Synthesis of Alcohols Using Grignard Reagents 1

Figure: 10-02-050UN Caption:

Figure: 10-02-052UN Caption:

Grignard reagents act as nucleophiles toward the carbonyl group diethyl ether d+ R C d– R MgX C + O O •• • • MgX • • •• – H3O+ •• R C OH • • two-step sequence gives an alcohol as the isolated product 23

Grignard reagents react with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols esters to give tertiary alcohols 3

Grignard reagents react with: formaldehyde to give primary alcohols 3

Figure: 10-02-054UN Caption:

Grignard reagents react with formaldehyde diethyl ether d+ R C d– R MgX H C MgX + O O •• • • • • •• – H3O+ H •• R C OH • • product is a primary alcohol H 23

Example Mg Cl MgCl diethyl ether C O H H3O+ CH2OH CH2OMgCl (64-69%) 5

Using Acetylenic Grignard Reagents CH CH3(CH2)3C + CH3CH2MgBr diethyl ether CMgBr CH3(CH2)3C + CH3CH3 1. H2C O 2. H3O+ Can you use a different reaction other than a Grignard? CCH2OH CH3(CH2)3C (82%) 13

Grignard reagents react with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols 3

Figure: 10-02-059UN Caption:

Grignard reagents react with aldehydes diethyl ether d+ R C d– R MgX R' C MgX + O O •• • • • • •• – H3O+ H •• R C OH • • product is a secondary alcohol R' 23

Example Mg CH3(CH2)4CH2Br CH3(CH2)4CH2MgBr diethyl ether C O H3C H H3O+ CH3(CH2)4CH2CHCH3 OH CH3(CH2)4CH2CHCH3 OMgBr (84%) 5

Grignard reagents react with: formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols 3

Figure: 10-02-062UN Caption:

Grignard reagents react with ketones diethyl ether d+ R C d– R MgX R' C MgX + O O •• • • • • •• – H3O+ R" •• R C OH • • product is a tertiary alcohol R' 23

Example Mg CH3Cl CH3MgCl diethyl ether O CH3 HO CH3 ClMgO H3O+ (62%) 5

Preparation of Alcohols From Epoxides 22

Figure: 10-02-074UN Caption:

Reaction of Grignard Reagents with Epoxides MgX R H2C CH2 O CH2 CH2 OMgX H3O+ RCH2CH2OH 9

Example CH2 H2C CH3(CH2)4CH2MgBr + O 1. diethyl ether 2. H3O+ CH3(CH2)4CH2CH2CH2OH (71%) 29

Preparation of Ketones From Acid Chlorides and Grignard Reagents & Preparation of Tertiary Alcohols From Esters and Grignard Reagents 24

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Acid Chlorides  Ketones

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Esters  3o Alcohols Step 1

Esters  3o Alcohols Step 2

Figure: 10-02-070UN Caption:

Grignard reagents react with esters OCH3 •• R' diethyl ether d+ R C OCH3 •• d– R MgX C + O O •• • • MgX • • •• – but species formed is unstable and dissociates under the reaction conditions to form a ketone 23

Grignard reagents react with esters OCH3 •• R' diethyl ether d+ R C OCH3 •• d– R MgX C + O O •• • • MgX • • •• – –CH3OMgX this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol C O R R' • • •• 23

Example O + 2 CH3MgBr (CH3)2CHCOCH3 1. diethyl ether 2. H3O+ Two of the groups attached to the tertiary carbon come from the Grignard reagent OH (CH3)2CHCCH3 CH3 (73%) 26

Retrosynthetic Analysis Retrosynthetic analysis is the process by which we plan a synthesis by reasoning backward from the desired product (the "target molecule"). 14

Retrosynthetic Analysis of Alcohols Step 1 Locate the carbon that bears the hydroxyl group. 15

Retrosynthetic Analysis of Alcohols Step 2 Disconnect one of the groups attached to this carbon. 15

Retrosynthetic Analysis of Alcohols 15

Retrosynthetic Analysis of Alcohols MgX C O What remains is the combination of Grignard reagent and carbonyl compound that can be used to prepare the alcohol. 15

There are two other possibilities. Can you see them? Example C OH CH3 CH2CH3 There are two other possibilities. Can you see them? CH3MgX C CH2CH3 O 20

Synthesis Mg, diethyl ether CH3Br CH3MgBr C CH2CH3 O 1. 2. H3O+ C OH 21

Synthesis of Alcohols Using Organolithium Reagents Organolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do. 10

Example CH O + H2C CHLi 1. diethyl ether 2. H3O+ CH2 CHCH OH (76%) 5