Synthesis of Alcohols Using Grignard Reagents

1. Synthesis of Alcohols Using Grignard Reagents

4. diethylether R C R O MgX •• •• •• R C OH •• •• Grignard reagents act as nucleophilestoward the carbonyl group d+ d– two-step sequence gives an alcohol as the isolated product C + MgX O •• – •• H3O+

5. Grignard reagents react with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols esters to give tertiary alcohols

6. Grignard reagents react with: formaldehyde to give primary alcohols

8. diethylether R C R + MgX O MgX •• •• •• R C OH •• •• Grignard reagents react with formaldehyde H product is a primary alcohol H H d+ d– H C O •• – •• H3O+ H H

9. Cl MgCl H O C H CH2OH CH2OMgCl Example Mg diethylether H3O+ (64-69%)

10. CH3(CH2)3C CH CH3(CH2)3C CMgBr 1. H2C O CH3(CH2)3C CCH2OH Using Acetylenic Grignard Reagents + CH3CH2MgBr diethyl ether + CH3CH3 2. H3O+ Can you use a different reaction other than a Grignard? (82%)

11. Grignard reagents react with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols

13. diethylether R C R + O MgX MgX •• •• •• R C OH •• •• Grignard reagents react with aldehydes H product is a secondary alcohol H R' d+ d– R' C O •• – •• H3O+ H R'

14. H3C O C H CH3(CH2)4CH2CHCH3 CH3(CH2)4CH2CHCH3 OH OMgBr Example Mg CH3(CH2)4CH2Br CH3(CH2)4CH2MgBr diethylether H3O+ (84%)

15. Grignard reagents react with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols

17. diethylether R C R + MgX O MgX •• •• •• R C OH •• •• Grignard reagents react with ketones R" product is a tertiary alcohol R" R' d+ d– R' C O •• – •• H3O+ R" R'

18. CH3 CH3 HO ClMgO Example Mg CH3Cl CH3MgCl diethylether O H3O+ (62%)

19. Preparation of Alcohols From Epoxides

21. R MgX CH2 H2C O Reaction of Grignard Reagentswith Epoxides R CH2 CH2 OMgX H3O+ RCH2CH2OH

22. Example CH2 H2C CH3(CH2)4CH2MgBr + O 1. diethyl ether 2. H3O+ CH3(CH2)4CH2CH2CH2OH (71%)

24. Preparation of KetonesFrom Acid Chlorides and Grignard Reagents & Preparation of Tertiary AlcoholsFrom Esters and Grignard Reagents

26. Acid Chlorides  Ketones

28. Esters  3o AlcoholsStep 1

29. Esters  3o AlcoholsStep 2

31. •• diethylether OCH3 •• •• OCH3 R C R •• O MgX •• •• •• Grignard reagents react with esters R' R' d+ d– but species formed is unstable and dissociates under the reaction conditions to form a ketone C + MgX O •• – ••

32. •• diethylether OCH3 •• •• OCH3 R C R •• O MgX •• •• •• R R' C O Grignard reagents react with esters R' R' d+ d– this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol C + MgX O •• – •• –CH3OMgX •• ••

33. O (CH3)2CHCOCH3 Example + 2 CH3MgBr Two of the groups attached to the tertiary carbon come from the Grignard reagent 1. diethyl ether 2. H3O+ OH (CH3)2CHCCH3 CH3 (73%)

34. Retrosynthetic Analysis Retrosynthetic analysis is the process by which we plan a synthesis by reasoning backward from the desired product (the "target molecule").

35. C OH Retrosynthetic Analysis of Alcohols Step 1 Locate the carbon that bears the hydroxyl group.

36. C OH Retrosynthetic Analysis of Alcohols Step 2 Disconnect one of the groups attached to this carbon.

37. C Retrosynthetic Analysis of Alcohols OH

38. MgX C O Retrosynthetic Analysis of Alcohols What remains is the combination of Grignard reagent and carbonyl compound that can be used to prepare the alcohol.

39. CH3 CH2CH3 C OH O C CH2CH3 Example There are two other possibilities. Can you see them? CH3MgX

40. O C CH2CH3 CH3 CH2CH3 C OH Synthesis Mg, diethyl ether CH3Br CH3MgBr 1. 2. H3O+

41. Synthesis of AlcoholsUsing Organolithium Reagents Organolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do.

42. O CH H2C CHLi CHCH CH2 OH Example + 1. diethyl ether 2. H3O+ (76%)