william h. brown & christopher s. footesst.nsu.edu/chm322/notes/oc_18.pdf · claisen...

1818

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Copyright © 1998 by Saunders College Publishing

William H. Brown &Christopher S. FooteWilliam H. Brown &William H. Brown &Christopher S. FooteChristopher S. Foote

Copyright © 1998 by Saunders College PublishingRequests for permission to make copies of any part of thework should be mailed to:Permissions Department,Harcourt Brace & Company, 6277 Sea Harbor Drive,Orlando, Florida 32887-6777

1818

18-2


Chapter 18Chapter 18

1818

18-3


Enolate AnionsEnolate Anionsu Enolate anions are nucleophiles and

•participate in SN2 reactions

•••• •• - ••••

+R

R

R

O O

R

CH2 RR

R

RCH2 -Br Br -+SN2

1818

18-4


Enolate AnionsEnolate Anions•and function as nucleophiles in carbonyl addition

reactions

u The special value of these two reactions is thateach results in formation of a new C-C bond

•••• •• - ••••

An enolateanion

nucleophilicaddition

RR

R

O O

R

CR

R

+R

CR

O

A ketone

O

RR

•••• •• -

A tetrahedral carbonyladdition intermediate

••••

1818

18-5


The Aldol ReactionThe Aldol Reactionu The most important reaction of enolate anions is

nucleophilic addition to the carbonyl group ofanother molecule of the same or differentcompound

u Although these reactions may be catalyzed byeither acid or base, base catalysis is morecommon

1818

18-6


The Aldol ReactionThe Aldol Reactionu The product of an aldol reaction is

•a -hydroxyaldehyde

+3-Hydroxybutanal

(a -hydroxyaldehyde)

O O OOHH

CH3 -C-H CH2 -C-H CH3 -CH-CH 2 -C-HNaOH

Ethanal(Acetaldehyde)

Ethanal(Acetaldehyde)

1818

18-7


The Aldol ReactionThe Aldol Reaction•or a -hydroxyketone

(a -hydroxyketone)4-Hydroxy-4-methyl-2-pentanone

+

O O

OH O

CH3

H

CH3 -C-CH 3 CH2 -C-CH 3

Ba(OH) 2

CH3 -C-CH 2 -C-CH 3

Propanone(Acetone)

Propanone(Acetone)

1818

18-8


The Aldol Reaction: baseThe Aldol Reaction: baseu The mechanism of a base-catalyzed aldol

reaction can be divided into three stepsStep 1: formation of a resonance-stabilized enolate

anion

••••••

•• •• •• -

-

Enolate anion

+

+O

O O

HO- H-CH 2 -C-H

HO-H CH2 -C-H CH2 =C-H

1818

18-9


The Aldol Reaction: baseThe Aldol Reaction: baseStep 2: addition of the enolate anion to the carbonyl

group of another carbonyl-containing molecule toform a TCAI

•••• •• ••

••

•• -

A tetrahedal carbonyladdition intermediate

-+

O O O O

CH3 -C-H CH2 -C-H CH3 -CH-CH 2 -C-H

1818

18-10


The Aldol Reaction: baseThe Aldol Reaction: baseStep 3: reaction of the TCAI with a proton donor to give

the aldol product

•• ••

••••••

+

+

- OO

OH O

CH3 -CH-CH 2 -C-H H-OH

CH3 -CH-CH 2 -C-H OH-

1818

18-11


The Aldol Reaction: acidThe Aldol Reaction: acidu The key step in an acid-catalyzed aldol reaction

is attack of the enol of one molecule on theprotonated carbonyl group of another. Protontransfer completes the reaction

O O

CH3 -C-H CH2 =C-H

H H

+

CH3 -CH-CH 2 -C-H

OH O

+ H-A

A -

1818

18-12


The Aldol Products:The Aldol Products: --HH22OOu Aldol products are very easily dehydrated

•the major product is an ,-unsaturated aldehyde orketone

•aldol reactions are reversible and, especially forketones, there is often little aldol present atequilibrium. Keq for dehydration is generally largeand, if reaction conditions bring about dehydration,good yields of product can be obtained

