Enols, Enolates and Aldol Condensation | Organic Chemistry 2
Acidity of Carbonyls
H on an α-carbon of a carbonyl is acidic ⇒ pKa ~ 16-18 (aldehyde) and ~ 19-21 (ketone).
Base has to be strong (pKa > 21) ⇒ LDA, KH, KOtBu, BuLi
Carbonyls are in equilibrium with their enol forms (10 kcal.mol-1 less stable):
Base-Catalyzed Enol-Keto Equilibration:
Acid-Catalyzed Enol-Keto Equilibration:
Alkylation of Carbonyls
R-X must be primary halide (SN2 reaction).
R-X must be primary or secondary halide (SN2 reaction).
Advantage of Enamine Alkylation:
- No polyalkylation ( = Enolate Alkylation)
- More reactive: R-X can be a secondary halide
Step 1: Enolate Generation
Step 2: Nucleophilic attack followed by a Protonation
Step 3: Aldol Dehydration
Aldol Condensation of ketones is possible but the step 1 is energically unfavorable (ketones are more stable than aldehydes).
To drive the equilibrium ⇒ removal of the water (or the aldol) formed.
Intramolecular aldol condensation succeeds with both aldehydes and ketones.
It gives the least strained cycloalkenones (highly regioselective).
Cross Aldol Condensation
Product mixtures unless one of the reaction partners cannot enolize
α,β-Unsaturated Aldehydes and Ketones
Stability: Stabilized by resonance
- reactions typical of alkenes and carbonyls
- 1,4-additions (and sometimes 1,2-additions)
with Nu = Nucleophile; E = Electrophile (generally H+)