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Chapter 20 Enols and Enolates

Chapter 20 Enols and Enolates. 20.1 Aldehyde, Ketone, and Ester Enolates. O. CH 3 CH 2 CH 2 CH. Terminology. The reference atom is the carbonyl carbon. Other carbons are designated  ,  ,  , etc. on the basis of their position with respect to the carbonyl carbon .

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Chapter 20 Enols and Enolates

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  1. Chapter 20Enols and Enolates

  2. 20.1Aldehyde, Ketone, and Ester Enolates

  3. O CH3CH2CH2CH Terminology • The reference atom is the carbonyl carbon. • Other carbons are designated , , , etc. on the basis of their position with respect to the carbonyl carbon. • Hydrogens take the same Greek letter as the carbon to which they are attached.   

  4. •• •• O O •• •• – R2C R2C CR' CR' •• H enolate ion •• – O pKa = 16-20 •• •• R2C CR' Acidity of -Hydrogen + H+

  5. O O (CH3)2CHCH CCH3 pKa = 15.5 pKa = 18.3 Acidity of -Hydrogen

  6. O O – •• •• RCH2CH RCHCH OH HOH •• •• •• With hydroxide as the base + + •• – pKa = 16-20 pKa = 16 A basic solution contains comparable amounts of the aldehyde and its enolate. A stronger base is required to completely convert the aldehyde or ketone to their enolates.

  7. O O C C C H3C CH3 H H O O – C C •• + H+ C H3C CH3 H -Diketones are much more acidic pKa = 9

  8. – •• •• O O •• •• •• C C C H3C CH3 H •• •• O O •• •• C C •• C H3C CH3 – H -Diketones are much more acidic • Enolate of -diketone is stabilized; Negative charge is shared by both oxygens

  9. – – •• •• •• •• O O O O •• •• •• •• •• •• C C C C C C H3C H3C CH3 CH3 H H •• •• O O •• •• C C •• C H3C CH3 – H -Diketones are much more acidic

  10. Esters are less acidic Hydrogensa to an ester carbonyl group are less acidic, pKa 24, than an a hydrogen 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.

  11. Deprotonation of Simple Esters Simple esters (such as ethyl acetate) are not completely deprotonated by alkoxide bases; the enolate reacts with the original ester, and Claisen condensation occurs (Section 20.5). Ethyl acetoacetate (pKa ~11) and diethyl malonate (pKa ~13) are completely deprotonated by alkoxide bases. LDA is strong enough to completely deprotonate simple esters, giving ester enolates quantitatively.

  12. CH3 CH3 – + •• Li C N C H H •• CH3 CH3 Lithium diisopropylamide (LDA) Lithium dialkylamides are very strong bases (just as NaNH2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups.

  13. O CH3CH2CH2COCH3 O – + + + Li CH3CH2CHCOCH3 HN[CH(CH3)2]2 •• pKa ~ 36 Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. + LiN[CH(CH3)2]2 pKa ~ 22

  14. O O O O O O C C C C C C pKa ~ 9 pKa ~ 13 pKa ~ 11 R RO R C C C OR' R' OR' H H H H H H

  15. 20.2Enolate Regiochemistry

  16. Enolate Regiochemistry Kinetic enolate Thermodynamic enolate Which enolate predominates depends upon many factors including base, solvent, and temperature.

  17. Enolate Regiochemistry Favored with very strong bases such as LDA, aprotic solvents, and low temperatures Favored with weaker bases and protic solvents and higher temperatures.

  18. 20.3The Aldol Condensation

  19. O O – •• •• RCH2CH RCHCH OH HOH •• •• •• Some thoughts... + + • A basic solution contains comparable amounts of the aldehyde and its enolate. • Aldehydes undergo nucleophilic addition. • Enolate ions are nucleophiles. • What about nucleophilic addition of enolate to aldehyde? •• – pKa = 16-20 pKa = 16

  20. •• O •• •• •• O – O •• •• RCHCH RCHCH RCHCH RCH2CH RCH2CH RCH2CH O O •• H O •• •• •• •• •• – •• O O NaOH RCH2CH CHCH 2RCH2CH R OH ••