An -unsaturatedaldehyde

+

OOH O

CH3 CHCH 2 CH CH3 CH=CHCH H2 O

warm in eitheracid or base

1818

18-13


The Aldol Reaction:The Aldol Reaction: --HH22OOu In base-catalyzed dehydration, an -hydrogen is

removed to form a new enolate anion, whichthen expels hydroxide ion

An -unsaturatedaldehyde

OOH

CH3 -CH-CH -CH

H OH

CH3 -CH-CH = CH

O-

OH-

An enolate anion

O

CH3 CH=CHCH-OH -

1818

18-14


The Aldol Reaction:The Aldol Reaction: --HH22OOu In acid, proton transfer to -OH and loss of H2O

gives the protonated form of the final product

OH

CH3 -C-CH = C-CH 3

O CH3 C=CHCCH 3

HHH3 C

CH3

CH3 -C-CH = C-CH 3

H3 C

O

OH

H

H+

+ H2 O

OH

OH H

The enol ofthe ketone

1818

18-15


Crossed Aldol ReactionsCrossed Aldol Reactionsu In a crossed aldol reaction, one kind of molecule

provides the enolate anion and another kindprovides the carbonyl group

4-Hydroxy-2-butanone+

OO O

CH3 CCH3 HCHNaOH

CH3 CCH2 CH2 OH

1818

18-16


Crossed Aldol ReactionsCrossed Aldol Reactionsu Crossed aldol reactions are most successful if

•one of the reactants has no -hydrogen and,therefore, cannot form an enolate anion and

•the other reactant has a more reactive carbonylgroup, namely an aldehyde

O

HCHFormal-dehyde

CHO CH

O O

Benzaldehyde Furfural

(CH 3 ) 3 CCH

O

2,2-Dimethyl-propanal

1818

18-17


Aldol ReactionsAldol Reactionsu Intramolecular aldol reactions (when the enolate

anion and the carbonyl acceptor are in the samemolecule) are most successful for formation offive- and six-membered rings

2,7-Octanedione

CH3

O

CH3OCH3

O

CH3

HO

CH3

O

CH3

KOH -H 2 O

1818

18-18


Aldol ReactionsAldol Reactionsu The -hydrogens of nitroalkanes are removed

by strong bases such as KOH and NaOH

HO + N

O

O

H-CH 2

HO-H + N

O

O

CH2 N

O

O

CH2

NitromethanepKa 10.2

WaterpKa 15.7

(stronger acid)

(weaker acid)

+

+ +

Resonance stabilized anion

1818

18-19


The Aldol ReactionThe Aldol Reactionu Reduction of a nitro group gives a 1° amine

1-(Aminomethyl)-cyclohexanol

1-(Nitromethyl)-cyclohexanol

(aldol)+

O

HO CH2 NO2 CH2 NH2HO

CH3 NO2NaOH

H2 , Ni

1818

18-20


Directed Aldol ReactionsDirected Aldol Reactionsu Kinetic vs thermodynamic control

•when alkali metal hydroxides or alkoxides are used asbases, the position of equilibrium for formation ofenolate anions favors reactants

(strongerbase)

+

+

(weakeracid)

(strongeracid)

Keq = 5 x 10 -5O

O- Na +NaOHCH3 CCH3

CH2 =CCH 3 H2 O

pKa 20

pKa 15.7

(weakerbase)

1818

18-21


Directed Aldol ReactionsDirected Aldol Reactionsu With stronger bases, however, the formation of

enolate anion can be driven to the rightu One of the most widely used bases for this

purpose is lithium diisopropylamide, LDA

u LDA is a very strong base but, because ofcrowding around nitrogen, is a poor nucleophile

Lithium diisopropylamide(LDA)

[(CH 3 ) 2 CH] 2 N - Li +

1818

18-22


Directed Aldol ReactionsDirected Aldol Reactionsu LDA is prepared by treatment of

diisopropylamine with butyllithium

Diisopropylamine+

+Butane

Butyllithium

(weaker acid)

