Copper in Cross-Coupling Reactions Copper in Cross-Coupling Reactions

Mechanistic Studies in Copper Catalysis

Jen Alleva May 1st 2013 Timeline of Achievements in Copper Chemistry General Historical Overview

ﬁrst cross-couplings

Ullmann–Goldberg

1869

Glaser 1903

Glaser, C. Ann. D. Chemie U. Pharm, 1869, 2, 137–171 Timeline of Achievements in Copper Chemistry General Historical Overview

ﬁrst cross-couplings

Ullmann–Goldberg

1869

Glaser 1903

Ullman, F. Ber. 1903, 36, 2382–2384 Goldberg, I. Ber. 1906, 39, 1691–1692 Timeline of Achievements in Copper Chemistry General Historical Overview

ﬁrst cross-couplings

Ullmann–Goldberg

1869 1923 1952

Glaser 1903 Reich Gilman

synthesis of ﬁrst copper organometallic reagents

Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem, 1952, 17, 1630–1634 Timeline of Achievements in Copper Chemistry General Historical Overview

ﬁrst cross-couplings "Click" Chemistry

Ullmann–Goldberg Huisgen

1869 1923 1952 2001

Glaser 1903 Reich Gilman 1961 Sharpless

synthesis of ﬁrst copper organometallic reagents

Huisgen, R. Proc. Chem Soc., 1961, 357–396 Timeline of Achievements in Copper Chemistry General Historical Overview

ﬁrst cross-couplings "Click" Chemistry

Ullmann–Goldberg Huisgen

1869 1923 1952 1998 2001

Glaser 1903 Reich Gilman 1961 Sharpless

synthesis of ﬁrst copper Chan-Evans-Lam organometallic reagents Cu C–N couplings

Huisgen, R. Proc. Chem Soc., 1961, 357–396 Copper in Cross-Coupling Reactions Copper in Cross-Coupling Reactions

RO OR B X Nu X O X

HN O

X = N, O, S X = halide nucleophile X = halide

oxidative coupling standard cross-coupling oxidative coupling

X Nu X

Chan-Evans-Lam Ullmann-Goldberg "Aromatic Glaser-Hay" Electronic Properties of Copper

E1/2= 0.16V E1/2= 2.4V CuI CuII CuIII

d10 d9 d8, metal cation isoelectronic with isoelectronic with Ni(0) Pd(II)

* Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21 Electronic Properties of Copper

E1/2= 0.16V E1/2= 2.4V CuI CuII CuIII

d10 d9 d8, metal cation isoelectronic with isoelectronic with Ni(0) Pd(II)

■ forms shorter bonds than Pd

■ harder Lewis acidity than Pd

■ higher afﬁnity for O, N ligands

■ smaller coordination shell can not accomodate large ancillary ligands

Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808 * Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21 Electronic Properties of Copper

E1/2= 0.16V E1/2= 2.4V CuI CuII CuIII

d10 d9 d8, metal cation isoelectronic with isoelectronic with Ni(0) Pd(II)

■ forms shorter bonds than Pd ■ highly electrophilic and unstable

■ harder Lewis acidity than Pd ■ potent oxidizer

■ higher afﬁnity for O, N ligands ■ requires highly stabilizing ligands ■ smaller coordination shell can not accomodate large ancillary ligands Br

N H CuIII H N N R

Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808 * Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21 Electronic Properties of Copper

E1/2= 0.16V E1/2= 2.4V CuI CuII CuIII

d10 d9 d8, metal cation isoelectronic with isoelectronic with Ni(0) Pd(II)

■ forms shorter bonds than Pd ■ highly electrophilic and unstable

■ harder Lewis acidity than Pd ■ potent oxidizer

■ higher afﬁnity for O, N ligands ■ requires highly stabilizing ligands

■ smaller coordination shell can not ■ unstable towards the reverse accomodate large ancillary ligands reductive elimination ■ can not take part in ligand exchange

■ requires the nucleophile to be in the coordination sphere prior to oxidative addition

