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Michael and Michael and AldolAldol

CH391 December 4, 2002

RCHRCH22CHCH

OO••••OHOH••••

••••–

RCHCHRCHCH

OO

––••••

EnolateEnolate anions...anions...

+–

•• So….a basic solution contains comparable amounts So….a basic solution contains comparable amounts of theof the aldehydealdehyde and itsand its enolateenolate..

•• Which gives rise to..the Which gives rise to..the AldolAldol CondensationCondensation

+ ++ ••••HOHHOH

••••

ppKKaa = 16= 16--2020 ppKKaa = 16= 16

••••RCHCHRCHCH

OO•••• ••••

––

RCHRCH22CHCH

OO••••

••••


OO•••• ••••

––

RCHRCH22CHCH

OO••••

••••

––

RCHRCH22CHCH

OO••••

••••

•••• ••••

RCHCHRCHCH

OO

••••

RCHRCH22CHCH

OO••••

•••• ••••

RCHCHRCHCH

OO

•••• HH


OO•••• ••••

––

RCHRCH22CHCH

OO••••

••••

––

RCHRCH22CHCH

OO••••

••••

•••• ••••

RCHCHRCHCH

OO

••••••••

RCHRCH22CHCH

OO

•••• ••••

RCHCHRCHCH

OO

•••• HH

2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CHCHCHCH

RR

OO

AldolAldol CondensationCondensation

••product is called an "product is called an "aldolaldol" because it is " because it is both anboth an aldehydealdehyde and an alcoholand an alcohol

RCHRCH22CHCH

OHOH

CHCHCHCH

RR

OO


2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CCHHCHCH

RR

OO

heatheat

GivesGives α,βα,β unsaturated carbonyl compoundsunsaturated carbonyl compounds

RCHRCH22CHCH CCHCCH

RR

OO


2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CCHHCHCH

RR

OO

heatheat

RCHRCH22CHCH CCHCCH

RR

NaOHNaOHheatheat

OO

Dehydration ofDehydration of AldolAldol Addition ProductAddition Product

••dehydration of dehydration of ββ--hydroxy aldehydehydroxy aldehyde can becan becatalyzed by either acids or basescatalyzed by either acids or bases

CC

CC

CC

OO

OHOH

HHCC

CC

CC

OO

Dehydration ofDehydration of AldolAldol Addition ProductAddition Product

•• in base, the in base, the enolateenolate loses hydroxide to form the loses hydroxide to form the αα,,ββ--unsaturatedunsaturated aldehydealdehyde

OHOH

HHCC

CC

CC OHOH

CC

CC

CC

••••––

OO OONaOHNaOH

Mixed Mixed AldolsAldols: What is the product?: What is the product?

CHCH33CHCH22CHCH

OO

CHCH33CHCH

OONaOHNaOH

++

•• There are 4 possibilities because There are 4 possibilities because the reaction mixture contains the the reaction mixture contains the twotwo aldehydesaldehydes plus theplus the enolateenolate of of eacheach aldehydealdehyde..

Aldehydes Aldehydes with no with no αα--hydrogenshydrogens

CHCH33CCHCCH33

OO

CHCH33OO CHCH

OO

++

NaOHNaOH, H, H22OO 30°C30°C

CHCH33OO CHCH CHCCHCHCCH33

OO

AldolAldol reactions of ketonesreactions of ketones

OO

CHCH33CCHCCH22CCHCCH33

OHOH

2CH2CH33CCHCCH33

OO2%2%

98%98%CHCH33

•• The equilibrium constant forThe equilibrium constant for aldolaldol addition addition reactions of ketones is usually unfavorable but can reactions of ketones is usually unfavorable but can be driven by dehydration.be driven by dehydration.

