Lewis-acid-catalyzed aldol
Mukaiyama aldol reaction
How the Mukaiyama aldol 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, aldehyde, TiCl₄ (or BF₃·OEt₂, Sc(OTf)₃). Conditions: CH₂Cl₂, –78 °C; aqueous work-up. Bonds formed: C–C (new σ); O–Si (silyl ether); bonds broken: C=O π; O–Si (enol ether). Stereochemistry: Open TS; syn/anti set by enol geometry and Lewis acid; chiral LAs give ee. Rate and selectivity: Lewis-acid activation of the aldehyde is essential.
At a glance
Step 1: Lewis acid activates the aldehyde
A Lewis acid (like TiCl₄) activates an aldehyde by coordinating its oxygen, making the carbonyl carbon far more electrophilic — the Lewis-acid equivalent of Brønsted-acid activation in Fischer esterification.
Step 2: Silyl enol ether attacks
A silyl enol ether — a pre-formed, isolable equivalent of an enolate — attacks the activated carbonyl carbon with its nucleophilic alpha carbon, exactly as any enolate would.
Step 3: Silyl transfer, Lewis acid released
Loss of the trimethylsilyl group (transferred to the newly formed alkoxide oxygen) gives the aldol product — using a stable, pre-formed silyl enol ether instead of a reactive metal enolate offers far more control over which enol geometry reacts.
Abbreviations and terms
- OTf
- Triflate. Trifluoromethanesulfonate – among the best leaving groups.
- TMS
- Trimethylsilyl. –Si(CH₃)₃; a small silicon group used to protect or activate.
- 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.
- BF3
- Boron trifluoride. Lewis acid (usually as the Et₂O complex).
- TiCl4
- Titanium tetrachloride. Strong, oxophilic Lewis acid that chelates carbonyls.
- TS
- Transition state. The highest-energy point on the pathway between two minima; it cannot be isolated.
- ee
- Enantiomeric excess. How much more of one enantiomer than the other is present.
How it compares with related reactions
| Mukaiyama aldol reaction | Mukaiyama-Michael reaction | Sakurai-Hosomi allylation | |
|---|---|---|---|
| Reagents | Silyl enol ether, aldehyde, TiCl₄ (or BF₃·OEt₂, Sc(OTf)₃) | Silyl enol ether, α,β-unsaturated ketone, TiCl₄ (or other Lewis acid) | Allyltrimethylsilane, aldehyde or ketone, TiCl₄ (or BF₃·OEt₂) |
| Conditions | CH₂Cl₂, –78 °C; aqueous work-up | CH₂Cl₂, –78 °C; aqueous workup | CH₂Cl₂, –78 °C → 0 °C; aqueous workup |
| Stereochemistry | Open TS; syn/anti set by enol geometry and Lewis acid; chiral LAs give ee | Enol-ether geometry and Lewis acid control syn/anti; new stereocentres possible | Open (acyclic) TS; allyl terminus attacks, product alkene transposed |
| Rate / selectivity | Lewis-acid activation of the aldehyde is essential | Lewis acid binding to the enone drives the conjugate addition | Lewis-acid activation of C=O makes addition fast even at –78 °C |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Mukaiyama aldol reaction?
Silyl enol ether, aldehyde, TiCl₄ (or BF₃·OEt₂, Sc(OTf)₃). Conditions: CH₂Cl₂, –78 °C; aqueous work-up.
Which bonds are formed and which are broken?
Formed: C–C (new σ); O–Si (silyl ether). Broken: C=O π; O–Si (enol ether).
What is the stereochemical outcome?
Open TS; syn/anti set by enol geometry and Lewis acid; chiral LAs give ee
What controls the rate or the selectivity?
Lewis-acid activation of the aldehyde is essential
Study guides that help with this reaction
- Carbonyl chemistry: addition, acyl substitution and enolates
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go