Chapter 21: Ester Enolates

1. O O C C R C OR' H H Chapter 21: Ester Enolates • The preparation and reactions of -dicarbonyl compounds, especially -keto esters, is the main focus of this chapter.

2. O O •• •• •• •• – O O C C O O •• •• •• •• •• R C OR' C C C C •• H H R C OR' R C OR' – – CH3CH2O H H b-H is Acidic carbanion is stabilized by enolate resonance involving both carbonyl groups. pKa ~ 11

3. O O O O O O 1. NaOCH2CH3 2CH3COCH2CH3 2RCH2COR' RCH2CCHCOR' CH3CCH2COCH2CH3 2. H3O+ (75%) R The Claisen CondensationSynthesis of b-Keto esters 1. NaOR' + R'OH 2. H3O+ b-Keto esters ethylacetoacetateor acetoaceticester.

4. •• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• •• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• Mechanism Step 1: Form nucleophile by removing acidic a-H.

5. •• – •• O O •• •• •• CH3C CH2 COCH2CH3 OCH2CH3 •• •• •• •• O O •• •• – CH2 CH3COCH2CH3 COCH2CH3 •• Mechanism Step 2: Nucleophile formed from one ester attacks carbon of a second ester molecule

6. •• – •• O O •• •• •• CH3C CH2 COCH2CH3 OCH2CH3 •• •• •• •• O O •• •• – •• + CH3C CH2 OCH2CH3 COCH2CH3 •• •• Mechanism Step 3: Leaving group leaves Acid Base

7. •• •• O O •• •• •• – OCH2CH3 CH3C CH H COCH2CH3 •• •• •• •• O O •• •• – •• + CH3C CH2 OCH2CH3 COCH2CH3 •• •• Mechanism Step 4: Acid-base reaction + Step 5: Add acid to protonate negative ion.

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

9. O O 1. NaOCH2CH3 2. H3O+ O O COCH2CH3 (74-81%) Intramolecular Claisen Condensation:The Dieckmann Reaction CH3CH2OCCH2CH2CH2CH2COCH2CH3

10. •• O O •• •• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• Step 1; Form Nucleophile by abstracting acidic b-H CH3CH2OCCH2CH2CH2CH2COCH2CH3 NaOCH2CH3

11. •• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 •• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• Step 2: Intramolecular reaction; Nu attacks electrophilic carbon

12. •• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 •• O •• •• O •• C •• – + CH3CH2O CHCOCH2CH3 H2C •• •• H2C CH2 Step 3; Reform carbonyl group; leaving group leaves

13. O O O O HCOR ROCOR ROC COR O COR Mixed Claisen Condensations • work best when the reaction mixture contains one compound that can form an enolate and another that cannot. These esters cannot form an enolate.

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

15. O O CH3CH2OCOCH2CH3 1. NaH 2. H3O+ O O COCH2CH3 (60%) Acylation of Ketones with Esters + Esters that cannot form an enolate can be used to acylate ketone enolates.

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

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

18. O O 1. NaOR' heat 2RCH2COR' 2. H3O+ RCH2CCHH R Ketone Synthesis via -Keto Esters 3. H2O • Form b-keto ester from two esters. • Add water to hydrolyze ester and form b-keto acid. • Decarboxylate (-CO2) b-ketoester.

19. O O O 2RCH2COR' RCH2CCHCOR' R 1. NaOR' + R'OH 2. H3O+ Step 1: Form b-keto ester from two esters.

20. O O O O RCH2CCHCOR' RCH2CCHCOH R R Step 2: Hydrolysis of Ester to form b-keto acid. H+ + H2O + R’OH

21. O O O RCH2CCHCOH R RCH2CCHH R Step 3: Decarboxylation (-CO2) to form Ketone heat + CO2

22. O 2 CH3CH2CH2CH2COCH2CH3 O O CH3CH2CH2CH2CCHCOCH2CH3 CH2CH2CH3 Example; Step 1- Formation of b-ketoester 1. NaOCH2CH3 2. H3O+ (80%)

23. O O CH3CH2CH2CH2CCHCOH CH2CH2CH3 O O CH3CH2CH2CH2CCHCOCH2CH3 CH2CH2CH3 Example(cont): step 2: Hydrolysis to form b-keto acid 1. KOH, H2O, 70-80°C 2. H3O+

24. O O CH3CH2CH2CH2CCHCOH CH2CH2CH3 O CH3CH2CH2CH2CCH2CH2CH2CH3 Example (cont): Step 3: Decarboxylation to form ketone 70-80°C (81%)