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Cu-mediated biaryl coupling

Ullmann coupling

How the Ullmann coupling works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.

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In short. A 3-step mechanism. Typical reagents: ArX (I > Br), Cu powder or Cu(I) salt. Conditions: Neat or DMF/nitrobenzene, 150–250 °C (milder with ligands). Bonds formed: Ar–Ar (C–C σ); CuX; bonds broken: two C–X bonds. Stereochemistry: Hindered biaryls can show axial chirality. Rate and selectivity: Oxidative addition to Cu is rate-limiting; needs high T.

At a glance

ReagentsArX (I > Br), Cu powder or Cu(I) salt
Solvent / conditionsNeat or DMF/nitrobenzene, 150–250 °C (milder with ligands)
Bonds formedAr–Ar (C–C σ); CuX
Bonds brokentwo C–X bonds
StereochemistryHindered biaryls can show axial chirality
Rate / selectivityOxidative addition to Cu is rate-limiting; needs high T

Step 1: Oxidative addition to copper

+oxidativeadditionCu(I)BrBrPhCu(III)BrBr1 · OXIDATIVE ADDITION TO COPPERcopper(I)CATALYSTbromobenzeneC₆H₅BrELECTROPHILEPh–Cu(III)Br₂INTERMEDIATECu(I) → Cu(III): insertion into C–Br, as with Pd but one oxidation state higher.

Copper metal (or a Cu(I) salt) oxidatively adds an aryl halide, forming an aryl-copper(III) species — the same oxidative-addition logic as Pd chemistry, just at copper and historically discovered decades earlier.

Step 2: Second aryl joins the copper

+aryl transfer−CuBrPhCu(III)BrBrPhCu(I)PhCu(III)PhBr2 · SECOND ARYL JOINS THE COPPERPh–Cu(III)Br₂INTERMEDIATEPh–Cu(I) (from a 2nd ArBr)NUCLEOPHILEPh₂–Cu(III)–BrINTERMEDIATEBoth aryl groups now sit on the same copper centre.

A second aryl halide equivalent reacts at the same or a neighboring copper center, and the two aryl groups are brought together on copper.

Step 3: Reductive elimination

reductiveelimination+PhCu(III)PhBrCu(I)Br3 · REDUCTIVE ELIMINATIONcis-Ph₂Cu(III)BrINTERMEDIATEbiphenylC₁₂H₁₀PRODUCTcopper(I) bromideCATALYSTNew biaryl C–C bond; Cu(III) → Cu(I). The Pd-catalyzed couplings refined this template.

Reductive elimination forges the new biaryl C–C bond directly — this classical, high-temperature reaction was the original template that Suzuki, Negishi, and the other Pd-catalyzed couplings later refined into far milder, more general methods.

Abbreviations and terms

Ar
Aryl group. Any aromatic ring substituent such as phenyl.
X
Halogen / leaving group. Cl, Br or I (sometimes any leaving group).
Ph
Phenyl. –C₆H₅.
DMF
N,N-Dimethylformamide. Polar aprotic solvent – dissolves ionic nucleophiles but does not H-bond to them, speeding SN2 and SNAr.

How it compares with related reactions

Ullmann couplingBuchwald-Hartwig aminationBuchwald-Hartwig etherification
ReagentsArX (I > Br), Cu powder or Cu(I) saltArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBuArBr, ROH, Pd₂(dba)₃ or Pd(OAc)₂ / bulky biaryl phosphine (RockPhos, tBuBrettPhos), Cs₂CO₃ or NaOtBu
ConditionsNeat or DMF/nitrobenzene, 150–250 °C (milder with ligands)Toluene or dioxane, 80–110 °CToluene or dioxane, 80–100 °C
StereochemistryHindered biaryls can show axial chiralityNo new stereocentre; retention of aryl geometryNo new stereocentre; aryl geometry retained
Rate / selectivityOxidative addition to Cu is rate-limiting; needs high TBulky, electron-rich ligand speeds oxidative addition and C–N reductive eliminationC–O reductive elimination is slow, so very bulky ligands are needed

Test yourself

Try to answer each question before opening it.

Which reagents and conditions are typical for the Ullmann coupling?

ArX (I > Br), Cu powder or Cu(I) salt. Conditions: Neat or DMF/nitrobenzene, 150–250 °C (milder with ligands).

Which bonds are formed and which are broken?

Formed: Ar–Ar (C–C σ); CuX. Broken: two C–X bonds.

What is the stereochemical outcome?

Hindered biaryls can show axial chirality

What controls the rate or the selectivity?

Oxidative addition to Cu is rate-limiting; needs high T

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