Beletskaya, I. P; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808 * Vs. SCE in MeCN, Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1–21 Cross-Coupling Classiﬁcations regular cross-coupling: transition metal mediated nucleophilic substitution

H R1 ML R1 X N B X N BH R2 R3 R2 R3

organic N–H base electrophile nucleophile Cross-Coupling Classiﬁcations regular cross-coupling: transition metal mediated nucleophilic substitution

H R1 ML R1 X N B X N BH R2 R3 R2 R3

organic N–H base electrophile nucleophile

R1 X H PdII N R R R1 X 2 3 B

Pd0/PdII Pd0 R2 R1 N R PdII 3

R1 N BH R2 R3 Cross-Coupling Classiﬁcations regular cross-coupling: transition metal mediated nucleophilic substitution

H R1 ML R1 X N B X N BH R2 R3 R2 R3

organic N–H base electrophile nucleophile

R R X 2 1 H I PdII N H N Cu R R N R1 X 2 3 R3 R2 R3 B R1 X

Pd0/PdII CuI/CuIII R Pd0 R2 2 I N CuIII R1 N R Cu II 3 R Pd 3 R1

R1 R 1 N N BH R2 R3 R2 R3 nucleophile plays the role of ancillary ligand in CuI/CuIII Cross-Coupling Classiﬁcations oxidative cross-coupling: transition metal mediated coupling of two nucleophiles

H R1 ML R1 M N M N M R2 R3 R2 R3 –2e– organic N–H nucleophile nucleophile Cross-Coupling Classiﬁcations oxidative cross-coupling: transition metal mediated coupling of two nucleophiles

H R1 ML R1 M N M N M R2 R3 R2 R3 –2e– organic N–H nucleophile nucleophile

R M H 1 N PdII R R R1 M 2 3

R2 II IV Pd /Pd R1 N R3 PdII PdII

R2 R N R1 1 R PdIV 3 N R2 R3 Cross-Coupling Classiﬁcations oxidative cross-coupling: transition metal mediated coupling of two nucleophiles

H R1 ML R1 M N M N M R2 R3 R2 R3 –2e– organic N–H nucleophile nucleophile

R2 H N II H Cu R1 M N N R R R R1 X PdII R R 2 3 3 R1 M 2 3

R II 2 Cu R2 PdII/PdIV I II III II R1 N R Cu /Cu /Cu N Cu II 3 II Pd R Pd 3 R1 O2

O2 CuI R2 CuII R N R 1 R R2 1 IV 3 Pd N III N R1 Cu R2 R3 R N 3 R1 R2 R3 Cross-Coupling Classiﬁcations inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution

LG R1 ML R1 X N LG N R2 R3 R2 R3

organic N–H nucleofugal leaving nucleophile electrophile group Cross-Coupling Classiﬁcations inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution

LG R1 ML R1 X N LG N R2 R3 R2 R3

organic N–H nucleofugal leaving nucleophile electrophile group

R2 LG R N LG 3 II N Pd R2 R3 R1 X

Pd0/PdII 0 Pd R2

R1 N R PdII 3

R1 N R2 R3 Cross-Coupling Classiﬁcations inverse or Umpolung cross-coupling: transition metal mediated electrophilic substitution

LG R1 ML R1 X N LG N R2 R3 R2 R3

organic N–H nucleofugal leaving nucleophile electrophile group

R2 LG N LG R3 PdII I N R1 Cu X R R R1 X LG 2 3 R1 X N R2 R3

Pd0/PdII CuI/CuIII R Pd0 R 2 2 III CuI N Cu R1 N R3 R PdII 3 R1

R1 R 1 N N R2 R3 R2 R3 Copper in Cross-Coupling Reactions

RO OR B X Nu X O X

HN O

X = N, O, S X = halide nucleophile X = halide

oxidative coupling standard cross-coupling oxidative coupling

X Nu X

Chan-Evans-Lam Ullmann-Goldberg "Aromatic Glaser-Hay" Mechanistic Studies in Copper Catalysis

