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Synthesis of Alcohols Using Grignard Reagents
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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
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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
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Grignard reagents react with:
formaldehyde to give primary alcohols 3
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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
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Example Mg Cl MgCl diethyl ether C O H H3O+ CH2OH CH2OMgCl (64-69%) 5
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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
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Grignard reagents react with:
formaldehyde to give primary alcohols aldehydes to give secondary alcohols 3
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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
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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
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Grignard reagents react with:
formaldehyde to give primary alcohols aldehydes to give secondary alcohols ketones to give tertiary alcohols 3
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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
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Example Mg CH3Cl CH3MgCl diethyl ether O CH3 HO CH3 ClMgO H3O+ (62%) 5
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Preparation of Alcohols From Epoxides
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Reaction of Grignard Reagents with Epoxides
MgX R H2C CH2 O CH2 CH2 OMgX H3O+ RCH2CH2OH 9
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Example CH2 H2C CH3(CH2)4CH2MgBr + O 1. diethyl ether 2. H3O+
CH3(CH2)4CH2CH2CH2OH (71%) 29
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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
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Esters 3o Alcohols Step 2
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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
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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
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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
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Retrosynthetic Analysis
Retrosynthetic analysis is the process by which we plan a synthesis by reasoning backward from the desired product (the "target molecule"). 14
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Retrosynthetic Analysis of Alcohols
Step 1 Locate the carbon that bears the hydroxyl group. 15
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Retrosynthetic Analysis of Alcohols
Step 2 Disconnect one of the groups attached to this carbon. 15
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Retrosynthetic Analysis of Alcohols
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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
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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
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Synthesis Mg, diethyl ether CH3Br CH3MgBr C CH2CH3 O 1. 2. H3O+ C OH
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Synthesis of Alcohols Using Organolithium Reagents
Organolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do. 10
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Example CH O + H2C CHLi 1. diethyl ether 2. H3O+ CH2 CHCH OH (76%) 5
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