1. OrgChem- Chap20 1 Chapter 20 Enolates / Other Carbon Nucleophiles C-C bond formation is very important  larger, more complex organic molecule can be made from smaller ones How? carbon nucleophile + carbon electrophile  Carbon electrophile: or  +  - ++  abundant

2. OrgChem- Chap20 2 How about carbon nucloephile?  limited Ex) cyanide ion: M + - CN acetylide ion: ylide: Grignard reagent and organo metallic compound: R-X + 2Li  RLi + LiX

3. OrgChem- Chap20 3  Grignard reagent and organometallic compund are not useful for S N 2 reactions because they are too reactive. For the S N 2 enolates are used Because they are not as reactive as organometallic compunds, then C-C bond through S N 2 can be formed

4. OrgChem- Chap20 4

5. 5 20.1 Enols and Enolate Anions  both are possible under acidic and basic conditions In acidic condition In basic condition

6. OrgChem- Chap20 6 Equilibrium constants of carbonyl and enol tautomers for base condition Higher value for 1,3-dicarbonyl compoundsdiketone > ketoester > diester

7. OrgChem- Chap20 7 What kinds of base can we use? Use base whose pK a s of conjugate acids are greater than those of the carbonyl base !

8. OrgChem- Chap20 8 For Use compunds whose pK a s of conjugate acids are greater than 30 such as Ethoxide can be used (pK a ~ 16) For

9. OrgChem- Chap20 9 20.2 Halogenation of the  -Carbon The reaction of an aldehyde or ketone with Cl 2, Br 2, or I 2, under either acid or basic condition Both acidic and basis conditions can be used

10. OrgChem- Chap20 10 Under acidic conditions The presence of the halogens retards the enolation, so the addition of single halogen is possible Examples

11. OrgChem- Chap20 11 Under basic conditions

12. OrgChem- Chap20 12 Example

13. OrgChem- Chap20 13 20.3 Alkylation of Enolate Anions  Enolates from esters, ketones, and nitriles can be used in S N 2 reactions (alkylations). Ex)

14. OrgChem- Chap20 14  Aldehydes cannot be used in such reactions because they are too reactive (side reactions) 1. Reactions with base No steric hidrance ! 2. Reactions with themselves: Aldol condensation (later) LDA: lithium diisopropylamide  It is a very strong base but not very nucleophilic due to the steric hindrance

15. OrgChem- Chap20 15 To avoid the formation of two products, deprotonation of the ketones must produce a single enolate ion. Examples

16. OrgChem- Chap20 16

17. OrgChem- Chap20 17 20.4 Alkylation of More Stabilized Anions Strong nucleophiles are normally strong bases, then many side reactions are possible. 1.Elimination 2.Unwanted substitution

18. OrgChem- Chap20 18 Therefore we might need to use less nucleophilic enolates, Then we might need more steps to, still the yield can be higher due to less side reaction. Example Ch 10.2 Ch 10.6

19. OrgChem- Chap20 19 Ch 10.2

20. OrgChem- Chap20 20 Ch 10.6 Why?

21. OrgChem- Chap20 21 This time, ethyl acetoacetate can be used instead of acetone!

22. OrgChem- Chap20 22 Mechanism

23. OrgChem- Chap20 23 Example

24. OrgChem- Chap20 24 Diethyl malonatate can be used instead of acetic acid

25. OrgChem- Chap20 25

26. OrgChem- Chap20 26 Preparation of substituted  -ketoesters,  -diester, and dinitrile  without hydrolysis

27. OrgChem- Chap20 27

28. OrgChem- Chap20 28 20.5 The Aldol Condensation (aldehyde + base) cannot be used for the alkylation of alkyl halide, because of the aldol condensation! Carbonyl carbon of aldehyde is much more electrophilic than those of ester, ketone, and nitrile! ester, ketone, and nitrile  S N 2

29. OrgChem- Chap20 29

30. OrgChem- Chap20 30 If the aldol condensation is conducted under very vigorous conditions (higher temperature, longer reaction time, and/or strong base

31. OrgChem- Chap20 31

32. OrgChem- Chap20 32 Ketones As less electrophilic, usually no aldol condensation. However when the product is 5- or 6- membered ring, then aldol condensation occurs!

33. OrgChem- Chap20 33 Mixed aldol condensation 4 products = 2 acidic compounds x 2 electrophilic compounds

34. OrgChem- Chap20 34 Use aromatic aldehyde (only electrophilic) to get one product. Product is more favorable: conjugation

35. OrgChem- Chap20 35

36. OrgChem- Chap20 36 20.6 Ester Condensation 20.3-4: enolates with alkyl halide using weak or strong bases depending on the acidity.

37. OrgChem- Chap20 37 20.6: enolate with ester using weaker bases.  Ester condensation or Claisen ester condensation 20.5: enolate with aldehyde using weaker bases.  Aldol condensation

38. OrgChem- Chap20 38 Mechanism of the Claisen Ester Condensation Step 4 is the reason why this reaction is possible

39. OrgChem- Chap20 39 For the compounds with only one on the  -carbon, Step 4 is impossible. Then the ester condensation is impossible If stronger base is used, then condensation is possible

40. OrgChem- Chap20 40 Dieckmann condensatoin  Intramolecular ester condensation Mixed ester condensation can be prevented if one of the component acts as only electrophile such as

41. OrgChem- Chap20 41

42. OrgChem- Chap20 42 20.7 Carbon and hydrogen leaving groups A carbanion as a leaving group

43. OrgChem- Chap20 43 A hydride as a leaving group, Cannizzaro reaction

44. OrgChem- Chap20 44 20.8 Enamines In ch 18.8 The enamine can be used as a carbon nucleophile !

45. OrgChem- Chap20 45  -carbon is nucleophilic, still weaker nucleophile than the enolates. Therefore for S N 2 reaction, the alkyl halide must be very reactive such as:

46. OrgChem- Chap20 46

47. OrgChem- Chap20 47 20.9 Other Carbon Nucleophiles

48. OrgChem- Chap20 48 Example reaction

49. OrgChem- Chap20 49 Example reaction

50. OrgChem- Chap20 50 Other Carbon Nucleophiles

51. OrgChem- Chap20 51 Using two equivalent of LDA more nucleophic site is reacted

52. OrgChem- Chap20 52 20.10 Conjugated Addition 1,2 addition: Grignard reagent, hydride  stronger nucleophile 1,4 addition: cyanide, amine  less reactive nucleophile or sterically hindered See CH 18.10

53. OrgChem- Chap20 53 In CH 20 Michael reaction  enolate and related carbanion + ,  -unsaturated carbonyl compound In Michael reaction only catalytic amount of base is needed

54. OrgChem- Chap20 54 Michael reaction mechanism

55. OrgChem- Chap20 55 Examples of Michael reaction

56. OrgChem- Chap20 56 Robinson annulation  Michael reaction + aldol condensation

57. OrgChem- Chap20 57 20.11 Synthesis Retrosynthetic Arrow

58. OrgChem- Chap20 58

59. OrgChem- Chap20 59

60. OrgChem- Chap20 60

61. OrgChem- Chap20 61

62. OrgChem- Chap20 62 Other example

63. OrgChem- Chap20 63 Summary

64. OrgChem- Chap20 64

65. OrgChem- Chap20 65