Enols, Enolates and Aldol Condensation - Part 1 | Organic Chemistry 2
Acidity of Carbonyls
H on an α-carbon of a carbonyl is acidic ⇒ pKa ~ 16-18 (aldehyde) and ~ 19-21 (ketone). A deprotonation reaction can occur using a strong base (pKa > 21) as LDA, KH, KOtBu, BuLi
Keto-Enol Equilibrium
Carbonyls are in equilibrium with their enol forms (10 kcal.mol-1 less stable):
Mechanisms:
Base-catalyzed enol-keto equilibrium:
Acid-catalyzed enol-keto equilibrium:
Alkylation of Carbonyls
Carbonyls alkylation:
Mechanism:
R-X must be a primary halide (SN2 reaction):
Enamines alkylation:
Mechanism:
R-X must be a primary or secondary halide (SN2 reaction):
Synthetic Strategy:
Advantage of alkylation of enamines over alkylation of carbonyls:
- no polyalkylation ( = enolates alkylation)
- more reactive intermediate: R-X can be a secondary halide
Aldol Condensation
Mechanism:
- Enolate formation:
- Nucleophilic attack followed by protonation
- Aldol dehydration
Aldol condensation of ketones is possible but the formation of enolate (step 1) is energically unfavorable (ketones are more stable than aldehydes). To drive the equilibrium towards the formation of enol, it is necessary to eliminate the water (or the aldol) formed ⇒ a Dean-stark apparatus is used
Intramolecular aldol condensation can occur with both aldehydes and ketones. This gives the least strained cycloalkenones (highly regioselective reaction)
Cross Aldol Condensation
Product mixtures unless one of the reaction partners cannot enolize
α,β-Unsaturated Aldehydes and Ketones
Stability:
α,β-unsaturated aldehydes and ketones are stabilized by resonance
Reactivities:
- typical reactions of alkenes and carbonyls
- 1,4-additions (and sometimes 1,2-additions)
1,4-additions:
Nu = Nucleophile; E = Electrophile (generally H+)