Organocuprate coupling
Corey-House synthesis
How the Corey-House synthesis 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: 2 R–Li, CuI; then R′–X (primary alkyl iodide, bromide or tosylate). Conditions: Et₂O or THF, –78 to 25 °C. Bonds formed: C–C (R–R′); bonds broken: C–X; one Cu–C. Stereochemistry: Inversion at a stereogenic sp³ C–X in many cases; best with 1° halides. Rate and selectivity: Soft, low-polarity C–Cu bond: little elimination or carbonyl attack vs RLi.
At a glance
Step 1: Gilman reagent forms
Two equivalents of an alkyllithium react with copper(I) iodide to form a lithium dialkylcuprate (Gilman reagent), R₂CuLi. The carbon-copper bond is much less polar than the carbon-lithium bond, which makes the cuprate soft and far more selective than a Grignard reagent.
Step 2: Oxidative addition of R′–I
The cuprate transfers one of its R groups to an alkyl halide. The mechanism is usually described as oxidative addition of R′–X to copper to give a transient Cu(III) species, rather than a plain SN2. Primary alkyl halides work best, and the halide can be an iodide, bromide, or tosylate.
Step 3: Reductive elimination
Reductive elimination from the Cu(III) intermediate forms the new C–C bond, giving R–R′ and RCu. This is a clean way to couple two different alkyl groups, a job Wurtz coupling does poorly because it gives mixtures.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- X
- Halogen / leaving group. Cl, Br or I (sometimes any leaving group).
- THF
- Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
- Et2O
- Diethyl ether. Low-boiling ether solvent, classic for Grignard reagents.
- CuI
- Copper(I) iodide. Co-catalyst for Sonogashira, Ullmann and click chemistry.
- SN2
- Bimolecular nucleophilic substitution. One concerted step with backside attack and inversion; rate = k[RX][Nu].
How it compares with related reactions
| Corey-House synthesis | Japp-Klingemann reaction | McMurry coupling | |
|---|---|---|---|
| Reagents | 2 R–Li, CuI; then R′–X (primary alkyl iodide, bromide or tosylate) | ArN₂⁺ Cl⁻, α-substituted β-ketoester, NaOAc or NaOH | TiCl₃ or TiCl₄, Zn (or Zn–Cu, LiAlH₄) |
| Conditions | Et₂O or THF, –78 to 25 °C | EtOH/H₂O, 0–5 °C | THF, reflux, inert atmosphere |
| Stereochemistry | Inversion at a stereogenic sp³ C–X in many cases; best with 1° halides | Hydrazone formed mainly as Z (H-bonded); E/Z mixtures possible | Mixture of E/Z for unsymmetrical alkenes |
| Rate / selectivity | Soft, low-polarity C–Cu bond: little elimination or carbonyl attack vs RLi | Azo coupling is fast; deacylation by hydroxide is rate-limiting | Pinacol coupling at low T; deoxygenation needs heat |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Corey-House synthesis?
2 R–Li, CuI; then R′–X (primary alkyl iodide, bromide or tosylate). Conditions: Et₂O or THF, –78 to 25 °C.
Which bonds are formed and which are broken?
Formed: C–C (R–R′). Broken: C–X; one Cu–C.
What is the stereochemical outcome?
Inversion at a stereogenic sp³ C–X in many cases; best with 1° halides
What controls the rate or the selectivity?
Soft, low-polarity C–Cu bond: little elimination or carbonyl attack vs RLi
Study guides that help with this reaction
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go