(stronger acid)

Keq = 1010

(stronger base)

(weaker base)

[(CH 3 ) 2 CH] 2 NH CH3 (CH 2 ) 3 Li

[(CH 3 ) 2 CH] 2 N- Li + CH3 (CH 2 ) 2 CH3

pKa 50

pKa 40

Lithium diisopropyl-amide (LDA)

1818

18-23


Directed Aldol ReactionsDirected Aldol Reactionsu With 1 mol of LDA, an aldehyde, ketone, or ester

can be converted completely to its enolate anion

+LDA

(weaker acid)

+

(stronger acid)

Keq = 1020

A lithium enolate

O

O- Li +

CH2 =CCH 3

CH3 CCH3 [(CH 3 ) 2 CH] 2 N- Li +

pKa 20

[(CH 3 ) 2 CH] 2 NHpKa 40

(stronger base)

(weaker base)

1818

18-24


Lithium Enolate AnionsLithium Enolate Anionsu For a ketone with two different sets of -

hydrogens, is formation of the enolate anionregioselective?

u The answer depends on experimentalconditions•when a slight excess of LDA, a ketone is converted

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

•this reaction is said to be under kinetic control

1818

18-25


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

1818

18-26


Kinetic ControlKinetic Controlu For a reaction under kinetic control, the

composition of the product mixture isdetermined by the relative rates of formation ofeach product

u For formation of lithium enolates, kinetic controlrefers to the rates of removal of alternative-hydrogens

1818

18-27


Thermodynamic ControlThermodynamic Controlu In a reaction under thermodynamic control:

•reaction conditions permit equilibration of alternativeproducts, under which conditions

•the composition of the product mixture is determinedby their relative stabilities

1818

18-28


Thermodynamic ControlThermodynamic Control•with the ketone in slight excess, the lithium enolate is

richer in the more substituted (the more stable)enolate anion

0°C

10%

++

LDA+

(i-pr) 2 NH

O

O- Li + O- Li +

90%

2-Methyl-cyclohexanone

slight excess

1818

18-29


Directed Aldol ReactionsDirected Aldol Reactionsu Consider the crossed aldol reaction between

phenylacetaldehyde and acetone

•each reactant has -hydrogens and a mixtureof four aldol products is possible

4-Hydroxy-5-phenyl-2-pentanone

AcetonePhenyl-acetaldehyde

?+

O O

OOHC6 H5 CH2 CH CH3 CCH3

C6 H5 CH2 CHCH 2 CCH3

1818

18-30


Directed Aldol ReactionsDirected Aldol Reactionsu The desired reaction can be carried out by

preforming the lithium enolate anion of acetoneand treating it with benzaldehyde

A lithium enolate

O O- Li +

O OH O

CH3 CCH3LDA

-78oCCH2 =CCH 3

1 . C 6 H5 CH2 CH2 . H 2 O

C6 H5 CH2 CHCH2 CCH3

1818

18-31


Claisen CondensationClaisen Condensationu Esters also form enolate anions which

participate in nucleophilic acyl substitution

u As illustrated by the above example, the productof a Claisen condensation is a -ketoester

Ethyl 3-oxobutanoate(Ethyl acetoacetate)

Ethyl ethanoate(Ethyl acetate)

+

O O O2 CH3 COEt

1 . Et O- Na +

2 . H 2 O, HClCH3 CCH2 COEt EtOH

1818

18-32


Claisen CondensationClaisen Condensationu Claisen condensation of ethyl propanoate gives

the following -ketoester

+

Ethylpropanoate

Ethyl 2-methyl-3-oxopentanoate

+

Ethylpropanoate

O

OEt CH3

O

OO

CH3

CH2 COEtCH3 CH2 C1 . Et O- Na +

2 . H 2 O, HCl

CH3 CH2 CCHCOEt EtOH

1818

18-33


Claisen CondensationClaisen CondensationStep 1: formation of an enolate anion

••

••

••

••

••

•• ••

••

••

••

•• •• ••

pKa = 22(weaker acid)

pKa = 15.9(stronger acid)