Shannon Stahl Xavi Ribas Ted Cohen Copper in Cross-Coupling Reactions

RO OR B X Nu X O X

HN O

X = N, O, S X = halide nucleophile X = halide

oxidative coupling standard cross-coupling oxidative coupling

X Nu X

Chan-Evans-Lam Ullmann-Goldberg "Aromatic Glaser-Hay" Chan-Evans-Lam Coupling oxidative cross-coupling

OH HO OH B O 2 equiv. Cu(OAc)2 4Å mol sieves, O 2 Me EtOAc Me

heteroatom boronic acid diaryl ether nucleophile

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. Chan-Evans-Lam Coupling oxidative cross-coupling

OH HO OH B O 2 equiv. Cu(OAc)2 4Å mol sieves, O 2 Me EtOAc Me

heteroatom boronic acid diaryl ether nucleophile

R2 H N CuII N R X R2 R3 R3 1

II Cu R2 CuI/CuII/CuIII N CuII R 3 R1 can be made catalytic with an O2 added oxidant CuI CuII CEL is stoichiometric in CuII

R2 N III R1 Cu R N 3 R1 R2 R3 Chan-Evans-Lam Coupling select catalytic methods

HO OH H B N 20 mol% [Cu(OH)•TMEDA]2Cl2 N N 72% CH Cl , O , r.t. N 2 2 2

Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236 Chan-Evans-Lam Coupling select catalytic methods

HO OH H B N 20 mol% [Cu(OH)•TMEDA]2Cl2 N N 72% CH Cl , O , r.t. N 2 2 2

Si(OMe)3 1.1 equiv Cu(OAc) H 2 N NH2 61% N N TBAF, DMF, O2, r.t. O O

Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429 Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236 Chan-Evans-Lam Coupling select catalytic methods

HO OH H B N 20 mol% [Cu(OH)•TMEDA]2Cl2 N N 72% CH Cl , O , r.t. N 2 2 2

Si(OMe)3 1.1 equiv Cu(OAc) H 2 N NH2 61% N N TBAF, DMF, O2, r.t. O O

HO OH H NH 5 mol% Cu(OAc)2 N 2 B 91% 10 mol% myristic acid 2,6-lutidine, PhMe, r.t.

Antilla, J. C.; Buchwald, S. L. Org Lett, 2001, 3, 2077–2079 Lam, P. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429 Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236 Chan-Evans-Lam Coupling determining reaction stoichiometry

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Chan-Evans-Lam Coupling determining reaction stoichiometry

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

Cu and O2 stoichiometry determined from anaerobic single-turnover experiment

CuII/product ratio is 2:1

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Chan-Evans-Lam Coupling determining reaction stoichiometry

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

Cu and O2 stoichiometry determined from anaerobic single-turnover experiment

result consistent with Cu oxidase mechanism

II I Cu /product ratio is 2:1 Cu /O2 ratio is 4:1

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Chan-Evans-Lam Coupling initial rates experiment reveals turnover-limiting step

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

Initial rates experiment: suggest transmetalation as turnover-limiting

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Chan-Evans-Lam Coupling initial rates experiment reveals turnover-limiting step

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

Initial rates experiment: suggest transmetalation as turnover-limiting

st ■ 1 order dependence on Cu(OAc)2 ■ saturation dependence on boronic ester

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Chan-Evans-Lam Coupling initial rates experiment reveals turnover-limiting step

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

Initial rates experiment: suggest transmetalation as turnover-limiting

st ■ 1 order dependence on Cu(OAc)2 ■ saturation dependence on boronic ester CuI oxidation is relatively fast compared to ■ 0 order dependence on O2 transmetalation

