Mechanistic Studies in Copper Catalysis

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  • Mechanistic Studies in Copper Catalysis

    Jen AllevaMay 1st 2013

  • Timeline of Achievements in Copper Chemistry

    UllmannGoldberg

    1903

    Glaser, C. Ann. D. Chemie U. Pharm, 1869, 2, 137171

    1869

    Glaser

    first cross-couplings

    General Historical Overview

  • Timeline of Achievements in Copper Chemistry

    UllmannGoldberg

    1903

    Ullman, F. Ber. 1903, 36, 23822384Goldberg, I. Ber. 1906, 39, 16911692

    1869

    Glaser

    first cross-couplings

    General Historical Overview

  • Timeline of Achievements in Copper Chemistry

    UllmannGoldberg

    1903

    Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem, 1952, 17, 16301634

    1923 1952

    Reich Gilman

    synthesis of first copperorganometallic reagents

    1869

    Glaser

    first cross-couplings

    General Historical Overview

  • Timeline of Achievements in Copper Chemistry

    UllmannGoldberg

    1903

    Huisgen, R. Proc. Chem Soc., 1961, 357396

    1923 1952

    Reich Gilman

    synthesis of first copperorganometallic reagents

    1869

    Glaser

    first cross-couplings

    Huisgen

    1961

    2001

    Sharpless

    "Click" Chemistry

    General Historical Overview

  • Timeline of Achievements in Copper Chemistry

    UllmannGoldberg

    1903

    Huisgen, R. Proc. Chem Soc., 1961, 357396

    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 CN couplings

  • Copper in Cross-Coupling Reactions

  • 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, 121

    d8, metal cationd9d10

    isoelectronic withNi(0)

    isoelectronic withPd(II)

  • 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, 121

    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, 77537808

  • 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, 121

    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, 77537808

  • 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, 121

    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, 77537808

  • Cross-Coupling Classifications

    R1 X R2

    HN

    R3B ML X

    R2N

    R3BH

    organic NHnucleophile

    base

    regular cross-coupling: transition metal mediated nucleophilic substitution

    electrophile

    R1

  • Cross-Coupling Classifications

    R1 X R2

    HN

    R3B ML X

    R2N

    R3BH

    organic NHnucleophile

    base

    regular cross-coupling: transition metal mediated nucleophilic substitution

    electrophile

    R1

    Pd0/PdII

    Pd0

    PdIIR1 X

    R1 X R2

    HN

    R3B

    PdIIR1 N R3

    R2

    R2N

    R3

    R1BH

  • Cross-Coupling Classifications

    R1 X R2

    HN

    R3B ML X

    R2N

    R3BH

    organic NHnucleophile

    base

    regular cross-coupling: transition metal mediated nucleophilic substitution

    electrophile

    R1

    Pd0/PdII CuI/CuIII

    Pd0

    PdIIR1 X

    R1 X R2

    HN

    R3B

    PdIIR1 N R3

    R2

    R2N

    R3

    R1BH

    CuI

    R2

    HN

    R3

    CuINR3

    R2

    R1 X

    CuIIINR3

    R2

    R1

    R2N

    R3

    R1

    nucleophile plays the role of ancillary ligand in CuI/CuIII

  • Cross-Coupling Classifications

    R1 M R2

    HN

    R3ML M

    R2N

    R3M

    organic NHnucleophile

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

    nucleophile

    R1

    2e

  • Cross-Coupling Classifications

    R1 M R2

    HN

    R3ML M

    R2N

    R3M

    organic NHnucleophile

    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

  • Cross-Coupling Classifications

    R1 M R2

    HN

    R3ML M

    R2N

    R3M

    organic NHnucleophile

    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

    R3CuIIN

    R3

    R2

    R1 X

    CuIINR3

    R2

    R1

    R2N

    R3

    R1

    2e

    PdII

    CuICuII

    CuIIINR3

    R2

    R1

    O2

    PdIVR1 N R3

    R2

    O2

  • Cross-Coupling Classifications

    R1 X R2N

    R3

    MLLG

    R2N

    R3

    organic NHelectrophile

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

    nucleophile

    R1LG

    nucleofugal leavinggroup

  • Cross-Coupling Classifications

    R1 X R2N

    R3

    MLLG

    R2N

    R3

    organic NHelectrophile

    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

  • Cross-Coupling Classifications

    R1 X R2N

    R3

    MLLG

    R2N

    R3

    organic NHelectrophile

    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

  • 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

  • Mechanistic Studies in Copper Catalysis

    Shannon Stahl Xavi Ribas Ted Cohen

  • 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

  • Chan-Evans-Lam Couplingoxidative cross-coupling

    OH

    Me

    BHO OH

    2 equiv. Cu(OAc)2

    4 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

    4 mol sieves, O2EtOAc

    O

    Me

    heteroatom boronic acid diaryl ethernucleophile

    CuI/CuII/CuIIICuII

    R2

    HN

    R3CuIIN

    R3

    R2

    R1 X

    CuIINR3

    R2

    R1

    R2N

    R3

    R1

    CuICuII

    CuIIINR3

    R2

    R1