Resonance-stabilized enolate anion

-

-+

O

CH2 -COEtH

O O

C2 H5 O

EtO-H CH2 =COEtCH2 -COEt

+

(stronger base)

(weaker base)

1818

18-34


Claisen CondensationClaisen CondensationStep 2: attack of the enolate anion on a carbonyl carbon

to give a TCAI••

••

••

••

••

••

•••• •• ••

A tetrahedral carbonyladdition intermediate

-

-+

••••

OO O

OEt

O

CH2 -COEtCH3 -COEt CH3 -C-CH 2 -COEt

1818

18-35


Claisen CondensationClaisen CondensationStep 3: collapse of the TCAI to form a -ketoester and

an alkoxide ion

••

••

••

••

••

••

••

••••••

+-

- •• •••• ••

OEt

O O OO

CH3 -C-CH 2 -COEt CH3 -C-CH 2 -COEt EtO

1818

18-36


Claisen CondensationClaisen CondensationStep 4: formation of the enolate anion of the -

ketoester, which drives the Claisen condensation tothe right

••

••

••

••

••••

(weaker acid)(weaker base)

(stronger base)(stronger acid)

pKa 15.9

pKa 10.7

-+

-+

O O

OO

H

CH3 -C-CH-COEt EtO

CH3 -C-CH-COEt Et OH

1818

18-37


Dieckman CondensationDieckman Condensationu An intramolecular Claisen condensation

+

Diethyl hexanedioate(Diethyl adipate)

Ethyl 2-oxocyclo-pentanecarboxylate

OCOEt

O

1 . Et O- Na +

2 . H 2 O, HCl

EtOH

Et OCCH2 CH2 CH2 CH2 COEt

O O

1818

18-38


Crossed Claisen CondsnsCrossed Claisen Condsnsu Crossed Claisen condensations between two

different esters, each with -hydrogens, givemixtures of products and are not syntheticallyuseful

u Crossed Claisen condensations are possible,however, if there is an appreciable difference inreactivity between the two esters, for example,when one of the esters has no -hydrogens

1818

18-39


Crossed Claisen CondsnsCrossed Claisen Condsnsu The following esters have no -hydrogens

Diethyl ethanedioate(Diethyl oxalate)

Diethyl carbonateEthyl formate

Ethyl benzoate

COEt

O

OO

O O

HCOEt Et OCOEt

Et OC-COEt

1818

18-40


Crossed Claisen CondsnsCrossed Claisen Condsnsu The ester with no -hydrogens is generally used

in excess

Methyl 2-methyl-3-oxo-3-phenylpropanoate

Methylpropanoate

Methylbenzoate

+

O O

O

CH3

O

PhCOCH 3 CH3 CH2 COCH31 . CH 3 O- Na +

2 . H 2 O, HCl

PhCCHCOCH 3

1818

18-41


Hydrolysis andHydrolysis and --COCO22u Saponification of a -ketoester followed by

acidification with HCl gives a -ketoacidu Heating the -ketoacid leads to decarboxylation

+

O5 . heat

CH3 CH2 CCH2 CH3 CO2

CH3

OO

O O

CH3

CH3 CH2 CCHCOEt

CH3 CH2 CCHCOH

3 . NaOH, H 2 O4 . H 2 O, HCl

1818

18-42


Claisen CondensationClaisen CondensationThe result of Claisen condensation, saponification,acidification, and decarboxylation is a ketone

++

from the ester furnishingthe enolate anion

from the ester furnishingthe carbonyl group

severalsteps

+

O

OR' R

O

O

R-CH 2 -C CH2 -C-OR'

R-CH 2 -C- CH2 -R CO22 HOR'

1818

18-43


From Acetyl Coenzyme AFrom Acetyl Coenzyme Au Carbonyl condensations are among the most

widely used reactions in the biological world forformation of new carbon-carbon bonds in suchbiomolecules as•fatty acids•cholesterol, bile acids, and steroid hormones•terpenes

u One source of carbon atoms for the synthesis ofthese biomolecules is acetyl coenzyme A(acetyl-CoA)

