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14.6
Synthesis of Alcohols Using
Grignard Reagents
Grignard reagents act as nucleophiles
toward the carbonyl group
d– R
d+
C
diethyl
ether
R
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
d– R
H
d+ H
C
H
diethyl
ether
R
C
•• O ••
•• –
MgX O ••
••
H
+
MgX
H3O+
product is a
primary alcohol
H
R
C
•• OH
••
H
Example
Mg
Cl
MgCl
diethyl
ether
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
d– R
H
d+ R'
C
MgX O ••
••
H
diethyl
ether
R
C
R'
•• O •• + MgX
•• –
H3O+
product is a
secondary alcohol
H
R
C
•• OH
••
R'
Example
Mg
CH3(CH2)4CH2Br
diethyl
ether
CH3(CH2)4CH2MgBr
H3C
C
O
H
CH3(CH2)4CH2CHCH3
OH
(84%)
H3O+
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
d– R
R"
d+ R'
C
R"
diethyl
ether
R
C
•• O ••
•• –
MgX O ••
••
R'
+
H3O+
product is a
tertiary alcohol
MgX
R"
R
C
•• OH
••
R'
Example
Mg
CH3Cl
HO
(62%)
CH3
diethyl
ether
H3O+
CH3MgCl
O
ClMgO
CH3
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
H2 C
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
HC
NH3
CNa
O
HO
C
1. NH3
HC
CNa +
2. H3O+
(65-75%)
CH
Using Acetylenic Grignard Reagents
CH3(CH2)3C
CH + CH3CH2MgBr
diethyl ether
CH3(CH2)3C
CMgBr
1. H2C
2. H3O+
CH3(CH2)3C
CCH2OH
(82%)
+ CH3CH3
O
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
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
C
OH
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.
Example
CH3
C
There are two
other
possibilities.
Can you see
them?
CH2CH3
OH
CH3MgX
O
C
CH2CH3
Synthesis
Mg, diethyl ether
CH3Br
CH3MgBr
O
1.
2. H3O+
CH3
C
OH
CH2CH3
C
CH2CH3
14.10
Preparation of Tertiary Alcohols
From Esters and Grignard Reagents
Grignard reagents react with esters
d– R
R'
••
d+ OCH
3
••
C
MgX O ••
••
R'
diethyl
ether
R
C
••
OCH3
••
• O • + MgX
• •• •–
but species formed is
unstable and dissociates
under the reaction
conditions to form a ketone
Grignard reagents react with esters
d– R
R'
••
d+ OCH
3
••
C
R'
diethyl
ether
R
OCH3
••
• O • + MgX
• •• •–
MgX O ••
••
this ketone then
goes on to react with
a second mole of the
Grignard reagent to
give a tertiary
alcohol
C
••
–CH3OMgX
R
R'
C
O ••
••
Example
O
2 CH3MgBr + (CH3)2CHCOCH3
1. diethyl ether
2. H3O+
OH
(CH3)2CHCCH3
CH3
(73%)
Two of the groups
attached to the
tertiary carbon
come from the
Grignard reagent