2. WWU Chemistry ADDITION-ELIMINATION: NITROGEN AND PHOSPHORUS NUCLEOPHILES Sections 16.12 - 16.14

3. WWU Chemistry Compounds that bear an amino group form Imines. The G group can be one of many different possibilities

4. WWU Chemistry Addition-Elimination: The Formation of Imines All of the imine reactions, regardless of G, go by the same mechanism.

5. WWU Chemistry Mechanism of Imine Formation What is the mechanism of this step?

6. WWU Chemistry Mechanism of Imine Formation (Part Two)

7. WWU Chemistry This is Addition-Elimination The first step is carbonyl addition of an amine, and the second step is a dehydration (elimination) to yield the C=N double bond. HA is the catalyst Step #1 is rate-determining, unless the amine is very basic (e.g., semicarbazide or aniline), in which case step #2 becomes rate-determining.

8. WWU Chemistry Carbonyl compounds react with:

9. WWU Chemistry Formation of Simple Imines Aldehydes and ketones react with simple primary amines to yield imines. The equilibrium is unfavorable; the products are much less stable than the reactants.

10. WWU Chemistry A Simple Model for Enzyme-Substrate Binding.

11. WWU Chemistry If lysine is part of the protein chain of the enzyme, the terminal amino group is available to bind to carbonyl groups to form an imine.

12. WWU Chemistry Once the substrate (aldehyde or ketone) is bound to the enzyme, the active site of the enzyme is in a position to react with and modify the substrate. At the end of the reaction, because imines come apart easily (remember the “unfavorable” equilibrium?), the modified substrate can dissociate from the enzyme and return to the solution. As we can see, often biological substrates possess carbonyl groups so that they can act as a “handle” in enzyme-substrate binding. The carbonyl group may have no other chemical purpose than just this one!

13. WWU Chemistry Formation of Oximes hydroxylamine Aldehydes and ketones react with hydroxylamine to yield oximes. Oximes are important derivatives in qualitative organic analysis.

14. WWU Chemistry What’s a Derivative? One of the principal tests for the correct identification of an unknown compound comes in trying to convert the compound by a chemical reaction into another known compound -- a derivative If the melting point of the derivative matches the expected value, according to the literature, then one can assume that the original substance had been correctly identified.

15. WWU Chemistry Formation of Hydrazones a hydrazine Aldehydes and ketones react with substituted hydrazines to yield substituted hydrazones. The equilibrium is generally unfavorable. Exception: when R is an aromatic ring.

16. WWU Chemistry 2,4-Dinitrophenylhydrazones 2,4-dinitrophenylhydrazine 2,4-DNP’s are the most important of all derivatives for aldehydes and ketones.

17. WWU Chemistry Formation of Semicarbazones semicarbazide Aldehydes and ketones react with semicarbazide to yield semicarbazones. Semicarbazones are the second-most important of the derivatives of aldehydes and ketones.

18. WWU Chemistry Formation of Phenylhydrazones In most cases, the equilibrium is unfavorable. However, this reaction is sometimes used to form derivatives of the sugars.

19. WWU Chemistry As we have already seen, substituted amines can react with aldehydes and ketones to form a variety of products. Primary amines can yield imines by an addition- elimination process.

20. WWU Chemistry Addition-Elimination: The Formation of Imines

21. WWU Chemistry When secondary amines are allowed to react with aldehydes or ketones, dehydration of the type shown in the elimination step cannot take place (there is no labile hydrogen on the nitrogen atom of the addition product).

22. WWU Chemistry If the starting aldehyde or ketone has an  - hydrogen, however, dehydration toward the  -carbon can occur, yielding an enamine.

23. WWU Chemistry Formation of Enamines

24. WWU Chemistry The equilibrium for the formation of enamine is not favorable. It can be shifted to the right, however, by removing the water by azeotropic distillation as it is formed.

25. WWU Chemistry The enamine is quite nucleophilic, owing to resonance of the type: As a consequence of this resonance, the  -carbon of an enamine has a great deal of carbanion-like (nucleophilic) character.

26. WWU Chemistry Amines that are used typically to form enamines :

27. WWU Chemistry Nucleophilic Character of Enamines

28. WWU Chemistry Reactions of Enamines as Nucleophiles SN2SN2

29. WWU Chemistry Hydrolysis of Iminium Salts (Part One)

30. WWU Chemistry Hydrolysis of Iminium Salts (Part Two)

31. WWU Chemistry Enamines can react with alkyl halides -- Here’s an example. Apply the previous mechanisms to this synthesis.

32. WWU Chemistry Another example: Try to apply the mechanisms to this synthesis.

33. WWU Chemistry In each of these reactions, the enamine, acting as a nucleophile, displaces the halide ion from the alkyl halide in an S N 2 process In each of these reactions, the enamine, acting as a nucleophile, displaces the halide ion from the alkyl halide in an S N 2 process.

34. WWU Chemistry  -Alkylation of a Ketone

35. WWU Chemistry  -Alkylation of a Ketone

36. WWU Chemistry Enamine Reactions -- Summary

37. WWU Chemistry The nucleophilic behavior of enamines has been used to prepare deuterium-labelled ketones. This reaction demonstrates that enamines are basic.

38. WWU Chemistry In the previous examples, we have been using nitrogen as the nucleophilic atom. Reasoning by analogy and using the periodicity that we associate with position in the Periodic Table, what would we predict if phosphorus were the nucleophile? When phosphorus is the nucleophilic atom, the behavior is similar to that of amines, but there are important differences. The chief application of phosphorus chemistry in this type of reaction is in the Wittig reaction.

39. WWU Chemistry The Wittig Reaction This is a type of condensation reaction -- we use it to “dock” two large structures together. This is another example of addition-elimination.

40. WWU Chemistry Ylide A compound or intermediate with both a positive and a negative formal charge on adjacent atoms.

41. WWU Chemistry Resonance in Ylides The ylide is nucleophilic, owing to the negative charge character on carbon (structure on the right).

42. WWU Chemistry Typical Solvents Ylides are highly reactive with water, alcohols, acids, carbonyl compounds, and esters. So, the solvents must exclude these classes of compounds. That limits us to hydrocarbons (and perhaps ethers). Toluene and xylene are used frequently.

43. WWU Chemistry Example of a Wittig Reaction

44. WWU Chemistry Mechanism (???)

45. WWU Chemistry Preparation of the Ylide Typical bases: NaOCH 3NaOCH 3 NaHNaH LiC 4 H 9LiC 4 H 9 This reaction is not stereospecific.

46. WWU Chemistry Preparation of trans,trans-1,4-Diphenyl-1,3-butadiene Major product Minor product

47. WWU Chemistry Green Chemistry Application More grinding!

48. WWU Chemistry The Wittig Reaction: A Reminder This is a type of condensation reaction -- we use it to “dock” two large structures together.