Synthesis of Synthesis of Alcohols Alcohols Using Using Grignard Grignard Reagents Reagents Grignard Grignard reagents act as reagents act as nucleophiles nucleophiles toward the carbonyl group toward the carbonyl group R MgX MgX C O •• •• • • – MgX MgX + δ– δ+ R C O •• •• • • • • •• •• R C OH OH • • H 3 O + diethyl diethyl ether ether two-step sequence two-step sequence gives an alcohol as gives an alcohol as the isolated product the isolated product formaldehyde formaldehyde to give primary to give primary alcohols alcohols aldehydes aldehydes to give secondary to give secondary alcohols alcohols ketones ketones to give tertiary to give tertiary alcohols alcohols esters esters to give tertiary to give tertiary alcohols alcohols Grignard Grignard reagents react with: reagents react with: formaldehyde formaldehyde to give primary to give primary alcohols alcohols Grignard Grignard reagents react with: reagents react with:
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Synthesis ofSynthesis of Alcohols Alcohols Using Using
GrignardGrignard Reagents Reagents
GrignardGrignard reagents act as reagents act as nucleophiles nucleophilestoward the carbonyl grouptoward the carbonyl group
RR
MgXMgX
CC
OO
•••••••• ––
MgXMgX++
δδ–– δδ++RR CC
OO••••
•••• ••••
••••
RR CC
OHOH••••
HH33OO++
diethyldiethyletherether
two-step sequencetwo-step sequencegives an alcohol asgives an alcohol asthe isolated productthe isolated product
formaldehydeformaldehyde to give primary to give primary alcohols alcohols
aldehydesaldehydes to give secondary to give secondary alcohols alcohols
ketonesketones to give tertiary to give tertiary alcohols alcohols
estersesters to give tertiary to give tertiary alcohols alcohols
GrignardGrignard reagents react with reagents react with ketones ketones
RR
MgXMgX
CC
OO
•••••••• ––
MgXMgX++
δδ–– δδ++RR CC
OO••••
•••• ••••
••••
RR CC
OHOH••••
HH33OO++
diethyldiethyletherether
product is aproduct is atertiary alcoholtertiary alcohol
R"R" R'R'R"R"
R'R'
R"R"
R'R'
ExampleExample
diethyldiethyletherether
MgMg
HH33OO++
(62%)(62%)
CHCH33ClCl CHCH33MgClMgCl
OO
CHCH33ClMgOClMgO CHCH33HOHO
Preparation ofPreparation of Alcohols Alcohols From From Epoxides Epoxides
Reaction ofReaction of Grignard Grignard Reagents Reagentswithwith Epoxides Epoxides
CHCH22 CHCH22 OMgXOMgX
HH33OO++
HH22CC CHCH22
OO
RR MgXMgX RR
RRCHCH22CHCH22OHOH
CHCH33(CH(CH22))44CHCH22MgBrMgBr HH22CC CHCH22
OO
++
1. diethyl ether1. diethyl ether2. H2. H33OO++
CHCH33(CH(CH22))44CHCH22CHCH22CHCH22OOHH
(71%)(71%)
Example Example
Preparation of KetonesFrom Acid Chlorides and Grignard Reagents
&
Preparation of Tertiary AlcoholsFrom Esters and Grignard Reagents
Acid Chlorides → Ketones
Esters → 3o AlcoholsStep 1
Esters → 3o AlcoholsStep 2
GrignardGrignard reagents react with esters reagents react with esters
RR
MgXMgX
CC
OO
•••••••• ––
MgXMgX++
δδ–– δδ++RR CC
OO••••
•••• ••••
diethyldiethyletherether
OCHOCH33
••••
•••• OCHOCH33
••••
••••
R'R'R'R'
but species formed isbut species formed isunstable and dissociatesunstable and dissociatesunder the reactionunder the reactionconditions to form aconditions to form a ketone ketone
GrignardGrignard reagents react with esters reagents react with esters
RR
MgXMgX
CC
OO
•••••••• ––
MgXMgX++
δδ–– δδ++RR CC
OO••••
•••• ••••
diethyldiethyletherether
OCHOCH33
••••
•••• OCHOCH33
••••
••••
R'R'R'R'
––CHCH33OOMgXMgX
CC
OO
RR R'R'
••••••••
thisthis ketone ketone then thengoes on to react withgoes on to react witha second mole of thea second mole of theGrignardGrignard reagent to reagent togive a tertiary alcoholgive a tertiary alcohol
ExampleExample
2 CH2 CH33MgBrMgBr ++ (CH(CH33))22CHCCHCOCHOCH33
OO
1. diethyl ether1. diethyl ether
2. H2. H33OO++
(CH(CH33))22CHCCHCCHCH33
OHOH
CHCH33
(73%)(73%)
Two of the groupsTwo of the groupsattached to theattached to thetertiary carbontertiary carboncome from thecome from theGrignardGrignard reagent reagent
Retrosynthetic Analysis
RetrosyntheticRetrosynthetic analysis is the process by analysis is the process bywhich we plan a synthesis by reasoningwhich we plan a synthesis by reasoningbackward from the desired product (thebackward from the desired product (the"target molecule")."target molecule").
RetrosyntheticRetrosynthetic Analysis of Analysis of Alcohols Alcohols
CC
OHOH
Step 1 Step 1 Locate the carbon that bears theLocate the carbon that bears thehydroxyl group.hydroxyl group.
RetrosyntheticRetrosynthetic Analysis of Analysis of Alcohols Alcohols
CC
OHOH
Step 2 Step 2 Disconnect one of the groupsDisconnect one of the groupsattached to this carbon.attached to this carbon.
RetrosyntheticRetrosynthetic Analysis of Analysis of Alcohols Alcohols
CC
OHOH
RetrosyntheticRetrosynthetic Analysis of Analysis of Alcohols Alcohols
CC
OO
What remains is the combination ofWhat remains is the combination of Grignard Grignardreagent and carbonyl compound that can bereagent and carbonyl compound that can beused to prepare the alcohol.used to prepare the alcohol.
MgXMgX
ExampleExample
CC
OHOH
CHCH33
CHCH22CHCH33
CC CHCH22CHCH33
OO
CHCH33MgXMgX
There are twoThere are twootherotherpossibilities.possibilities.
Can you seeCan you seethem?them?
SynthesisSynthesis
CC
OHOH
CHCH33
CHCH22CHCH33
CC CHCH22CHCH33
OO
1.1.
2. H2. H33OO++
CHCH33BrBrMgMg, diethyl ether, diethyl ether
CHCH33MgMgBrBr
OrganolithiumOrganolithium reagents react with reagents react with aldehydesaldehydes and and ketones ketones in the same in the same
way thatway that Grignard Grignard reagents do. reagents do.