Chapter 18

1. Chapter 18 Reactions at the a Carbon of Carbonyl Compounds Enols and Enolates

2. About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3. Reactions at the a Carbon of Carbonyl Compounds:Enols and Enolates a Hydrogens are weakly acidic (pKa = 19 – 20)

4. The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Anions

5. Resonance structures for the delocalized enolates

7. Keto and Enol Tautomers • Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization

9. Resonance stabilization of the enol form

10. Reactions via Enols & Enolates 3A. Racemization Racemization at an a carbon takes place in the presence of acids or bases

11. Base-Catalyzed Enolization

12. Acid-Catalyzed Enolization

13. 3B. Halogenation at the a Carbon

14. Base-Promoted Halogenation

15. Acid-Promoted Halogenation

16. 3C. The Haloform Reaction

18. Mechanism

19. Acyl Substitution Step

20. 3D. a-Halo Carboxylic Acids: The Hell–Volhard–Zelinski Reaction

21. Example

25. Lithium Enolates

26. Preparation of lithium diisopropylamide (LDA)

27. 4A. Regioselective Formation of Enolates • Formation of a Kinetic Enolate This enolate is formed faster because the hindered strong base removes the less hindered proton faster.

28. Formation of a Thermodynamic Enolate This enolate is more stable because the double bond is more highly substituted. It is the predominant enolate at equilibrium.

29. 4B. Direct Alkylation of Ketones via Lithium Enolates

30. 4C. Direct Alkylation of Esters

31. Examples

32. Enolates of b-Dicarbonyl Compounds

33. Recall • a-hydrogens of b-dicarbonyl compounds are more acidic

34. Contributing resonance structures Resonance hybrid

35. Synthesis of Methyl Ketones: The Acetoacetic Ester Synthesis

36. Synthesis of monosubstituted methyl ketones

37. Synthesis of disubstituted methyl ketones

39. Synthesis of g-keto acids and g-diketones

40. 6A. Acylation • Synthesis b-diketones

41. Synthesis of Substituted Acetic Acids: The Malonic Ester Synthesis

43. Synthesis of monoalkylacetic acid

44. Synthesis of dialkylacetic acid

45. Example 1

46. Example 2

47. Further Reactions of Active Hydrogen Compounds

48. Example

49. Synthesis of Enamines: Stork Enamine Reactions

50. 2° amines most commonly used to prepare enamines • e.g.