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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
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Copyright © 1998 by Saunders College Publishing
Chapter 18Chapter 18
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
••••
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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-
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Copyright © 1998 by Saunders College Publishing
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 -
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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 -
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Copyright © 1998 by Saunders College Publishing
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
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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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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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
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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
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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 +
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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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
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Copyright © 1998 by Saunders College Publishing
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
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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
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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
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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
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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'
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Copyright © 1998 by Saunders College Publishing
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)
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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
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Copyright © 1998 by Saunders College Publishing
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- +
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Copyright © 1998 by Saunders College Publishing
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-
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Copyright © 1998 by Saunders College Publishing
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
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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
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Copyright © 1998 by Saunders College Publishing
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
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EnaminesEnamines -- AlkylationAlkylation
An iminium bromide
Allyl bromideThe morpholineenamine of
cyclohexanone
+
+SN2
N
O
N
O
CH2 CH=CH 2
CH2 =CHCH 2 - Br
Br -
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Copyright © 1998 by Saunders College Publishing
EnaminesEnamines -- AlkylationAlkylation
Morpholiniumchloride
2-Allylcyclohexanone
++
++
CH2 CH=CH 2
N
O
NH
OO
CH2 CH=CH 2
H
Br - HCl/H 2 O
Cl -
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Copyright © 1998 by Saunders College Publishing
EnaminesEnamines -- AcylationAcylationu Enamines undergo acylation when treated with
acid chlorides and acid anhydrides
u The reaction is an example of nucleophilic acylsubstitution
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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 -
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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
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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
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Copyright © 1998 by Saunders College Publishing
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
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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
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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-
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Copyright © 1998 by Saunders College Publishing
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 +
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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
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Copyright © 1998 by Saunders College Publishing
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
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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
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Copyright © 1998 by Saunders College Publishing
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
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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
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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 +
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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
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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
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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
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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