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:

formaldehydeformaldehyde to give primary to give primary alcohols alcohols

GrignardGrignard reagents react with: reagents react with:

GrignardGrignard reagents react with formaldehyde reagents react with formaldehyde

RR

MgXMgX

CC

OO

•••••••• ––

MgXMgX++

δδ–– δδ++RR CC

OO••••

•••• ••••

••••

RR CC

OHOH••••

HH33OO++

diethyldiethyletherether

product is aproduct is aprimary alcoholprimary alcohol

HH HHHH

HH

HH

HH

ExampleExample

diethyldiethyletherether

ClClMgMg

MgClMgCl

CC OO

HH

HH

CCHH22OMgClOMgClHH33OO++

CCHH22OHOH

(64-69%)(64-69%)

CHCHCHCH33(CH(CH22))33CC ++ CHCH33CHCH22MgMgBrBr

CCMgMgBrBrCHCH33(CH(CH22))33CC ++ CHCH33CHCH33

diethyl etherdiethyl ether

1. H1. H22CC OO

2. H2. H33OO++

CCCCHH22OHOHCHCH33(CH(CH22))33CC

(82%)(82%)

UsingUsing Acetylenic Grignard Acetylenic Grignard Reagents Reagents

Can you use aCan you use adifferent reactiondifferent reactionother than aother than aGrignardGrignard??

formaldehydeformaldehyde to give primary to give primary alcohols alcohols

aldehydesaldehydes to give secondary to give secondary alcohols alcohols

GrignardGrignard reagents react with: reagents react with:

GrignardGrignard reagents react with reagents react with aldehydes aldehydes

RR

MgXMgX

CC

OO

•••••••• ––

δδ–– δδ++RR CC

OO••••

•••• ••••

••••

RR CC

OHOH••••

HH33OO++

diethyldiethyletherether

product is aproduct is asecondary alcoholsecondary alcohol

HH R'R'HH

R'R'

HH

R'R'

MgXMgX++

ExampleExample

diethyldiethyletherether

MgMg

CC OO

HH33CC

HH

HH33OO++

(84%)(84%)

CHCH33(CH(CH22))44CHCH22BrBr CHCH33(CH(CH22))44CHCH22MgBrMgBr

CHCH33(CH(CH22))44CHCH22CCHHCHCH33

OMgBrOMgBr

CHCH33(CH(CH22))44CHCH22CCHHCHCH33

OHOH

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

GrignardGrignard reagents react with: reagents react with:

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.

Synthesis of AlcoholsUsing Organolithium Reagents

ExampleExample

(76%)(76%)

HH22CC CHLiCHLi ++

CCHH

OO

1. diethyl ether1. diethyl ether

2. H2. H33OO++

CHCH22CCHCHHCH

OHOH