Pd-catalyzed C–O coupling
Buchwald-Hartwig etherification
How the Buchwald-Hartwig etherification works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: ArBr, ROH, Pd₂(dba)₃ or Pd(OAc)₂ / bulky biaryl phosphine (RockPhos, tBuBrettPhos), Cs₂CO₃ or NaOtBu. Conditions: Toluene or dioxane, 80–100 °C. Bonds formed: Ar–O (C–O σ); bonds broken: Ar–Br; O–H. Stereochemistry: No new stereocentre; aryl geometry retained. Rate and selectivity: C–O reductive elimination is slow, so very bulky ligands are needed.
At a glance
Step 1: Oxidative addition
Pd(0), supported by a bulky phosphine ligand, oxidatively adds an aryl halide, forming Ar–Pd(II)–X — identical first step to Buchwald-Hartwig amination covered earlier.
Step 2: Alcohol binds, base removes O–H
An alcohol coordinates to palladium and is deprotonated by base, forming an aryl-palladium-alkoxide complex — the oxygen analog of the amido complex formed in the amination version, occupying the same structural role that transmetalation fills in Suzuki-type couplings.
Step 3: Reductive elimination
Reductive elimination forges the new C–O bond and regenerates Pd(0) — swapping the nitrogen nucleophile for an oxygen one turns the identical three-step catalytic logic into a general method for building diaryl and alkyl-aryl ethers.
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).
- L
- Ligand. A Lewis-base group (often a phosphine) bound to a metal centre.
- Ph
- Phenyl. –C₆H₅.
- OAc
- Acetoxy. –OC(=O)CH₃, an acetate group.
- Cs2CO3
- Cesium carbonate. Mild, soluble inorganic base (the “cesium effect”).
- Pd(OAc)2
- Palladium(II) acetate. Pd(II) pre-catalyst, reduced in situ to Pd(0).
- Pd2(dba)3
- Tris(dibenzylideneacetone)dipalladium(0). Air-stable source of Pd(0).
- dba
- Dibenzylideneacetone. Weakly bound alkene ligand on Pd(0).
How it compares with related reactions
| Buchwald-Hartwig etherification | Buchwald-Hartwig amination | Cadiot-Chodkiewicz coupling | |
|---|---|---|---|
| Reagents | ArBr, ROH, Pd₂(dba)₃ or Pd(OAc)₂ / bulky biaryl phosphine (RockPhos, tBuBrettPhos), Cs₂CO₃ or NaOtBu | ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu | terminal alkyne, 1-bromoalkyne, cat. CuCl, amine base (EtNH₂ or BuNH₂), NH₂OH·HCl |
| Conditions | Toluene or dioxane, 80–100 °C | Toluene or dioxane, 80–110 °C | MeOH or aq. amine, 0–25 °C, under N₂ |
| Stereochemistry | No new stereocentre; aryl geometry retained | No new stereocentre; retention of aryl geometry | None (linear sp carbons) |
| Rate / selectivity | C–O reductive elimination is slow, so very bulky ligands are needed | Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination | Cross-selective; NH₂OH keeps copper as Cu(I) |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Buchwald-Hartwig etherification?
ArBr, ROH, Pd₂(dba)₃ or Pd(OAc)₂ / bulky biaryl phosphine (RockPhos, tBuBrettPhos), Cs₂CO₃ or NaOtBu. Conditions: Toluene or dioxane, 80–100 °C.
Which bonds are formed and which are broken?
Formed: Ar–O (C–O σ). Broken: Ar–Br; O–H.
What is the stereochemical outcome?
No new stereocentre; aryl geometry retained
What controls the rate or the selectivity?
C–O reductive elimination is slow, so very bulky ligands are needed
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam