Pd/Cu-catalyzed cross-coupling
Sonogashira coupling: full catalytic cycle
How the Sonogashira 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: ArI/ArBr, terminal alkyne, Pd(PPh₃)₂Cl₂ (cat.), CuI (cat.), Et₃N. Conditions: THF or DMF, 25 °C (amine as base/solvent). Bonds formed: C(sp)–C(sp²); Et₃NH⁺X⁻; bonds broken: C–X; alkyne C–H. Stereochemistry: Alkyne linear; no stereocentres. Rate and selectivity: Pd oxidative addition or transmetalation limiting; Cu accelerates it.
At a glance
Step 1: Pd cycle: oxidative addition; Cu cycle: acetylide
Pd(0) oxidatively adds an aryl halide, forming Ar–Pd(II)–X, while separately, Cu(I) coordinates a terminal alkyne and, with base, deprotonates its acidic C–H to form a copper acetylide.
Step 2: Transmetalation Cu → Pd
The copper acetylide performs transmetalation onto palladium, transferring the alkynyl group and displacing halide, regenerating Cu(I) to continue its half of the cycle.
Step 3: Reductive elimination
Reductive elimination forges the new C(sp)–C(sp²) bond and regenerates Pd(0) — this dual Pd/Cu relay is what lets the reaction proceed efficiently at room temperature, unlike most other cross-couplings.
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.
- THF
- Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
- DMF
- N,N-Dimethylformamide. Polar aprotic solvent – dissolves ionic nucleophiles but does not H-bond to them, speeding SN2 and SNAr.
- Et3N
- Triethylamine. Common tertiary-amine base that scavenges HCl.
- PPh3
- Triphenylphosphine. Nucleophilic phosphine; forms very strong P=O bonds, driving Wittig, Appel and Mitsunobu reactions.
- CuI
- Copper(I) iodide. Co-catalyst for Sonogashira, Ullmann and click chemistry.
- L2
- Ligand set. Spectator ligands on the metal that tune its reactivity.
How it compares with related reactions
| Sonogashira coupling | Buchwald-Hartwig amination | Heck reaction | |
|---|---|---|---|
| Reagents | ArI/ArBr, terminal alkyne, Pd(PPh₃)₂Cl₂ (cat.), CuI (cat.), Et₃N | ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu | ArBr, alkene (e.g. methyl acrylate), Pd(OAc)₂/PPh₃, Et₃N |
| Conditions | THF or DMF, 25 °C (amine as base/solvent) | Toluene or dioxane, 80–110 °C | DMF or MeCN, 80–120 °C |
| Stereochemistry | Alkyne linear; no stereocentres | No new stereocentre; retention of aryl geometry | Syn insertion, syn β-H elimination; E-alkene favoured |
| Rate / selectivity | Pd oxidative addition or transmetalation limiting; Cu accelerates it | Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination | Aryl adds to the less hindered alkene carbon |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Sonogashira coupling?
ArI/ArBr, terminal alkyne, Pd(PPh₃)₂Cl₂ (cat.), CuI (cat.), Et₃N. Conditions: THF or DMF, 25 °C (amine as base/solvent).
Which bonds are formed and which are broken?
Formed: C(sp)–C(sp²); Et₃NH⁺X⁻. Broken: C–X; alkyne C–H.
What is the stereochemical outcome?
Alkyne linear; no stereocentres
What controls the rate or the selectivity?
Pd oxidative addition or transmetalation limiting; Cu accelerates it
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam