Download Synthesis of Alcohols Using Grignard Reagents Grignard reagents

Synthesis of Alcohols Using
Grignard Reagents
Grignard reagents act as nucleophiles
toward the carbonyl group
δ–
R
δ+
C
diethyl
ether
R
C
+
•O•
MgX
• •
•• –
MgX O ••
••
H3O+
two-step sequence
gives an alcohol as
the isolated product
Grignard reagents react with:
formaldehyde to give primary alcohols
aldehydes to give secondary alcohols
ketones to give tertiary alcohols
esters to give tertiary alcohols
R
Grignard reagents react with:
formaldehyde to give primary alcohols
C
• OH
•
••
Grignard reagents react with formaldehyde
H
δ–
R
δ+ H
C
diethyl
ether
H
R
C
H
•• O ••
•• –
MgX O ••
••
+
MgX
H3O+
product is a
primary alcohol
Example
diethyl
ether
CH3(CH2)3C
MgCl
C
• OH
•
••
CH + CH3CH2MgBr
MgBr
diethyl ether
H
C
O
H
CH2OH
R
Using Acetylenic Grignard Reagents
Mg
Cl
H
H3O+
CH2OMgCl
(64-69%)
Grignard reagents react with:
formaldehyde to give primary alcohols
aldehydes to give secondary alcohols
CH3(CH2)3C
CMgBr
MgBr
+ CH3CH3
1. H2C O
2. H3O+ Can you use a
different reaction
CH3(CH2)3C CCH2OH other than a
Grignard?
Grignard?
(82%)
H
Example
Grignard reagents react with aldehydes
Mg
H
δ–
R
δ+ R'
C
diethyl
ether
CH3(CH2)4CH2Br
H
R
C
R'
diethyl
ether
CH3(CH2)4CH2MgBr
H 3C
+
MgX
•• O ••
•• –
MgX O ••
••
H3O+
C
H
C
R
product is a
secondary alcohol
R'
H3O+
CH3(CH2)4CH2CHCH3
CH3(CH2)4CH2CHCH3
OH
• OH
•
••
OMgBr
(84%)
Grignard reagents react with:
formaldehyde to give primary alcohols
aldehydes to give secondary alcohols
ketones to give tertiary alcohols
Example
Grignard reagents react with ketones
Mg
R"
δ–
R
δ+ R'
C
diethyl
ether
CH3Cl
R"
R
C
•• O ••
•• –
MgX O ••
••
R'
+
H3O+
product is a
tertiary alcohol
diethyl
ether
CH3MgCl
O
MgX
HO CH3
R"
R
C
• OH
•
••
O
H
R'
(62%)
H3O+
ClMgO
CH3
Preparation of Alcohols From Epoxides
Reaction of Grignard Reagents
with Epoxides
R
MgX
CH2
H 2C
O
CH2
CH3(CH2)4CH2MgBr + H2C
R
CH2
Example
O
CH2
OMgX
H3O+
RCH2CH2OH
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
Esters → 3o Alcohols
Step 1
Esters → 3o Alcohols
Step 2
Grignard reagents react with esters
δ–
R'
R
••
R'
diethyl
ether
δ+ OCH3
••
C
Grignard reagents react with esters
R
C
••
OCH3
••
• • + MgX
•O •
•• –
MgX O ••
••
but species formed is
unstable and dissociates
under the reaction
conditions to form a ketone
Example
δ–
R'
R
••
δ+ OCH3
••
C
R'
diethyl
ether
R
MgX O ••
••
this ketone then
goes on to react with
a second mole of the
Grignard reagent to
give a tertiary alcohol
C
••
• • + MgX
•O •
•• –
–CH3OMgX
R
C
R'
O ••
••
O
CHCOCH3
2 CH3MgBr + (CH3)2CHCOCH
1. diethyl ether
Retrosynthetic Analysis
2. H3O+
Two of the groups
attached to the
tertiary carbon
come from the
Grignard reagent
OH
(CH3)2CHCCH
CHCCH3
CH3
(73%)
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
Retrosynthetic Analysis of Alcohols
C
C
OH
OH
Step 1 Locate the carbon that bears the
hydroxyl group.
••
OCH3
Step 2 Disconnect one of the groups
attached to this carbon.
Retrosynthetic Analysis of Alcohols
Retrosynthetic Analysis of Alcohols
MgX
C
C
OH
O
What remains is the combination of Grignard
reagent and carbonyl compound that can be
used to prepare the alcohol.
Example
C
There are two
other
possibilities.
Can you see
them?
Synthesis
CH3
CH2CH3
Mg,
Mg, diethyl ether
CH3Br
CH3MgBr
MgBr
OH
O
1.
2. H3O+
CH3MgX
CH3
O
C
C
C
CH2CH3
CH2CH3
OH
Example
H 2C
O
CHLi +
Synthesis of Alcohols
Using Organolithium Reagents
Organolithium reagents react with
aldehydes and ketones in the same
way that Grignard reagents do.
CH
1. diethyl ether
2. H3O+
CHCH
OH
(76%)
CH2
CH2CH3