Intramolecular AldolIntramolecular Aldol CondensationCondensation

OO OO

OO NaNa22COCO33, H, H22O O

heatheat

(96%!!!)(96%!!!)OO

OHOH

via:via:

EnolateEnolate AnionsAnions• When a ketone has two different α-hydrogens,

is formation of the enolate anion regioselective?• The answer depends on experimental

conditions– when a slight excess of LDA, a ketone is converted

to its lithium enolate anion, which consists almost entirely of the less substituted enolate anion

– this reaction is said to be under kinetic control

Kinetic ControlKinetic Control

–with slight excess of LDA

0°C

99%

++LDA+ (i-pr) 2 NH

O O- Li + O- Li +

1%2-Methyl-cyclohexanone

slight excess

“fastest” but least stable

Thermodynamic ControlThermodynamic Control–With slight excess of ketone

10%

++ (i-pr)2 NH

O- Li + O- Li +

90%

0°CLDA+

Oslight excess

Slow but most Stable

Kinetic ControlKinetic Control•• When a reaction is under kinetic control, the When a reaction is under kinetic control, the

composition of the product mixture is composition of the product mixture is determined by thedetermined by the relative ratesrelative rates of formation of formation of each productof each product

Thermodynamic ControlThermodynamic Control•• When a reaction is under thermodynamic When a reaction is under thermodynamic

control, the composition of the product control, the composition of the product mixture is determined by themixture is determined by the relative relative stabilitiesstabilities of each productof each product

Relative StabilityRelative Stability

• aldehydes and ketones that contain a carbon-carbon double bond are more stable when the double bond is conjugated with the carbonyl group than when it is not

• compounds of this type are referred to as α,β unsaturated aldehydes and ketones

AcroleinAcrolein

HH22CC CHCHCHCH

OO

Resonance DescriptionResonance Description

CCOO•••• ••••

CCCC

++

––

CCOO•••• ••••

CCCC ••••

Resonance DescriptionResonance Description

CCOO•••• ••••

CCCC

++

––

CCOO•••• ••••

CCCC ••••

++

––

CCOO•••• ••••

CCCC ••••

PropertiesProperties

α,β-Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones.

α,β-Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack

carbonyl carbon

β-carbonCC

OO•••• ••••

CCCC

ββ

NucleophilicNucleophilic Addition to Addition to α,βα,β--UnsaturatedUnsaturated AldehydesAldehydes and Ketones and Ketones

•1,2-addition (direct addition)

–nucleophile attacks carbon of C=O

•1,4-addition (conjugate addition)

–nucleophile attacks β-carbon

Kinetic versus Thermodynamic ControlKinetic versus Thermodynamic Control

•attack is faster at C=O

•attack at β-carbon gives the more stable product

CC

CC

OO

HH YY++CC

1,21,2--additionaddition

CC CC

CC

OOHH

YY

• formed faster• major product under

conditions of kinetic control (i.e. when addition is not readily reversible)

CC

CC

OO

HH YY++CC


CC

CC

OOHH• enol• goes to keto form

under reaction conditions CCYY

CC

CC

OO

HH YY++CC


CC

CC

OO

HH

• keto form is isolated product of 1,4-addition

• is more stable than 1,2-addition product CCYY

CC

CC

OO

HH YY++CC


CC CC

CC

OOHH

YY


C=O is stronger than C=C

C=O is stronger C=O is stronger than C=Cthan C=C

CC

CC

OO

HHCCYY

1,21,2--AdditionAddition

•observed with strongly basic nucleophiles

–Grignard reagents

–LiAlH4

–NaBH4

–Sodium acetylide

•strongly basic nucleophiles add irreversibly

ExampleExample

OO

CHCHCHCH ++CHCH33CHCH HCHC CMgBrCMgBr

1. THF1. THF2. H2. H33OO++

OHOH

CHCHCCHCHCCHCH33CHCH CHCH

1,41,4--AdditionAddition

•observed with weakly basic nucleophiles

–cyanide ion (CN–)

–thiolate ions (RS–)

–ammonia and amines

–azide ion (N3–)

weakly basic nucleophiles add reversibly

ExampleExampleOO

CHCCCHCC66HH55CC66HH55CHCH

KCNKCN ethanol,ethanol,acetic acidacetic acid

OO

CC66HH55CHCHCHCH22CCCC66HH55

CNCN

Addition ofAddition of CarbanionsCarbanions totoα,βα,β--Unsaturated Carbonyl Compounds:Unsaturated Carbonyl Compounds:

The Michael ReactionThe Michael Reaction

Michael AdditionMichael Addition

•Stabilized carbanions, such as those derived from β-diketones undergo conjugateaddition to α,β-unsaturated ketones.

