Crossed aldol condensation
Claisen-Schmidt condensation: chalcone synthesis
How the Claisen-Schmidt condensation 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: Methyl ketone (ArCOCH₃), ArCHO (no α-H), NaOH or KOH. Conditions: EtOH/H₂O, 0–25 °C. Bonds formed: C–C (new bond); C=C (conjugated enone); H₂O; bonds broken: α C–H; C=O π (aldehyde); C–OH. Stereochemistry: E-chalcone (thermodynamic). Rate and selectivity: Aldol addition reversible; E1cB dehydration drives it forward.
At a glance
Step 1: Ketone enolate forms
Base deprotonates a methyl ketone's alpha carbon (which has no competing aldehyde alpha-protons of its own, since the other partner is an aromatic aldehyde with none), forming an enolate selectively at the ketone.
Step 2: Crossed aldol addition
This enolate attacks the aromatic aldehyde's carbonyl carbon in an ordinary aldol addition — because the aldehyde partner can't enolize, this crossed aldol proceeds cleanly rather than giving the statistical mixture a self-aldol would produce.
Step 3: E1cB dehydration to chalcone
E1cb dehydration (identical to the aldol condensation covered early in this library) gives a chalcone — an aryl-conjugated enone — directly. This specific application of aldol condensation chemistry to aryl aldehydes plus methyl ketones is how the chalcone core found throughout natural flavonoids is built.
Abbreviations and terms
- EtOH
- Ethanol. Polar protic solvent.
- NaOH
- Sodium hydroxide. Strong aqueous base and nucleophile.
- KOH
- Potassium hydroxide. Strong aqueous/alcoholic base.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- E1cB
- Elimination, unimolecular conjugate base. Deprotonation first to a carbanion, then loss of the leaving group.
How it compares with related reactions
| Claisen-Schmidt condensation | Perkin reaction | Claisen condensation of ethyl acetate | |
|---|---|---|---|
| Reagents | Methyl ketone (ArCOCH₃), ArCHO (no α-H), NaOH or KOH | Ac₂O, NaOAc (or Et₃N), ArCHO | Ethyl acetate (2 equiv), NaOEt (≥ 1 equiv); then H₃O⁺ |
| Conditions | EtOH/H₂O, 0–25 °C | 140–180 °C, then H₂O workup | EtOH, reflux; same alkoxide as ester OR group |
| Stereochemistry | E-chalcone (thermodynamic) | (E)-cinnamic acid strongly favored | None (achiral product) |
| Rate / selectivity | Aldol addition reversible; E1cB dehydration drives it forward | Enolate formation and aldol addition limit rate; needs heat | Equilibrium pulled forward by deprotonating the β-keto ester (pKa ≈ 11) |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Claisen-Schmidt condensation?
Methyl ketone (ArCOCH₃), ArCHO (no α-H), NaOH or KOH. Conditions: EtOH/H₂O, 0–25 °C.
Which bonds are formed and which are broken?
Formed: C–C (new bond); C=C (conjugated enone); H₂O. Broken: α C–H; C=O π (aldehyde); C–OH.
What is the stereochemical outcome?
E-chalcone (thermodynamic)
What controls the rate or the selectivity?
Aldol addition reversible; E1cB dehydration drives it forward
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