Cu-catalyzed oxidative homocoupling
Glaser coupling
How the Glaser coupling 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: Terminal alkyne, CuCl (cat.), amine base (TMEDA/Et₃N), O₂ (air). Conditions: Acetone, MeOH or CH₂Cl₂, 25 °C (Hay variant: CuCl/TMEDA). Bonds formed: C(sp)–C(sp) σ (1,3-diyne); H₂O; bonds broken: terminal C–H (×2); Cu–C. Stereochemistry: Linear product; no stereocenters. Rate and selectivity: Copper acetylide formation fast; oxidative coupling step limits rate.
At a glance
Step 1: Base and Cu(I) make the copper acetylide
Cu(I), with O₂ or another mild oxidant present, deprotonates a terminal alkyne's acidic C–H, forming a copper acetylide — the same first step used in Sonogashira coupling and CuAAC.
Step 2: O₂ oxidizes copper; two acetylides meet
O₂ oxidizes this copper acetylide to a copper(II) or copper(III) acetylide, activating it toward radical or two-electron coupling with a second equivalent of copper acetylide.
Step 3: Reductive elimination gives the diyne
Reductive elimination-type coupling joins the two alkynyl fragments directly, forming a 1,3-diyne and regenerating Cu(I) — this is the symmetrical partner reaction to Cadiot-Chodkiewicz's unsymmetrical cross-coupling, using the identical copper acetylide chemistry.
Abbreviations and terms
- Ph
- Phenyl. –C₆H₅.
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- Et3N
- Triethylamine. Common tertiary-amine base that scavenges HCl.
- TMEDA
- N,N,N′,N′-Tetramethylethylenediamine. Chelates Li⁺ and breaks up RLi aggregates, making them more reactive.
- CuAAC
- Copper-catalysed azide–alkyne cycloaddition. The copper-catalysed “click” reaction giving 1,4-triazoles.
How it compares with related reactions
| Glaser coupling | Buchwald-Hartwig amination | Buchwald-Hartwig etherification | |
|---|---|---|---|
| Reagents | Terminal alkyne, CuCl (cat.), amine base (TMEDA/Et₃N), O₂ (air) | ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu | ArBr, ROH, Pd₂(dba)₃ or Pd(OAc)₂ / bulky biaryl phosphine (RockPhos, tBuBrettPhos), Cs₂CO₃ or NaOtBu |
| Conditions | Acetone, MeOH or CH₂Cl₂, 25 °C (Hay variant: CuCl/TMEDA) | Toluene or dioxane, 80–110 °C | Toluene or dioxane, 80–100 °C |
| Stereochemistry | Linear product; no stereocenters | No new stereocentre; retention of aryl geometry | No new stereocentre; aryl geometry retained |
| Rate / selectivity | Copper acetylide formation fast; oxidative coupling step limits rate | Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination | C–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 Glaser coupling?
Terminal alkyne, CuCl (cat.), amine base (TMEDA/Et₃N), O₂ (air). Conditions: Acetone, MeOH or CH₂Cl₂, 25 °C (Hay variant: CuCl/TMEDA).
Which bonds are formed and which are broken?
Formed: C(sp)–C(sp) σ (1,3-diyne); H₂O. Broken: terminal C–H (×2); Cu–C.
What is the stereochemical outcome?
Linear product; no stereocenters
What controls the rate or the selectivity?
Copper acetylide formation fast; oxidative coupling step limits rate
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam