Synthesis of Alcohols Using Grignard Reagents

Grignard reagents act as nucleophiles toward the carbonyl group

diethyl d– d+ R C ether R C + MgX O • • O • MgX •• • •• – + H3O

two-step sequence R C gives an alcohol as the isolated product • OH • •• Grignard reagents react with: formaldehyde to give primary alcohols

aldehydes to give secondary alcohols

ketones to give tertiary alcohols

esters to give tertiary alcohols Grignard reagents react with: formaldehyde to give primary alcohols

Grignard reagents react with formaldehyde

H H H diethyl d– d+ R C ether R C H + MgX O • • O • MgX •• • •• –

+ H3O H

product is a R C H primary alcohol • OH • •• Example

Mg Cl MgCl diethyl ether H C O H

+ H3O CH2OH CH2OMgCl

(64-69%) Using Acetylenic Grignard Reagents

CH3(CH2)3C CH + CH3CH2MgBr

diethyl ether

CH3(CH2)3C CMgBr + CH3CH3

1. H2C O + 2. H3O Can you use a different reaction

CH3(CH2)3C CCH2OH other than a Grignard? (82%) Grignard reagents react with: formaldehyde to give primary alcohols

aldehydes to give secondary alcohols

Grignard reagents react with aldehydes

H H R' diethyl d– d+ R C ether R C R' + MgX O • • O • MgX •• • •• – H O+ 3 H

product is a R C R' secondary alcohol • OH • •• Example

CH3(CH2)4CH2Br CH3(CH2)4CH2MgBr diethyl ether H3C C O H + H3O CH3(CH2)4CH2CHCH3 CH3(CH2)4CH2CHCH3

OH OMgBr (84%) Grignard reagents react with: formaldehyde to give primary alcohols

aldehydes to give secondary alcohols

ketones to give tertiary alcohols

Grignard reagents react with ketones

R" R" R' diethyl d– d+ R C ether R C R' + MgX O • • O • MgX •• • •• –

+ H3O R"

product is a R C R' tertiary alcohol • OH • •• Example

CH3Cl CH3MgCl diethyl ether O

HO CH ClMgO CH 3 + 3 H3O

(62%) SYNTHESIS OF ALCOHOLS USING GRIGNARD REAGENTS AND CARBONYL COMPOUNDS:

Draw the structures of the Grignard reagent and the carbonyl compound that can be combined to give the following alcohols.

2-hexanol 

3-phenyl-1-propanol 

2-methyl-2-butanol 

cyclohexylmethanol 

Preparation of Alcohols From Epoxides

Reaction of Grignard Reagents with Epoxides

R MgX R

CH CH OMgX H2C CH2 2 2

O + H3O

RCH2CH2OH Example

CH CH3(CH2)4CH2MgBr + H2C 2 O 1. diethyl ether + 2. H3O

CH3(CH2)4CH2CH2CH2OH (71%)

Preparation of Ketones From Acid Chlorides and Grignard Reagents

Preparation of Tertiary Alcohols From Esters and Grignard Reagents

Acid Chlorides  Ketones

QuickTime™ and a Cinepak decompressor are needed to see this picture.

Esters  3o Alcohols Step 1

QuickTime™ and a Cinepak decompressor are needed to see this picture. Esters  3o Alcohols Step 2

QuickTime™ and a Cinepak decompressor are needed to see this picture.

Grignard reagents react with esters

R' R' •• d+ OCH3 diethyl d– •• •• R C ether R C OCH •• 3 + MgX O • • O • MgX •• • •• –

but species formed is unstable and dissociates under the reaction conditions to form a ketone Grignard reagents react with esters

R' R' •• d+ OCH3 diethyl d– •• •• R C ether R C OCH3 •• + MgX O • • O • MgX •• • •• –

–CH OMgX this ketone then 3 goes on to react with R R' a second mole of the C Grignard reagent to give a tertiary O • •• alcohol Example O

2 CH3MgBr + (CH3)2CHCOCH3 1. diethyl ether

+ 2. H3O

Two of the groups OH attached to the tertiary carbon (CH ) CHCCH 3 2 3 come from the Grignard reagent CH3 (73%) Retrosynthetic Analysis

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

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

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

OH Retrosynthetic Analysis of Alcohols

MgX

What remains is the combination of Grignard reagent and carbonyl compound that can be used to prepare the alcohol. Example CH3

C CH2CH3

There are two OH other possibilities.

Can you see them? CH3MgX

C CH2CH3 Synthesis Mg, diethyl ether

CH3Br CH3MgBr

1. C CH2CH3

+ 2. H3O

CH3

C CH2CH3

OH Synthesis of Alcohols Using Organolithium Reagents

Organolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do. Example O

H2C CHLi + CH

1. diethyl ether

+ 2. H3O

CHCH CH2

OH (76%)