1818

18-44


AcetylAcetyl--CoACoAu Claisen condensation of acetyl-CoA is catalyzed

by the enzyme thiolase

Acetoacetyl-CoA

Acetyl-CoA

+

Acetyl-CoAClaisen

condensation

thiolase+

OO

O O

CH3 CSCoACH3 CSCoA

CH3 CCH2 CSCoA CoASHCoenzyme A

1818

18-45


AcetylAcetyl--CoACoAu This is followed by an aldol reaction with a

second molecule of acetyl-CoA

(S)-3-Hydroxy-3-methylglutaryl-CoA

Acetoacetyl-CoA Acetyl-CoA+

enzyme

condensation hereOO O

C- OCCH2 CH2 CSCoA

H3 C OH

OO

CH3 CCH2 CSCoA CH3 CSCoA

+CoASH

1818

18-46


AcetylAcetyl--CoACoAu Enzyme-catalyzed reduction of the thioester

group gives a 1° alcohol

(S)-3-Hydroxy-3-methylglutaryl-CoA

(R)-Mevalonate

enzyme

O OC

OHH3 C

CH2 CSCoA- OCCH 2

C- OCCH 2 CH2 CH2 OH

H3 C OH

O

2 NADH 2 NAD +

1

23

4

1

2 3

4

1818

18-47


AcetylAcetyl--CoACoAu Phosphorylation by ATP followed by -

elimination gives isopentenyl pyrophosphate

Isopentenyl pyrophosphate

-eliminationO

C

OPO32-H3 C

CH2 CH2 OP2 O63-- O-C-CH 2

CH3

CH2 =CCH 2CH2 OP2 O63-

a pyrophosphoricester

a phosphoricester

+CO2 PO43- +

1818

18-48


AcetylAcetyl--CoACoAu Isopentenyl pyrophosphate has the carbon

skeleton of isoprene and is a key intermediate inthe synthesis of these classes of biomolecules

bile acidssteroid hormones

terpenes

Isopentenyl pyrophosphate

cholesterol

CH3

CH2 =CCH 2 CH2 OP2 O63-

1818

18-49


EnaminesEnaminesu Enamines are formed by the reaction of a 2°

amine with the carbonyl group of an aldehyde orketone (Section 15.10A)

u The 2° amines most commonly used to prepareenamines are pyrrolidine and morpholine

Pyrrolidine Morpholine

N

O

NH

H

1818

18-50


EnaminesEnaminesu The value of enamines is that the -carbon is

nucleophilic and resembles enols and enolateanions in its reactions

An enamine as a resonance hybridof two contributing structures

••

••

+

-the -carbon ofan enamine isnucleophilic

C

N

C

N

CC

1818

18-51


EnaminesEnamines -- AlkylationAlkylationu Enamines undergo SN2 reactions with methyl

and 1° alkyl halides, -haloketones, and -haloestersStep 1: the enamine is treated with one equivalent of an

alkylating agent to give an iminium halide

Step 2: hydrolysis of the iminium halide gives analkylated aldehyde or ketone

1818

18-52


EnaminesEnamines -- AlkylationAlkylation

An iminium bromide

Allyl bromideThe morpholineenamine of

cyclohexanone

+

+SN2

N

O

N

O

CH2 CH=CH 2

CH2 =CHCH 2 - Br

Br -

1818

18-53


EnaminesEnamines -- AlkylationAlkylation

Morpholiniumchloride

2-Allylcyclohexanone

++

++

CH2 CH=CH 2

N

O

NH

OO

CH2 CH=CH 2

H

Br - HCl/H 2 O

Cl -

1818

18-54


EnaminesEnamines -- AcylationAcylationu Enamines undergo acylation when treated with

acid chlorides and acid anhydrides

u The reaction is an example of nucleophilic acylsubstitution

1818

18-55


EnaminesEnamines -- AcylationAcylation+

+

The pyrrolidineenamine of

cyclohexanone

Acetylchloride

An iminium chloride

2-Acetylcyclo-hexanone

++

N N

HN

H

CCH3O

O

O

CCH3

O

CH3 CCl

Cl -HCl/H 2 O

Cl -

1818

18-56


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u Acetoacetic ester (AAE) and other -ketoesters

are versatile starting materials for the formationof new carbon-carbon bonds because•the -hydrogens between the two carbonyls (pKa 10-

11) can be removed by alkoxide bases to form anenolate anion and

•the resulting enolate anion is a nucleophile andundergoes SN2 reactions with methyl and 1° alkylhalides, -haloketones, and -haloesters

1818

18-57


Acetoacetic Ester Synth.Acetoacetic Ester Synth.

