Synthesis of Alcohols Using Grignard Reagents

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

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:

Grignard reagents react with formaldehyde RMgX C O – MgX+ –––– ++++ R C O R C OH H3O+H3O+H3O+H3O+ diethyl ether product is a primary alcohol HH H H H H

Example diethyl ether Cl Mg MgCl C OHH CH 2 OMgCl H3O+H3O+H3O+H3O+ CH 2 OH (64-69%)

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

Grignard reagents react with aldehydes RMgX C O – –––– ++++ R C O R C OH H3O+H3O+H3O+H3O+ diethyl ether product is a secondary alcohol HR' H R' H R' MgX+

Example diethyl ether Mg C O H3CH3CH3CH3CH H3O+H3O+H3O+H3O+ (84%) CH 3 (CH 2 ) 4 CH 2 Br CH 3 (CH 2 ) 4 CH 2 MgBr CH 3 (CH 2 ) 4 CH 2 CHCH 3 OMgBr OH

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

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

Example diethyl ether Mg H3O+H3O+H3O+H3O+ (62%) CH 3 Cl CH 3 MgCl O CH 3 ClMgO HO

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

Example (76%) H2CH2CH2CH2CCHLi + CHCHCHCHO 1. diethyl ether 2. H 3 O + CH 2 CHCH OH

Synthesis of Acetylenic Alcohols

Using Sodium Salts of Acetylenes HCCH NaNH 2 NH 3 HC CNa HC + 1. NH 3 2. H 3 O + O HOC CHCHCHCH (65-75%)

CH CH 3 (CH 2 ) 3 C + CH 3 CH 2 MgBr CMgBr CH 3 (CH 2 ) 3 C + CH 3 CH 3 diethyl ether 1. H 2 C O 2. H 3 O + CCH 2 OH CH 3 (CH 2 ) 3 C (82%) Using Acetylenic Grignard Reagents

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

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

Retrosynthetic Analysis of Alcohols COH

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

Example C OH CH 3 CH 2 CH 3 C O CH 3 MgX There are two other possibilities. Can you see them?

Synthesis C OH CH 3 CH 2 CH 3 C O1. 2. H 3 O + CH 3 Br Mg, diethyl ether CH 3 MgBr

Preparation of Tertiary Alcohols From Esters and Grignard Reagents

Grignard reagents react with esters RMgX C O – MgX + –––– ++++ R C O diethyl ether OCH 3 R' R' but species formed is unstable and dissociates under the reaction conditions to form a ketone

Grignard reagents react with esters RMgX C O – MgX + –––– ++++ R C O diethyl ether OCH 3 R' R' –CH 3 OMgX C ORR' this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol

Example 2 CH 3 MgBr + (CH 3 ) 2 CHCOCH 3 O 1. diethyl ether 2. H 3 O + (CH 3 ) 2 CHCCH 3 OH CH 3 (73%) Two of the groups attached to the tertiary carbon come from the Grignard reagent