Chapter 21 Ester Enolates

1. Chapter 21Ester Enolates

2. 21.1Ester a-Hydrogens and their pKas

3. Introduction O O O • 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. O R O R O R H H H

4. O O C C R C OR' H H Introduction • 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.

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

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

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

8. 21.2The Claisen Condensation

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

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

11. •• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• •• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• Mechanism Step 1:

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

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

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

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

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

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

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

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

20. 21.3Intramolecular Claisen Condensation:The Dieckmann Reaction

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

22. •• O O •• •• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• via CH3CH2OCCH2CH2CH2CH2COCH2CH3 NaOCH2CH3

23. •• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 •• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• via

24. •• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 via

25. •• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 •• O •• •• O •• C •• – + CH3CH2O CHCOCH2CH3 H2C •• •• H2C CH2 via

26. 21.4Mixed Claisen Condensations

27. Mixed Claisen Condensations • As with mixed aldol condensations, mixedClaisen condensations are best carried outwhen the reaction mixture contains one compound that can form an enolate and another that cannot.

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

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

30. 21.5Acylation of Ketones with Esters

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

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

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

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

35. 21.6Ketone Synthesis via -Keto Esters

36. O O O RCH2CCHCOH R Ketone Synthesis • -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.) + RCH2CCH2R CO2

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

38. O O O RCH2CCHCOR' R Ketone Synthesis 1. NaOR' • -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. + 2 RCH2COR' R'OH 2. H3O+

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

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

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

42. 21.7The Acetoacetic Ester Synthesis

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

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

45. O O C C •• H3C C OCH2CH3 – H R X O O C C H3C C OCH2CH3 H R Alkylation of Ethyl Acetoacetate • 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).

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

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

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

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

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