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 dx –y

dxy

2 dz

dyz dxz

ground state Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 2 2 dx –y dx –y

dxy dxy

2 2 dz dz

dyz dxz dyz dxz

ground state coupling excited state Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 2 2 2 2 dx –y dx –y dx –y

dxy dxy dxy

2 2 2 dz dz dz

dyz dxz dyz dxz dyz dxz

2 ground state coupling excited state dz does not couple orbitals have incorrect symmetry Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 2 2 2 2 dx –y dx –y dx –y

dxy dxy dxy

2 2 2 dz dz dz

dyz dxz dyz dxz dyz dxz

2 ground state coupling excited state dz does not couple orbitals have incorrect symmetry

gobs = ge – xλ ΔE Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 2 2 2 2 dx –y dx –y dx –y

dxy dxy dxy

2 2 2 dz dz dz

dyz dxz dyz dxz dyz dxz

2 ground state coupling excited state dz does not couple orbitals have incorrect symmetry

gobs = ge – xλ gobs: empirical value from spectrum ΔE ge: energy of free electron (2.00023) Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 2 2 2 2 dx –y dx –y dx –y

dxy dxy dxy

2 2 2 dz dz dz

dyz dxz dyz dxz dyz dxz

2 ground state coupling excited state dz does not couple orbitals have incorrect symmetry

gobs = ge – xλ gobs: empirical value from spectrum ΔE ge: energy of free electron (2.00023) x: modiﬁcation factor of the free electron based on orbital mixing Electron Paramagnetic Resonance Spectroscopy

CuII: d9, square planar

2 2 2 2 2 2 dx –y dx –y dx –y

dxy dxy dxy

2 2 2 dz dz dz

dyz dxz dyz dxz dyz dxz

2 ground state coupling excited state dz does not couple orbitals have incorrect symmetry

gobs = ge – xλ gobs: empirical value from spectrum ΔE 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 Chan-Evans-Lam Coupling initial rates experiment reveals turnover-limiting step

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

EPR spectroscopy shows catalyst resting state as CuII

no strong ﬁeld aryl ligand evident reaction progress correlated with consistent with transmetalation being as EPR spectra turnover-limiting

King, A. E.; Brunold, T. C.; Stahl. S. S. J. Am. Chem. Soc. 2009, 131, 5044–5045 Chan-Evans-Lam Coupling equilibrium prior to transmetalation

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling equilibrium prior to transmetalation

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

deviation from standard conditions effect on efﬁciency

added acetate inhibition

added acetic acid inhibition

Cu(ClO4)2 instead of Cu(OAc)2 no reactivity

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling equilibrium prior to transmetalation

MeO OMe B OMe OH

5 mol% Cu(OAc)2 B(OMe)2(OH) 1 atm O2, MeOH 27°C, 6h Me Me Me 88% 12%

deviation from standard conditions effect on efﬁciency

added acetate inhibition

added acetic acid inhibition

Cu(ClO4)2 instead of Cu(OAc)2 no reactivity

Cu(ClO4)2 + 1 equiv NaOAc rate acceleration

Cu(ClO4)2 + 1 equiv NaOMe rate acceleration

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling EPR spectroscopy

EPR signals appears after addition of boronic ester

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling EPR spectroscopy

EPR signals appears after addition of boronic ester exhibits a saturation depedence on concentration of ester

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling EPR spectroscopy

acetic acid additive sodium acetate additive

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

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling EPR spectroscopy

EPR signal obtained immediately after mixing

Cu(OAc)2 and boronic ester displays two species

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling EPR spectroscopy

EPR signal obtained immediately after mixing

Cu(OAc)2 and boronic ester displays two species relative concentrations of the two species are altered by the addition of additives

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of transmetalation

O CuII(OAc) O CuII MeO OMe –OAc B Me OMe Me OMe O B OMe O B OMe 1/2[Cu(OAc)2]2

inhibitory effect of added acetate

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of transmetalation

O CuII(OAc) O CuII MeO OMe –OAc B Me OMe Me OMe O B OMe O B OMe 1/2[Cu(OAc)2]2

II O Cu CuII Me OMe MeOH Me O O B OMe B OMe OMe –HOAc

inhibitory effect of added acetic acid

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of transmetalation

O CuII(OAc) O CuII MeO OMe –OAc B Me OMe Me OMe O B OMe O B OMe 1/2[Cu(OAc)2]2

II O Cu CuII irreversible Me OMe Me O CuII MeOH transmetalation O B OMe B OMe OMe –HOAc