  21. O RCH2CH CHCH R OH Aldol Addition • Product is called an "aldol" because it is both an aldehyde and an alcohol

  22. O O NaOH, H2O 2CH3CH CH3CH CH2CH 5°C OH Aldol Addition of Acetaldehyde Acetaldol(50%)

  23. O 2CH3CH2CH2CH O CHCH CH3CH2CH2CH CH2CH3 OH (75%) Aldol Addition of Butanal KOH, H2O 6°C

  24. O O RCH2CH CHCH 2RCH2CH R OH Aldol Condensation NaOH

  25. O O RCH2CH CHCH 2RCH2CH R OH heat NaOHheat O RCH2CH CCH R Aldol Condensation NaOH

  26. O 2CH3CH2CH2CH O CCH CH3CH2CH2CH CH2CH3 (86%) Aldol Condensation of Butanal NaOH, H2O 80-100°C

  27. C C O O H C C OH C C Dehydration of Aldol Addition Product • Dehydration of -hydroxy aldehyde can becatalyzed by either acids or bases

  28. C C O O H – C C •• OH OH C C Dehydration of Aldol Addition Product • in base, the enolate is formed NaOH

  29. C C O O H – C C •• OH OH C C Dehydration of Aldol Addition Product • The enolate loses hydroxide to form the ,-unsaturated aldehyde NaOH

  30. O O OH 2% 2CH3CCH3 CH3CCH2CCH3 98% CH3 Aldol reactions of ketones • The equilibrium constant for aldol addition reactions of ketones is usually unfavorable

  31. O O O O (96%) via: OH Intramolecular Aldol Condensation Na2CO3, H2O heat

  32. O O O (96%) Intramolecular Aldol Condensation • Even ketones give good yields of aldol condensation products when the reaction is intramolecular. Na2CO3, H2O heat

  33. 20.4Mixed Aldol Condensations

  34. O O CH3CH2CH CH3CH What is the product? • There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde. NaOH +

  35. O O CH3CH2CH CH3CH O CH3CH CH2CH O O OH – CH2CH •• What is the product? + – CH3CHCH ••

  36. O O CH3CH2CH CH3CH O CH3CH2CH CHCH O O CH3 OH – CH2CH •• What is the product? + – CH3CHCH ••

  37. O O CH3CH2CH CH3CH O CH3CH CHCH O O CH3 OH – CH2CH •• What is the product? + – CH3CHCH ••

  38. O O CH3CH2CH CH3CH O CH3CH2CH CH2CH O O OH – CH2CH •• What is the product? + – CH3CHCH ••

  39. In order to effectively carry outa mixed aldol condensation: • Need to minimize reaction possibilities • Usually by choosing one component that cannot form an enolate

  40. O HCH Formaldehyde • Formaldehyde cannot form an enolate • Formaldehyde is extremely reactive toward nucleophilic addition

  41. O O O HCH (CH3)2CHCH2CH (CH3)2CHCHCH CH2OH Formaldehyde K2CO3 + water-ether (52%)

  42. O CH3O CH Aromatic Aldehydes • Aromatic aldehydes cannot form an enolate

  43. O O CH3CCH3 CH3O CH O CHCCH3 CH3O CH Aromatic Aldehydes + via Adol condensation followed by dehydration to give conjugated product NaOH, H2O 30°C (83%)

  44. O CH3CH2CC(CH3)3 O 2. CH3CH2CH O CH3CHCC(CH3)3 HOCHCH2CH3 Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. 1. LDA, THF 3. H3O+ (81%)

  45. O CH3COCH2CH3 2. (CH3)2C O O HO C CH2COCH2CH3 H3C CH3 Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. 1. LiNR2, THF 3. H3O+ (90%)

  46. 20.5The Claisen Condensation

  47. O O O 2RCH2COR' RCH2CCHCOR' R The Claisen Condensation 1. NaOR' + R'OH 2. H3O+ -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.

  48. O O O 2CH3COCH2CH3 CH3CCH2COCH2CH3 Example 1. NaOCH2CH3 2. H3O+ (75%) Product from ethyl acetate is called ethylacetoacetate.

  49. •• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• •• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• Mechanism Step 1: pKa = pKa =

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