Enols, Enolates and Aldol Condensation - Part 1 | Organic Chemistry 2

Enols, enolates and aldol condensation are studied in this chapter: acidity of carbonyls, keto-enol equilibria, alkylation of carbonyls, aldol and cross-aldol condensation, unsaturated aldehydes and ketones (1,2- and 1,4-additions)

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:

  1. Enolate formation:


     
  2. Nucleophilic attack followed by protonation


     
  3. 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+)