MeO OMe inhibitory effect of added B aryl Cu(II) OMe acetic acid

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of oxidative coupling

OH Cu(II) O

nucleophile coordination Me lowersCuII/CuIII redox potential

Cu(II)

Copper Oxidase mechanism

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of oxidative coupling

OH HO OH Cu(II) B O

irreversible and turnover-limiting Me transmetalation nucleophile coordination Me lowersCuII/CuIII redox potential

Cu(II) O Cu(II)

Copper Oxidase mechanism Me

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of oxidative coupling

OH HO OH Cu(II) B O

irreversible and turnover-limiting Me transmetalation nucleophile coordination Me lowersCuII/CuIII redox potential

Cu(II) O Cu(II)

Copper Oxidase mechanism Me

Cu(II)

Oxidation to Cu(III) O Cu(III) stoichiometry determined Cu(I) from single turnover experiment Me

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of oxidative coupling

OH HO OH Cu(II) B O

irreversible and turnover-limiting Me transmetalation nucleophile coordination Me lowersCuII/CuIII redox potential

Cu(II) O Cu(II)

Copper Oxidase mechanism Me

Cu(I) Cu(II)

Oxidation to Cu(III) O Cu(III) reductive elimination stoichiometry determined Cu(I) O from single turnover experiment Me Me

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Chan-Evans-Lam Coupling mechanism of oxidative coupling

OH HO OH Cu(II) B O

irreversible and turnover-limiting Me transmetalation nucleophile coordination Me lowersCuII/CuIII redox potential

Cu(II) O Cu(II)

H2O Copper Oxidase stoichiometry determined mechanism from single turnover Me O experiment 2 Cu(I) Cu(II)

Oxidation to Cu(III) O Cu(III) reductive elimination stoichiometry determined Cu(I) O from single turnover experiment Me Me

King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Organometallics, 2012, 31, 7948. Copper in Cross-Coupling Reactions

RO OR B X Nu X O X

HN O

X = N, O, S X = halide nucleophile X = halide

oxidative coupling standard cross-coupling oxidative coupling

X Nu X

Chan-Evans-Lam Ullmann-Goldberg "Aromatic Glaser-Hay" Ullmann-Goldberg Reaction cross-coupling reaction mediated by CuI/CuIII redox cycle

Classic Ullmann-Goldberg reaction

2 equiv. CuIL

2 equiv. symmetric biaryl bond X = Br, Cl, I Ullmann-Goldberg Reaction cross-coupling reaction mediated by CuI/CuIII redox cycle

Classic Ullmann-Goldberg reaction

2 equiv. CuIL

2 equiv. symmetric biaryl bond X = Br, Cl, I

Ullmann-type coupling

X Nu CuIL H Nu X H

X = Br, Cl, I C–heteroatom bond Ullmann-Goldberg Reaction cross-coupling reaction mediated by CuI/CuIII redox cycle

nucleophile coordination/

deprotonation R1 N CuI H R2 N R1 R2

proposed mechanism CuI Ullmann-Goldberg Reaction cross-coupling reaction mediated by CuI/CuIII redox cycle

nucleophile coordination/ reversible

deprotonation R1 oxidative addition N CuI H R2 X N R1 R2

proposed mechanism CuI III R1 Cu N

R2 Ullmann-Goldberg Reaction cross-coupling reaction mediated by CuI/CuIII redox cycle

nucleophile coordination/ reversible

deprotonation R1 oxidative addition N CuI H R2 X N R1 R2

proposed mechanism CuI III R1 Cu N

reductive elimination

R1 N

R2 Ullmann-Goldberg Reaction cross-coupling reaction mediated by CuI/CuIII redox cycle

