chapter 20 enols and enolates n.
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Chapter 20 Enols and Enolates
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  1. Chapter 20Enols and Enolates

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

  7. •• •• 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

  8. – •• •• •• •• 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

  9. Esters • Hydrogens a to an ester carbonyl group are less acidic, pKa 24, than a of aldehydes and ketones, pKa 16-20. • The decreased acidity is due the decreased electron withdrawing ability of an ester carbonyl. • Electron delocalization decreases the positive character of the ester carbonyl group.

  10. O O C C R C OR' H H Esters • A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions.

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

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

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

  14. The Aldol Condensation

  15. 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

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

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

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

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

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

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

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

  23. 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

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

  25. 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

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

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

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

  29. Mixed Aldol Condensations

  30. 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 +

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

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

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

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

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

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

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

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

  39. O O CH3CCH3 CH3O CH O CHCCH3 CH3O CH Aromatic Aldehydes + NaOH, H2O 30°C (83%)

  40. Deprotonation of Aldehydes, Ketones, and Esters • Simple aldehydes, ketones, and esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original carbonyl, and Aldol or Claisen condensation occurs. • Are there bases strong enough to completely deprotonate simple carbonyls, giving enolates quantitatively?

  41. CH3 CH3 – + •• Li C N C H H •• CH3 CH3 Lithium diisopropylamide • Lithium dialkylamides are 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.

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

  43. O CH3CH2CHCOCH3 Lithium diisopropylamide (LDA) • Enolates generated from esters and LDA can be alkylated. O CH3CH2CHCOCH3 CH2CH3 CH3CH2I (92%) – ••

  44. 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%)

  45. 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%)

  46. The Claisen Condensation(gives -keto esters)

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

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

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

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