nucleophile

Mechanistic Studies in Copper Catalysis

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