1. Chapter 18 Additions to the Carbonyl Group Reactions of Aldehydes and Ketones

2. General Mechanism some react further two mechanisms in acidH + adds first in baseNu − adds first

3. Basic conditions are used with strong nucleophiles. Acid would destroy these.

4. Nu adds in slow step in each case – Nucleophilic Addition regiochemistry: Nu always adds to carbonyl carbon no stereochemistry equilibrium

5. Addition of Hydride (Reduction) H:¯ is a strong Nu, so equilibrium favors product LiAlH 4 lithium aluminum hydride reacts explosively with H 2 O and ROH use ether as solvent, H 3 O + workup NaBH 4 sodium borohydride less reactive use CH 3 OH or H 2 O solvent

7. Addition of Water (Hydration) base catalyzed

8. acid catalyzed both reactions are fast H 2 O is a relatively weak Nu, so equilibrium usually favors reactants (C=O is very stable) Hydrates usually cannot be isolated.

9. Inductive Effect An EWG destabilizes the reactant and shifts the equilibrium more in favor of the product.

10. steric and inductive effect Aldehydes react faster and have larger K’s than ketones in these reactions.

11. more than 99.9% hydrated (formalin) chloral hydrate (mp = 57 o C)

12. Addition of Hydrogen Cyanide

13. loss of resonance stabilization in product ¯CN is stronger Nu than H 2 O, so equilibrium is more favorable

14. Preparation and Properties of Organometallic Nucleophiles

15. Grignard reagents (organomagnesium halides)1912 Nobel Prize need an ether as solvent (usually diethyl ether)

16. organolithium reagents

17. reaction as bases must keep H 2 O and ROH out of solvent and atmosphere This is usually the best method to prepare R-C≡C-MgX because R-C≡C-X is difficult to obtain.

18. strong Nu, so equilibrium lies entirely toward the product (irreversible)

19. tertiary alcohol is prone to dehydration in acid (E1) so use weaker acid (NH 4 Cl) to protonate

22. original carbonyl carbon

23. Addition of Phosphorus Ylides; The Wittig Reaction G. Wittig shared the 1979 Nobel Prize with H. C. Brown (hydroboration) (strong base) stabilized by inductive effect of P + and resonance SN2SN2

24. Wittig Reaction addition-elimination

26. Addition of Nitrogen Nucleophiles

27. best in the pH range of 4 - 6 C=O is stronger than C=N, so must drive the equilibrium remove water

29. derivative formation

32. The Wolff-Kishner Reduction

34. Reductive Amination Use a reducing agent that will react with C=N but not C=O. sodium cyanoborohydride

35. Addition of Alcohols

38. stable to base and nucleophiles H3O+H3O+

40. Protecting Group“protects” one functional group from reacting while reaction is done at another functional group molecule has two reactive functional groups convert FG’ to protected functional group desire reaction here but this FG is reactive also protected functional group do desired reaction remove protecting group

42. Conjugate Additions α,β-unsaturated carbonyl compounds

43. conjugate addition 1,4-addition normal addition 1,2-addition

44. Less reactive Nu’s give conjugate addition because the reaction is reversible and the more stable product is formed (the stable C=O group is retained).

45. Addition of the more reactive nucleophiles is irreversible. The product depends on the relative rates of normal and conjugate additions. LiAlH 4 gives mainly 1,2-addition. NaBH 4 gives a mixture. (useful) (not useful)

46. The product of Grignard additions depends on the steric hindrance at the two electrophilic carbons.

47. lithium diorganocuprate reagents

48. Synthesis

49. Wittig [Ox] Grignard

51. Organocuprate reagent

52. Summary Nu = ¯CN, E = H + Nu = H:¯, E = H + Nu = R:¯, E = H + Nu = RNH 2 or Ph 3 PCR 2 (Wittig) Nu = ROH or RSH