III R1 Cu N

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

III R1 Cu N

putative aryl CuIII

N H X H N N R

utilization of constraining macrocyclic ligands

UV-Vis spectroscopy (NMR, CV, X-ray) kinetics Ullmann-Goldberg Reaction kinetics reveal reversible oxidative addition

NO2 NO2 NO CuOTf, aq. NH3 2

Br acetone

O2N

Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753 Ullmann-Goldberg Reaction kinetics reveal reversible oxidative addition

NO2 NO2 NO CuOTf, aq. NH3 2

Br acetone

O2N

formation of 2, 2'-dinitro-biphenyl: formation of nitrobenzene:

NO2 NO2 CuOTf CuOTf Br Br

2nd order dependence 1st order 1st order 1st order

Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753 Ullmann-Goldberg Reaction kinetics reveal reversible oxidative addition

NO2 NO2 NO CuOTf, aq. NH3 2

Br acetone

O2N

k NO2 NO2 1 Cu OTf CuIII Br k Br –1

NO2 NO2 CuIII NO2 k Br 2

Br O2N

Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753 Ullmann-type Coupling Reaction direction observation of CuI/CuIII redox steps

Ribas and Stahl's strategy:

N H X Cu X H N H X CuI N CuIII H H N N N R R

macrocyclic ligand shown to highly constrained and stabilized undergo C–H insertion with Cu aryl CuIII species

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction direction observation of CuI/CuIII redox steps

Ribas and Stahl's strategy:

N H X Cu X H N H X CuI N CuIII H H N N N R R

macrocyclic ligand shown to highly constrained and stabilized undergo C–H insertion with Cu aryl CuIII species

■ allows for characterization by 1H NMR, CV and UV-Vis

■ allows for study of reductive elmination

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction direction observation of CuI/CuIII redox steps

Ribas and Stahl's strategy:

x X CuI N H X N H N CuIII H O H N N N R NH R

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction direction observation of CuI/CuIII redox steps

Ribas and Stahl's strategy:

x X CuI N H X N H N CuIII H O H N N N R NH R

■ allows for study of oxidative addition

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

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction characterization of aryl-CuIII complex

x CuCl2 or CuBr2 N H H N H CuCl or CuBr N CuIII H H N N N R R

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction characterization of aryl-CuIII complex

x CuCl2 or CuBr2 N H H N H CuCl or CuBr N CuIII H H N N N R R

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction characterization of aryl-CuIII complex

x CuCl2 or CuBr2 N H H N H CuCl or CuBr N CuIII H H N N N R R

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

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

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction characterization of aryl-CuIII complex

x CuCl2 or CuBr2 N H H N H CuCl or CuBr N CuIII H H N N N R R

cyclic voltammetry: values for CuIII/CuII redox couple

–330mV –310mV –300mV

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction reductive elimination

x CuCl2 HOTf (1.5-10 equiv) N H N H H N H Cl N CuIII N H H N MeCN, 298K H N N N <1hr R R R quantitative

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction reductive elimination

x CuCl2 HOTf (1.5-10 equiv) N H N H H N H Cl N CuIII N H H N MeCN, 298K H N N N <1hr R R R quantitative

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction reductive elimination

x CuCl2 HOTf (1.5-10 equiv) N H N H H N H Cl N CuIII N H H N MeCN, 298K H N N N <1hr R R R quantitative

–1 X R E1/2 (mV) kobs(S ) (298K) complex Cl H –330 7.12(6)x10-2 x

N H Br H –300 4.08(5)x10-4 CuIII H N N Cl Me –400 5.05(5)x10-3 R

rate of reductive elimination controlled by C–halogen bond strength

C–X reductive elimination rates do not correlate with E1/2 values

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction reductive elimination

N H N-pyr H N N Br R N H N H Br III H N Cu N H N N R R

O 3.3 mol% Cu(MeCN) PF N H 4 6 N H Br NH N-pyr H N H N N CD3CN, 298K N R R

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction relationship of this study to the Ullmann reaction

