Cu-catalyzed unsymmetrical coupling
Cadiot-Chodkiewicz coupling
How the Cadiot-Chodkiewicz 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, 1-bromoalkyne, cat. CuCl, amine base (EtNH₂ or BuNH₂), NH₂OH·HCl. Conditions: MeOH or aq. amine, 0–25 °C, under N₂. Bonds formed: C(sp)–C(sp) bond (unsymmetrical 1,3-diyne); bonds broken: C–H (alkyne), C–Br. Stereochemistry: None (linear sp carbons). Rate and selectivity: Cross-selective; NH₂OH keeps copper as Cu(I).
At a glance
Step 1: Cu(I) acetylide forms
Cu(I) deprotonates one terminal alkyne to form a copper acetylide, exactly as in Glaser coupling — but here, a haloalkyne (rather than a second terminal alkyne) is the coupling partner.
Step 2: Acetylide displaces bromide
The copper acetylide's nucleophilic carbon performs an oxidative-addition-like displacement of halide from the haloalkyne, joining the two alkynyl fragments on copper.
Step 3: Reductive elimination
Reductive elimination releases the unsymmetrical 1,3-diyne and regenerates Cu(I) — using a haloalkyne instead of a second terminal alkyne is what makes this cross-selective, avoiding the statistical mixture of products that plain Glaser homocoupling would give with two different alkynes.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- HCl
- Hydrochloric acid / hydrogen chloride. Strong acid; chloride is the nucleophile in additions/substitutions.
How it compares with related reactions
| Cadiot-Chodkiewicz coupling | Buchwald-Hartwig amination | Buchwald-Hartwig etherification | |
|---|---|---|---|
| Reagents | terminal alkyne, 1-bromoalkyne, cat. CuCl, amine base (EtNH₂ or BuNH₂), NH₂OH·HCl | 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 | MeOH or aq. amine, 0–25 °C, under N₂ | Toluene or dioxane, 80–110 °C | Toluene or dioxane, 80–100 °C |
| Stereochemistry | None (linear sp carbons) | No new stereocentre; retention of aryl geometry | No new stereocentre; aryl geometry retained |
| Rate / selectivity | Cross-selective; NH₂OH keeps copper as Cu(I) | 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 Cadiot-Chodkiewicz coupling?
terminal alkyne, 1-bromoalkyne, cat. CuCl, amine base (EtNH₂ or BuNH₂), NH₂OH·HCl. Conditions: MeOH or aq. amine, 0–25 °C, under N₂.
Which bonds are formed and which are broken?
Formed: C(sp)–C(sp) bond (unsymmetrical 1,3-diyne). Broken: C–H (alkyne), C–Br.
What is the stereochemical outcome?
None (linear sp carbons)
What controls the rate or the selectivity?
Cross-selective; NH₂OH keeps copper as Cu(I)
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam