Chapter 21 Ester Enolates 3

21.1 Ester a-Hydrogens and their pKas 3

Introduction O O O O R O R O R H H H Protons a to an ester carbonyl group are less acidic, pKa  24, than a protons of aldehydes and ketones, pKa  16-20. The decreased acidity is due to the decreased electron-withdrawing ability of an ester carbonyl. Electron delocalization decreases the positive character of the ester carbonyl group. 6

Introduction C R OR' H O The preparation and reactions of -dicarbonyl compounds, especially -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.

21.2 The Claisen Condensation 3

The Claisen Condensation RCH2CCHCOR' R 1. NaOR' 2 RCH2COR' + R'OH 2. H3O+ -Keto esters are prepared by a reaction known as the Claisen condensation. Ethyl esters are typically used, with sodium ethoxide as the base. 6

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

Mechanism Step 1: CH3CH2 O – COCH2CH3 CH2 H – COCH2CH3 O CH2 CH3CH2 H •• • • COCH2CH3 CH2 H – • • •• COCH2CH3 O CH2 CH3CH2 H 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 CH3C – O COCH2CH3 CH2 OCH2CH3 Step 2: – COCH2CH3 O CH2 O •• • • COCH2CH3 CH2 OCH2CH3 Step 2: •• – • • •• COCH2CH3 O CH2 O • • CH3COCH2CH3 6

Mechanism CH3C – O COCH2CH3 CH2 OCH2CH3 Step 3: – OCH2CH3 CH3C O •• • • COCH2CH3 CH2 OCH2CH3 Step 3: – OCH2CH3 •• • • CH3C O COCH2CH3 CH2 + 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: + OCH2CH3 H – COCH2CH3 O CH3C CH CH3C O COCH2CH3 CH2 •• H – COCH2CH3 O • • CH3C CH 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  carbon of one ethyl propanoate molecule and the carbonyl carbon of the other. O CH3CH2CCHCOCH2CH3 CH3 (81%) 6

21.3 Intramolecular Claisen Condensation: The Dieckmann Reaction

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

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

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

21.4 Mixed Claisen Condensations 3

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

21.5 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+ (60%) O COCH2CH3 6

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

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

21.6 Ketone Synthesis via -Keto Esters 3

-Keto acids decarboxylate readily to give ketones. Ketone Synthesis O RCH2CCHCOH R O RCH2CCH2R + CO2 -Keto acids decarboxylate readily to give ketones. (You don’t need to know the mechanism, although it is summarized in Section 19.17, if you are curious.) 6

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

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

Example O 2 CH3CH2CH2CH2COCH2CH3 Claisen condensation 1. NaOCH2CH3 of ester to form -keto ester. 1. NaOCH2CH3 2. H3O+ CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 (80%) 6

Hydrolysis of -keto ester to form -keto acid. 2. H3O+ Example CH3CH2CH2CH2CCHCOH O CH2CH2CH3 1. KOH, H2O, 70-80°C Hydrolysis of -keto ester to form -keto acid. 2. H3O+ CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 6

Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 Decarboxylation of -keto acid to form ketone. 70-80°C O CH3CH2CH2CH2CCH2CH2CH2CH3 (81%) 6

21.7 The Acetoacetic Ester Synthesis 3

Acetoacetic ester is another name for ethyl acetoacetate. OCH2CH3 H O H3C Acetoacetic ester is another name for ethyl acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. 6

Deprotonation of Ethyl Acetoacetate OCH2CH3 H O H3C – + CH3CH2O Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. pKa ~ 11 pKa ~ 16 C OCH2CH3 H O •• – H3C + CH3CH2OH 6

Alkylation of Ethyl Acetoacetate OCH2CH3 H O •• – H3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: methyl and primary alkyl halides work best; secondary alkyl halides work also but give lower yields; tertiary alkyl halides undergo elimination). R X C OCH2CH3 H O H3C 6

The -keto acid then undergoes decarboxylation to form a ketone. Conversion to Ketone C OH H O H3C R 1. HO–, H2O 2. H+ Saponification and acidification convert the alkylated derivative to the corresponding -keto acid. The -keto acid then undergoes decarboxylation to form a ketone. C OCH2CH3 H O H3C R 6

The -keto acid then undergoes decarboxylation to form a ketone. Conversion to Ketone C OH H O H3C R Saponification and acidification convert the alkylated derivative to the corresponding -keto acid. The -keto acid then undergoes decarboxylation to form a ketone. heat O C + CO2 H3C CH2R 6

Example O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br O (70%) O CH3CCHCOCH2CH3 CH2CH2CH2CH3 6

Example O (60%) CH3CCH2CH2CH2CH2CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3CCHCOCH2CH3 CH2CH2CH2CH3 6

Example: Dialkylation CH3CCHCOCH2CH3 CH2CH CH2 1. NaOCH2CH3 2. CH3CH2I O CH3CCCOCH2CH3 CH2CH CH2 CH3CH2 (75%) 6

Example: Dialkylation 1. NaOH, H2O 2. H+ 3. heat, -CO2 CH3CCH CH2CH CH2 O CH3CH2 Example: Dialkylation O CH3CCCOCH2CH3 CH2CH CH2 CH3CH2 6

-Keto esters other than ethyl acetoacetate may be used. Another Example O H COCH2CH3 -Keto esters other than ethyl acetoacetate may be used. 6

Another Example O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br O COCH2CH3 (89%) 6

Another Example O H (66%) CH2CH CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O COCH2CH3 CH2CH CH2 6