(stronger base)

Sodium salt ofethyl acetoacetate

Sodium ethoxide

(weaker acid)

(stronger acid)

pKa 15.9

pKa 10.7

Ethanol

+-••

+

Ethyl acetoacetate

OO

O O

CH3 C-CH-COEt Et O- Na +

CH3 C-CH-COEt

Na +

EtOH

(weaker base)

H

1818

18-58


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u The acetoacetic ester (AAE) synthesis is useful

for the preparation of mono- and disubstitutedacetones of the following types

A disubstitutedacetone

A monosubstitutedacetone

Ethyl acetoacetate(Acetoacetic ester)

O

O O

O

R'

CH3 CCH2 COEt

CH3 CCH2 R

CH3 CCHR

1818

18-59


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u Consider the AAE synthesis of this target

molecule, which is a monosubstituted acetone

these three carbonsare from ethylacetoacetate

the -R group of amonosubstitutedacetone

5-Hexen-2-one

O

CH3 -C-CH 2 -CH 2 -CH=CH 2

1818

18-60


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u Alkylation of the enolate anion of AAE with allyl

bromide forms the new carbon-carbon bond

+

SN2+

-••OO

O O

CH2 CH=CH 2

CH3 C-CH-COEt

Na +

CH2 =CHCH 2 Br

CH3 C-CH-COEt Na + Br-

1818

18-61


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u Saponification, acidification, and

decarboxylation gives the target molecule

CH2 CH=CH 2

OO

3 . NaOH, H 2 O4 . HCl, H 2 O

CO2CH3 C-CH-COH

O O

CH2 CH=CH 2

CH3 C-CH-COEt

5. heat

CH2 CH=CH 2

O

CH3 C-CH 2 +

1818

18-62


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u To prepare a disubstituted acetone, treat the

monoalkylated AAE with a second mol of base

+

+

••-

O O

CH2 CH=CH 2

CH2 CH=CH 2

OO

CH3 C-CH-COEt Et O- Na +

CH3 C-C-COEt

Na +

EtOH

1818

18-63


Acetoacetic Ester Synth.Acetoacetic Ester Synth.u Then, a 2nd alkylation, saponification,

acidification, and decarboxylation

CH2 CH=CH 2

OO CH3

CH3 C-C COH

3 . NaOH, H 2 O4 . HCl, H 2 O

••-

CH2 CH=CH 2

OO

CH3 C-C-COEt

Na +2' . CH 3 I

5. heat

CH2 CH=CH 2

O CH3

CH3 C-CH + CO2

1818

18-64


Malonic Ester SynthesisMalonic Ester Synthesisu The strategy of a malonic ester (ME) synthesis

is identical to that of an acetoacetic estersynthesis, except that the starting material is a-diester rather than a -ketoester

A disubstitutedacetic acid

A monosubstitutedacetic acid

Diethyl malonate(Malonic ester)

OR

OO

O

RCHCOH

Et OCCH2 COEt

RCH2 COH

1818

18-65


Malonic Ester SynthesisMalonic Ester Synthesisu Consider the synthesis of this target molecule

•malonic ester is first converted to its enolate anion byan alkali metal alkoxide

3-Phenylpropanoic acid

O

C6 H5 CH2 -CH 2 -COH

These two carbonsare from diethyl malonate

1818

18-66


Malonic Ester SynthesisMalonic Ester Synthesis

(Stronger base)

+

EthanolpKa 15.9

(Weaker acid)

