Lewis-acid-catalyzed conjugate addition
Mukaiyama-Michael reaction
How the Mukaiyama-Michael reaction 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: Silyl enol ether, α,β-unsaturated ketone, TiCl₄ (or other Lewis acid). Conditions: CH₂Cl₂, –78 °C; aqueous workup. Bonds formed: C–C (β-carbon to enol α-carbon); silyl enol ether or ketone; bonds broken: C=C π (enone); C=C π (enol ether). Stereochemistry: Enol-ether geometry and Lewis acid control syn/anti; new stereocentres possible. Rate and selectivity: Lewis acid binding to the enone drives the conjugate addition.
At a glance
Step 1: Lewis acid activates the enone
A Lewis acid activates an α,β-unsaturated carbonyl (a Michael acceptor) by coordinating its oxygen, making the β-carbon significantly more electrophilic.
Step 2: Silyl enol ether adds 1,4
A silyl enol ether's nucleophilic alpha carbon attacks that activated β-carbon — conjugate addition, exactly like the ordinary Michael addition covered much earlier, but using a stable, pre-formed enol equivalent instead of a reactive metal enolate.
Step 3: Silyl transfer, then workup
Loss of the silyl group (transferred to the enolate oxygen generated in the addition) gives the 1,4-addition product — this combination of Mukaiyama activation with Michael-type conjugate addition offers much finer control over enolate geometry than the classic base-mediated version.
Abbreviations and terms
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- Lewis acid
- Lewis acid. Electron-pair acceptor (AlCl₃, BF₃, TiCl₄…) that activates carbonyls and halides.
- TiCl4
- Titanium tetrachloride. Strong, oxophilic Lewis acid that chelates carbonyls.
How it compares with related reactions
| Mukaiyama-Michael reaction | Acid-catalyzed hydration of an alkene | Michael addition | |
|---|---|---|---|
| Reagents | Silyl enol ether, α,β-unsaturated ketone, TiCl₄ (or other Lewis acid) | Dilute H₂SO₄ or H₃PO₄ (H₃O⁺), H₂O | Diethyl malonate, cat. NaOEt; methyl vinyl ketone (MVK) |
| Conditions | CH₂Cl₂, –78 °C; aqueous workup | 25–100 °C; heat and excess water favour the alcohol | EtOH, 0–25 °C |
| Stereochemistry | Enol-ether geometry and Lewis acid control syn/anti; new stereocentres possible | Planar carbocation: racemic; Markovnikov regiochemistry | Prochiral enolate; new stereocentre formed racemic unless catalyst is chiral |
| Rate / selectivity | Lewis acid binding to the enone drives the conjugate addition | Protonation of the alkene is rate-determining | Soft, stabilised nucleophiles favour 1,4-(conjugate) over 1,2-addition |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Mukaiyama-Michael reaction?
Silyl enol ether, α,β-unsaturated ketone, TiCl₄ (or other Lewis acid). Conditions: CH₂Cl₂, –78 °C; aqueous workup.
Which bonds are formed and which are broken?
Formed: C–C (β-carbon to enol α-carbon); silyl enol ether or ketone. Broken: C=C π (enone); C=C π (enol ether).
What is the stereochemical outcome?
Enol-ether geometry and Lewis acid control syn/anti; new stereocentres possible
What controls the rate or the selectivity?
Lewis acid binding to the enone drives the conjugate addition
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