O 3.3 mol% Cu(MeCN) PF N H 4 6 N H Br NH N-pyr H N H N N CD3CN, 298K N R R

R2 I H N Cu N R3 R2 R3 R1 X

CuI/CuIII R2 III CuI N Cu R 3 R1

R1 N R2 R3

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction relationship of this study to the Ullmann reaction

O 3.3 mol% Cu(MeCN) PF N H 4 6 N H Br NH N-pyr H N H N N CD3CN, 298K N R R

R1 N R2 R3

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Ullmann-type Coupling Reaction relationship of this study to the Ullmann reaction

O 3.3 mol% Cu(MeCN) PF N H 4 6 N H Br NH N-pyr H N H N N CD3CN, 298K N R R

R2 I H N Cu ■ macrocyclic ligand lowers barrier to oxidative addition N R3 R2 R3 ■ macrocyclic ligand stabilizes CuIII R1 X *effectively inverts the relative rates of both redox steps CuI/CuIII R2 III CuI N Cu ■ mechanism of Ullmann-Goldberg can vary R 3 R1 *use of less coordinating nucleophiles or higher coordinate ligands can affect key redox steps R1 N R2 R3

Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem Sci. 2010, 1, 326–330 Copper in Cross-Coupling Reactions

RO OR B X Nu X O X

HN O

X = N, O, S X = halide nucleophile X = halide

oxidative coupling standard cross-coupling oxidative coupling

X Nu X

Chan-Evans-Lam Ullmann-Goldberg "Aromatic Glaser-Hay" Glaser-Hay Type Couplings oxidative cross-coupling

Oxidative coupling of a Cu-bound nucleophile and a C–H bond

R H Cu 2 N R R N R Z 2 O2 Z

Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835 Glaser-Hay Type Couplings oxidative cross-coupling

Oxidative coupling of a Cu-bound nucleophile and a C–H bond

R H Cu 2 N R R N R Z 2 O2 Z

CuII

R CuIII R CuI

Hamada, T; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835 Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 1932–1934 Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings oxidative cross-coupling

Oxidative coupling of a Cu-bound nucleophile and a C–H bond

R H Cu 2 N R R N R Z 2 O2 Z

H N Ar Cu N R X R Ar H O2 X X= N, O

LiX H Cu X R R X= Cl, Br O2

Oxidative coupling of a Cu-bound nucleophile and a C–H bond

R H Cu 2 N R R N R Z 2 O2 Z

H N Ar Cu N R X R Ar H O2 X X= N, O

LiX H Cu X R R X= Cl, Br O2

OMe OMe

2 equiv. CuX2 O Me

O MeO AcOH MeO

Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings oxidative cross-coupling

LiX H Cu X R R X= Cl, Br O2

OMe OMe

2 equiv. CuX2 O Me X O MeO AcOH MeO

Cu(OAc)2

Cu(OTf)2

Cu(ClO4)2

CuF2

CuCl2

CuBr2

Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings oxidative cross-coupling

LiX H Cu X R R X= Cl, Br O2

OMe OMe OMe OMe Cl Cl 2 equiv. CuX2 O Me

O MeO AcOH MeO MeO MeO Cl

70% 7% Cu(OAc)2

Cu(OTf)2

Cu(ClO4)2

CuF2

CuCl2

CuBr2

Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings preliminary investigations

LiX H Cu X R R X= Cl, Br O2

OMe OMe Br 25 mol% CuBr2 LiBr

MeO AcOH, 60°C MeO

Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings preliminary investigations

LiX H Cu X R R X= Cl, Br O2

OMe OMe Br 25 mol% CuBr2 LiBr

MeO AcOH, 60°C MeO

OMe OMe 25 mol% CuCl Cl LiCl 2

MeO 6 equiv. AcOH, 100°C MeO

Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings preliminary investigations