Sodiumethoxide

Sodium salt ofdiethyl malonate

+-••

Diethyl malonate

(Stronger acid)pKa 13.3

O O

OO

EtOC-CH-COEt

EtOC-CH-COEt

Na +

Et OH

EtO - Na +

(Weaker base)

H

1818

18-67


Malonic Ester SynthesisMalonic Ester Synthesisu Alkylation of this enolate anion with benzyl

chloride forms the new carbon-carbon bond

+

SN2OO

CH2 C6 H5

C6 H5 CH2 Br

EtOC-CH-COEt Na +Br -

-••OO

EtOC-CH-COEt

Na +

1818

18-68


Malonic Ester SynthesisMalonic Ester Synthesisu Saponification of the diester followed by

acidification and thermal decarboxylation givesthe target molecule

OO

CH2 C6 H5

3 . NaOH, H 2 O4 . HCl, H 2 O

HOC-CH-C OH

OO

CH2 C6 H5

EtOC-CH-COEt

5 . heatO

CH2 C6 H5

HOC-CH 2 + CO2

1818

18-69


Michael ReactionMichael Reactionu Michael reaction: the nucleophilic addition of

an enolate anion to an ,-unsaturated carbonylcompound

u 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

1818

18-70


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

1818

18-71


Michael ReactionMichael Reaction

+

2-Cyclohex-enoneEthyl 3-oxobutanoate

(Ethyl acetoacetate)

O

O

O O

CH3 CCH2

EtOC

O

EtOCCH

CH3 C

O

EtO - Na +

EtOH

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Michael ReactionMichael Reactionu We can write the following 4 step mechanism for

a Michael reactionStep 1: proton transfer to the base to form the

nucleophile, Nu:-

Base+ -•• +

••Nu-H B- Nu H-B

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Michael ReactionMichael ReactionStep 2: addition of Nu:- to the carbon of the , -

unsaturated carbonyl compound

-•• ••••

••••

•• - + C C C

O

CCNu C

O

Nu

CCNu C••

••O

••

-

Resonance-stabilized enolate anion

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Michael ReactionMichael ReactionStep 3: proton transfer to HB to form an enol

Step 4: tautomerism of the less stable enol to the morestable keto form gives the observed product

An enol(a product of 1,4-addition)

1

4 3 2 ••

+

•• ••

+

•••••• -O

CC CNu CCNu C

O- H

H-B B-

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Retro of 2,6Retro of 2,6--HeptadioneHeptadione

+

lost bydecarboxylation

formed in aMichael reaction

Ethylacetoacetate

Methyl vinylketone

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 acetoaceticester

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Michael ReactionsMichael Reactionsu Enamines also participate in Michael reactions

Acrylonitrile

Pyrrolidineenamine of

cyclohexanone+ +

+

+N N

CH2 CH2 CN

NHH

CH2 CH2 CNO

CH2 =CHCN

H2 OCl -

HCl

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Robinson AnnulationRobinson Annulationu A combination of aldol, Michael, and

dehydration reactions

+

CO2 Et

O

CO2 Et

O

CO2 Et

O

O

NaOEt

CO2 Et

OOH

-H 2 O

EtOH

O NaOEt

EtOH

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Gilman ReagentsGilman Reagentsu Gilman reagents undergo conjugate addition to, -unsaturated aldehydes and ketones, in areaction closely related to the Michael reaction

O

1 . (CH 3 ) 2 CuLi, ether, - 78°C

2 . H 2 O, HCl

O

3-Methyl-2-cyclohexenone

3,3-Dimethyl-cyclohexanone

CH3 CH3

CH3

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Gilman ReagentsGilman Reagentsu Gilman reagents are unique among

organometallic compounds in that they givealmost exclusively 1,4- addition

u Other organometallic compounds, includingGrignard reagents, add to the carbonyl carbonby 1,2-addition

u The mechanism of conjugate addition of Gilmanreagents is not fully understood

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End Chapter 18End Chapter 18

william h. brown & christopher s. footesst.nsu.edu/chm322/notes/oc_18.pdf · claisen...

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