ExampleExample

CHCH33

OO

OO

OO

CHCCHCHCCH33+ HH22C+ C

KOH, methanolKOH, methanol

OOCHCH33

OO

OO

CHCH22CHCH22CCHCCH33

Michael AdditionMichael Addition

•The Michael reaction is a useful method forforming carbon-carbon bonds.

•Gives 1,5 dioxo derivatives!

•It is also useful in that the product of the reaction can undergo an intramolecularaldol condensation to form a six-membered ring. One such application is called the Robinsonannulation.

ExampleExample

OHOH

OO CHCH33

OO

OO

CHCH33

OO

OO


NaOHNaOHheatheat

not isolated;not isolated;dehydrates under dehydrates under reaction conditionsreaction conditions

ExampleExample

OHOH

OO CHCH33

OO

OO

CHCH33

OO

OO


NaOHNaOHheatheat

OO

OO

CHCH33

Michael ReactionMichael Reaction• Michael reaction: the 1,4-addition

nucleophilic addition of an enolate anion to an α,β-unsaturated carbonyl compound!!

• Following are two examples– in the first, the nucleophile is the enolate anion of

malonic ester – in the second, it is the enolate anion of

acetoacetic ester

Michael ReactionMichael Reaction

+ 3-Buten-2-one (Methyl vinyl ketone)

Diethyl propanedioate (Diethyl malonate)

O

EtOCCH2

EtOC

O

O

EtOCCHCH2 CH2 CCH3

EtOC

OO

OEt O- Na +

EtOHCH2 =CHCCH 3

RetroRetro--synthesis of 2,6synthesis of 2,6--HeptadioneHeptadione

+

lost by decarboxylation

formed in a Michael reaction

Ethyl acetoacetate

Methyl vinyl ketone

O O OO

CO2 H

CO2 Et

O O

CH3 CCH2 CH2 CH2 CCH3 CH3 CCH-CH 2 CH2 CCH3

CH3 CCH2 CH2 =CHCCH 3

from acetoacetic ester

Conjugate Addition ofConjugate Addition of OrganocopperOrganocopper Reagents to Reagents to α,βα,β--Unsaturated Carbonyl CompoundsUnsaturated Carbonyl Compounds

Addition ofAddition of OrganocopperOrganocopper Reagents toReagents toα,βα,β--UnsaturatedUnsaturated AldehydesAldehydes and Ketonesand Ketones

•The main use of organocopper reagents is toform carbon-carbon bonds by conjugate addition to α,β-unsaturated ketones.

OO

CHCH33

++

ExampleExample

LiCuLiCu((CHCH33))22

1. diethyl ether1. diethyl ether2. H2. H22OO

OO

CHCH33

CHCH33

Gilman ReagentsGilman Reagents• Gilman reagents are unique among

organometallic compounds in that they give almost exclusively 1,4- addition

• Other organometallic compounds, includingGrignard reagents, add to the carbonyl carbon by 1,2-addition

• The mechanism of conjugate addition of Gilman reagents is not fully understood

Selectivity!!Selectivity!!

ORMgX

HO R

R2CuLiO

R

The Signature PageThe Signature Page

Claisen Condensation: β-ketoesters

Dieckmann: Cyclic β-ketoesters

Aldol: α, β-unsaturated aldehydes and ketones

Acetoacetic ester synthesis: decorated acetones

Malonic ester synthesis: decorated acetic acids

Grignard Reaction: Alcohols…, etc.

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