LiX H Cu X R R X= Cl, Br O2

OMe OMe Br 25 mol% CuBr2 LiBr

MeO AcOH, 60°C MeO

Δ CuBr2 2 CuBr Br2

regioselectivity follows that of electrophilic aromatic bromination

Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448 Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings preliminary investigations

LiX H Cu X R R X= Cl, Br O2

O O 20 mol% NaNO2 Me Me

1.3 equiv HBr Br

Δ CuBr2 2 CuBr Br2

regioselectivity follows that of electrophilic aromatic bromination

Zhang, G.; Liu, R.; Xu, Q.; Ma, L.; Liang, X. Adv. Synth. Catal. 2006, 346, 862–866 Barnes, J. C.; Hume, D. N. Inorg. Chem. 1963, 2, 445–448 Yang, L.; Lu, Z.; Stahl, S. S. Chem Commun, 2009, 6460–6462 Glaser-Hay Type Couplings preliminary investigations

LiX H Cu X R R X= Cl, Br O2

25 mol% CuBr2 Br

Br AcOH, O2, LiBr

75%

Δ CuBr2 2 CuBr Br2

regioselectivity follows that of electrophilic aromatic bromination

Oxidative coupling of a Cu-bound nucleophile and a C–H bond

R H Cu 2 N R R N R Z 2 O2 Z

H N Ar Cu N R X R Ar H O2 X X= N, O

LiX H Cu X R R X= Cl, Br O2

Oxidative coupling of a Cu-bound nucleophile and a C–H bond

R H Cu 2 N R R N R Z 2 O2 Z

H N Ar Cu N R X R Ar H O2 X X= N, O

LiX H Cu X R R X= Cl, Br O2

N H H H N N R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings evidence for an aryl-CuIII

Br –HBr N H N H H N H I N CuBr2 CuIII Cu H MeCN N N N H H N N R R R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings evidence for an aryl-CuIII

Br –HBr N H N H H N H I N CuBr2 CuIII Cu H MeCN N N N H H N N R R R

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings evidence for an aryl-CuIII

Br –HBr N H N H H N H I N CuBr2 CuIII Cu H MeCN N N N H H N N R R R

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

O Br N H N H III Npyr HN Cu N H N MeCN H N N R R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings kinetics of methoxylation reaction using the method of intial rates

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

kinetics determined by O2 consumption

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

II arene ligand (mM) Cu (mM) pO2 (torr)

1st order dependence 1st order dependence 0 order dependence

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

II arene ligand (mM) Cu (mM) pO2 (torr)

1st order dependence 1st order dependence 0 order dependence

catalytic steps involving O2 are comparatively fast Cu reoxidation is not rate-determining

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

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

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

CuIII

CuII

Br MeOH N H N H III OMe Cu N H N MeCN H N N R R

CuIII

CuII

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings proposed mechanism of Aromatic Glaser-Hay coupling

N H CuII N N H H H N H N N R R

CuII

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings proposed mechanism of Aromatic Glaser-Hay coupling

N H CuI N H N CuII H N N N H H H N R H N N R R

N H CuIII H N CuII N R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings proposed mechanism of Aromatic Glaser-Hay coupling

N H CuI N H N CuII H N N N H H H N R H N N R R

N H CuIII H N CuII N R

H2O I MeOH O2 Cu

N H OMe H N N R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Glaser-Hay Type Couplings proposed mechanism of Aromatic Glaser-Hay coupling

N H CuI N H N CuII H N N N H H H N R H N N R R

N H CuIII accounts for apparent H N CuII N II build-up of Cu during R reaction

H2O I MeOH O2 Cu

N H OMe H N N R

King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am Chem. Soc, 2010, 1147–1169 Copper in Cross-Coupling Reactions

RO OR B X Nu X O X

HN O

X = N, O, S X = halide nucleophile X = halide

oxidative coupling standard cross-coupling oxidative coupling

X Nu X

Chan-Evans-Lam Ullmann-Goldberg "Aromatic Glaser-Hay" Copper in Cross-Coupling Reactions