14.

6 Synthesis of Alcohols Using Grignard Reagents

Grignard reagents act as nucleophiles toward the carbonyl group

R

+ C

diethyl ether

C
O + MgX

MgX O

H3O+ two-step sequence gives an alcohol as the isolated product R C

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 diethyl ether R C

O

+ H C

H + MgX H R

MgX O

H3O+ product is a primary alcohol

C
OH

Example

Mg
Cl diethyl ether MgCl H C O

H
CH2OH (64-69%) H3O+ CH2OMgCl

Grignard reagents react with:

formaldehyde to give primary alcohols aldehydes to give secondary alcohols

Grignard reagents react with aldehydes H diethyl ether R C R'

+ R' C

MgX O

O + MgX

H3O+
product is a secondary alcohol R

C
OH

R'

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

CH3(CH2)4CH2CHCH3
OH (84%)

CH3(CH2)4CH2CHCH3
OMgBr

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" diethyl ether R C

O

R"

+ R' C

R'

MgX O

MgX R"

H3O+ product is a tertiary alcohol R

C
OH

R'

Example Mg CH3Cl diethyl ether CH3MgCl

HO

CH3

H3O+

ClMgO

CH3

(62%)

14.7 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 OH (76%)

CH2

14.8 Synthesis of Acetylenic Alcohols

Using Sodium Salts of Acetylenes NaNH2 HC CH NH3 O HC CNa HO C

CH

1. NH3
HC CNa +

2. H3O+
(65-75%)

Using Acetylenic Grignard Reagents CH3(CH2)3C CH + CH3CH2MgBr diethyl ether CH3(CH2)3C CMgBr 1. H2C 2. H3O+ CH3(CH2)3C CCH2OH + CH3CH3 O

(82%)

14.9 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

OH Step 1 Locate the carbon that bears the hydroxyl group.

Retrosynthetic Analysis of Alcohols

OH Step 2 Disconnect one of the groups attached to this carbon.

Retrosynthetic Analysis of Alcohols

OH

Retrosynthetic Analysis of Alcohols

MgX

O
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 other possibilities.

OH

Can you see them?

CH3MgX

O
C CH2CH3

Synthesis

Mg, diethyl ether CH3Br CH3MgBr

O 1. 2. H3O+ C CH2CH3

CH3
C OH CH2CH3

14.10 Preparation of Tertiary Alcohols From Esters and Grignard Reagents

Grignard reagents react with esters

R'

R'

+ OCH3 C

diethyl ether

OCH3

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'

+ OCH3 C

diethyl ether

OCH3

MgX O this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol

O + MgX

CH3OMgX R C O

R'

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%)