Synthesis of Aldehydes and Ketones

1. Synthesis of Aldehydes and Ketones WWU -- Chemistry

2. Aldehydes can be prepared byreduction. • This would be desirable to do: • The problem is, how to stop the reduction at the aldehyde state, without reducing all the way to a primary alcohol? WWU -- Chemistry

3. Rosenmund Reduction The catalyst is selectively poisoned. The reaction generally goes in very good yield. Quinoline is: WWU -- Chemistry

4. Example WWU -- Chemistry

5. Another, similar, method uses a new reagent: Lithium Tri-tert-butoxy-aluminum Hydride WWU -- Chemistry

6. The tert-butyl groups provide steric hindrance. • This diminishes the ability of the reagent to act as a hydride donor (as compared with LiAlH4). • Also, there is only one reducing hydrogen per molecule of this reagent. WWU -- Chemistry

7. Example WWU -- Chemistry

8. Reduction of Esters to Aldehydes An ester is reduced by lithium aluminum hydride to yield two different alcohols: WWU -- Chemistry

9. WWU -- Chemistry

10. The lithium aluminum hydride reduces the acyl part of the ester to a primary alcohol. • The alkyl part of the ester simply drops off as a second alcohol -- it is not reduced in this reaction. • You would generally do this reaction to prepare the primary alcohol deriving from the acyl portion of the ester. WWU -- Chemistry

11. Lithium aluminum hydride is such a powerful reducing agent that it reduces the ester throughtwo 2-electron reduction stages, all the way to the alcohol WWU -- Chemistry

12. Chemists have wondered if it might be possible to modify the structure of the aluminum hydride reducing agent so as to reduce an ester through one 2-electron reduction step, but no further. • You have already seen a similar modification in the example of lithium tri-tert-butoxyaluminum hydride. WWU -- Chemistry

13. Among the most useful modified aluminum hydride reducing agents is Diisobutylaluminum Hydride, also known as DIBALH. WWU -- Chemistry

14. Reductions are typically carried out in toluene or hexane solution at -78 °C (dry ice-acetone bath). • The reduction is followed by hydrolysis with aqueous acid to decompose the aluminum salts and liberate the aldehyde. • After hydrolysis, the reaction is allowed to warm to room temperature. WWU -- Chemistry

15. Reduction of Esters to Aldehydes WWU -- Chemistry

16. In more detail... WWU -- Chemistry

17. Reduction of esters with DIBALH has become a valuable method for the synthesis of aldehydes. WWU -- Chemistry

18. Example WWU -- Chemistry

19. If the temperature of the reaction is not maintained at dry ice temperatures, the ester will be reduced all the way to the alcohol. WWU -- Chemistry

20. This will not lose an alkoxy group at low temperatures -- thus, no leaving group! WWU -- Chemistry

21. Loss of the alkoxy group does not happen until after the hydride reagent has been destroyed with acid, so a second reduction step cannot happen. Thus, temperature control is critical for the selective reduction of an ester to an aldehyde. WWU -- Chemistry

22. Hydrolysis Step WWU -- Chemistry

23. Nitriles can also be reduced to aldehydes, using DIBALH WWU -- Chemistry

24. Ketone Synthesis Using Organometallic Reagents • We want to do: • Too bad it doesn’t work! No ketone is obtained. WWU -- Chemistry

25. Instead, we get alcohol: The Grignard reagent reacted twice. WWU -- Chemistry

26. The problem is that the organomagnesium reagent is too reactive -- we need something milder. • So, we use an organocadmium reagent, instead: WWU -- Chemistry

27. Ketone Synthesis using Organocadmium Reagents WWU -- Chemistry

28. Example WWU -- Chemistry

29. Alternative: Apparently, both Grignard addition steps are too slow at low temperature. But, the ferric chloride catalyzes the first addition, making it proceed fast enough to be useful. Ferric chloride does not catalyze the second addition, so it remains very slow and is not observed! WWU -- Chemistry

30. Lithium dialkylcuprates can also be used to prepare ketones from acid chlorides. WWU -- Chemistry

31. Ketone Synthesis using Lithium Dialkylcuprates WWU -- Chemistry

32. Example WWU -- Chemistry

33. Synthesis Problem WWU -- Chemistry

34. Another Synthesis Problem WWU -- Chemistry

35. Are We Having Fun Yet? WWU -- Chemistry

36. Let’s Make Some Drugs! WWU -- Chemistry

37. WWU -- Chemistry