Chapter 21 Ester Enolates 3

Introduction C R OR' H O The preparation and reactions of b-dicarbonyl compounds, especially b-keto esters, is the main focus of this chapter. A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions. 6

Introduction C R OR' H O pKa ~ 11 CH3CH2O – C R OR' H O •• – 6

Introduction C R OR' H O – C R OR' H O – •• – • • C R OR' H O – •• • • The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups.

Introduction C R OR' H O – C R OR' H O – •• – • • C R OR' H O – • • •• •• The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups.

21.1 The Claisen Condensation 3

The Claisen Condensation 2RCH2COR' O O RCH2CCHCOR' R 1. NaOR' + R'OH 2. H3O+ b-Keto esters are made by the reaction shown, which is called the Claisen condensation. Ethyl esters are typically used, with sodium ethoxide as the base. 6

Example 2CH3COCH2CH3 O O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. H3O+ (75%) Product from ethyl acetate is called ethyl acetoacetate or acetoacetic ester. 6

Mechanism Step 1: CH3CH2 O – •• • • COCH2CH3 CH2 H 6

Mechanism Step 1: CH3CH2 O – COCH2CH3 CH2 H O CH3CH2 O H – CH2 •• • • COCH2CH3 CH2 H •• O • • CH3CH2 O •• H – CH2 COCH2CH3 • • 6

Mechanism Step 1: – O CH2 COCH2CH3 •• COCH2CH3 O CH2 • • Anion produced is stabilized by electron delocalization; it is the enolate of an ester. – • • •• COCH2CH3 O CH2 6

Mechanism Step 2: •• – • • •• COCH2CH3 O CH2 O • • CH3COCH2CH3 6

Mechanism CH3C – O COCH2CH3 O CH2 Step 2: OCH2CH3 – COCH2CH3 O CH2 O •• • • •• COCH2CH3 O CH2 • • Step 2: OCH2CH3 • • •• •• – • • •• COCH2CH3 O CH2 O • • CH3COCH2CH3 6

Mechanism CH3C – O •• • • COCH2CH3 CH2 OCH2CH3 Step 2: 6

Mechanism CH3C – O COCH2CH3 CH2 OCH2CH3 Step 3: CH3C O COCH2CH3 CH2 – •• • • COCH2CH3 CH2 OCH2CH3 Step 3: CH3C O •• • • COCH2CH3 CH2 – OCH2CH3 •• • • + 6

Mechanism Step 3: CH3C O COCH2CH3 CH2 – OCH2CH3 + The product at this point is ethyl acetoacetate. However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small. Something else does happen. Ethoxide abstracts a proton from the CH2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable. CH3C O •• • • COCH2CH3 CH2 – OCH2CH3 •• • • + 6

Mechanism Step 4: – COCH2CH3 O CH3C CH OCH2CH3 H + CH3C O COCH2CH3 CH2 •• COCH2CH3 O • • CH3C CH OCH2CH3 •• H + CH3C O •• • • COCH2CH3 CH2 – OCH2CH3 •• • • + 6

Mechanism Step 5: CH3C O CH O – COCH2CH3 •• • • CH •• O – COCH2CH3 •• In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate. 6

Mechanism Step 5: CH3C O CH O + O H – COCH2CH3 CH3C O COCH2CH3 CH H O •• • • CH •• O + O H • • – COCH2CH3 •• CH3C O •• • • COCH2CH3 CH H O H • • + 6

Another example O 2CH3CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ Reaction involves bond formation between the a-carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other. O CH3CH2CCHCOCH2CH3 CH3 (81%) 6

21.2 Intramolecular Claisen Condensation: The Dieckmann Reaction 3

CH3CH2OCCH2CH2CH2CH2COCH2CH3 Example O O CH3CH2OCCH2CH2CH2CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ COCH2CH3 O (74-81%) 6

CH3CH2OCCH2CH2CH2CH2COCH2CH3 via •• • • O O CH3CH2OCCH2CH2CH2CH2COCH2CH3 NaOCH2CH3 •• • • •• • • CH3CH2OCCH2CH2CH2CHCOCH2CH3 O •• – 6

CH3CH2OCCH2CH2CH2CHCOCH2CH3 O via •• • • •• • • CH3CH2OCCH2CH2CH2CHCOCH2CH3 O •• – 6

CH3CH2OCCH2CH2CH2CHCOCH2CH3 O via CHCOCH2CH3 O – •• • • CH2 H2C C CH3CH2O •• • • •• • • CH3CH2OCCH2CH2CH2CHCOCH2CH3 O •• – 6

via CHCOCH2CH3 O – •• • • CH2 H2C C CH3CH2O 6

via CHCOCH2CH3 O – CH2 H2C C CH3CH2O CHCOCH2CH3 O CH2 H2C C CH3CH2O – •• • • CH2 H2C C CH3CH2O •• • • CHCOCH2CH3 O CH2 H2C C CH3CH2O •• • • – + 6

21.3 Mixed Claisen Condensations

Mixed Claisen Condensations As with mixed aldol condensations, mixed Claisen condensations are best carried out when the reaction mixture contains one compound that can form an enolate and another that cannot. 6

Mixed Claisen Condensations These types of esters cannot form an enolate. HCOR O ROCOR O ROC O COR COR O 6

Example O O + COCH3 CH3CH2COCH3 1. NaOCH3 2. H3O+ O CCHCOCH3 (60%) CH3

21.4 Acylation of Ketones with Esters 3

Acylation of Ketones with Esters Esters that cannot form an enolate can be used to acylate ketone enolates. 6

Example O CH3CH2OCOCH2CH3 O + 1. NaH 2. H3O+ O COCH2CH3 (60%) 6

Example COCH2CH3 O CH3C O + 1. NaOCH2CH3 2. H3O+ O CCH2C O (62-71%) 6

Example CH3CH2CCH2CH2COCH2CH3 O 1. NaOCH3 2. H3O+ O CH3 (70-71%) 6

21.5 Ketone Synthesis via b-Keto Esters 3

b-Keto acids decarboxylate readily to give ketones (Section 19.17). Ketone Synthesis O RCH2CCHCOH R O RCH2CCH2R + CO2 b-Keto acids decarboxylate readily to give ketones (Section 19.17). 6

b-Keto acids decarboxylate readily to give ketones (Section 19.17). Ketone Synthesis O RCH2CCHCOR' R O RCH2CCHCOH R H2O + R'OH b-Keto acids decarboxylate readily to give ketones (Section 19.17). b-Keto acids are available by hydrolysis of b-keto esters. 6

b-Keto acids decarboxylate readily to give ketones (Section 19.17). Ketone Synthesis 2RCH2COR' O O RCH2CCHCOR' R 1. NaOR' + R'OH 2. H3O+ b-Keto acids decarboxylate readily to give ketones (Section 19.17). b-Keto acids are available by hydrolysis of b-keto esters. b-Keto esters can be prepared by the Claisen condensation. 6

Example O 2 CH3CH2CH2CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ O CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 (80%) 6

Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 1. KOH, H2O, 70-80°C 2. H3O+ O CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 6

Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 70-80°C O CH3CH2CH2CH2CCH2CH2CH2CH3 (81%) 6