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Chapter 19
Enolates and Enamines
19-1
Formation of an Enolate Anion
 Enolate
anions are formed by treating an
aldehyde, ketone, or ester, which has at least one
a-hydrogen, with base,
O
CH3 -C- H + N aOH
O Na +
O
H C C-H + H2 O
H C C-H
H
H
An enolate anion
• Most of the negative charge in an enolate anion is on
oxygen.
oxygen
Reactive carbon
19-2
Enolate Anions
 Enolate
anions are nucleophiles in SN2 reactions
and carbonyl addition reactions,
O
SN2
– R
R
R
An enolate
anion
Carbonyl
addition
+
R'
Br
R' + Br
R
SN 2
R R
A 1° haloalkane
or sulfonate
O
R
O
nucleophilic
subs titution
– R +
R
An enolate
anion
R'
nucleophilic
addition
O
R'
A ketone
O
O
R
R'
R'
R R
A tetrahedral carbonyl
addition intermediate
19-3
The Aldol Reaction
 The
most important reaction of enolate anions is
nucleophilic addition to the carbonyl group of
another molecule of the same or different
compound.
• Catalysis: Base catalysis is most common although
acid also works. Enolate anions only exist in base.
19-4
The Aldol Reaction
 The
product of an aldol reaction is:
acid
• a -hydroxyaldehyde.
OH
O
O
H
O
a
N aOH

+
CH3 - C-H
CH2 - C-H
CH3 - CH- CH 2 -C- H
Acetaldehyde
Acetaldehyde
3-Hydroxybutanal
(a -hydroxyaldehyde;
racemic )
• or a -hydroxyketone.
O
H
O
CH3 -C-CH3 + CH2 -C-CH3
Acetone
Acetone
acid
OH
O
a

CH3 -C-CH2 -C-CH3
CH3
4-Hydroxy-4-meth yl-2-p entanone
(a -hydroxyketone)
Ba(OH) 2
19-5
Mechanism: the Aldol Reaction, Base
 Base-catalyzed
aldol reaction (good nucleophile)
Step 1: Formation of a resonance-stabilized enolate
anion.
H- O
O
+ H- CH2 - C-H
p Ka 20
(weaker acid)
H- O-H +
O
CH2 - C-H
pK a 15.7
(stronger acid)
O
CH2 = C- H
An enolate anion
Step 2: Carbonyl addition gives a TCAI.
O
CH3 -C-H +
O
CH2 -C-H
O
OCH3 -CH-CH2 -C-H
A tetrahed al carbon yl
addition intermediate
Step 3: Proton transfer to O- completes the aldol
reaction.
19-6
Mechanism: the Aldol Reaction: Acid catalysis
 Before
showing the mechanism think about what
is needed.
• On one molecule the beta carbon must have
nucleophilic capabilities to supply an electron pair.
• On the second molecule the carbonyl group must
function as an electrophile.
• One or the other molecules must be sufficiently
reactive.
19-7
Mechanism: the Aldol Reaction: Acid catalysis
 Acid-catalyzed
aldol reaction (good electrophile)
• Step 1: Acid-catalyzed equilibration of keto and enol
forms.
O
OH
Nucleophilic
HA
carbon
CH3 - C-H
CH2 = C- H
• Step 2: Proton transfer from HA to the carbonyl group
of a second molecule of aldehyde or ketone.
O
CH3 -C-H + H A
H
O
CH3 -C-H + A
Reactive carbonyl
19-8
Mechanism: the Aldol Reaction: Acid catalysis
• Step 3: Attack of the enol of one molecule on the
protonated carbonyl group of the other molecule.
• Step 4: Proton transfer to A- completes the reaction.
H
H
O
O
CH3 -C-H + CH2 =C-H + :A
OH
O
CH3 -CH-CH2 -C-H + H-A
(racemic)
This may look a bit strange but compare to
19-9
The Aldol Products: Dehydration to alkene
• Aldol products are very easily dehydrated to a,unsaturated aldehydes or ketones.
OH
O
CH3 CHCH 2 CH
warm in either
acid or base
O

a
CH3 CH= CHCH + H2 O
An a -unsaturated
aldehyde
• Aldol reactions are reversible and often little aldol is
present at equilibrium.
• Keq for dehydration is generally large.
• If reaction conditions bring about dehydration, good
yields of product can be obtained.
19-10
Crossed Aldol Reactions
 In
a crossed aldol reaction, one kind of molecule
provides the enolate anion and another kind
provides the carbonyl group.
O
O
NaOH
CH3 CCH3 + HCH
acid
O
CH3 CCH2 CH2 OH
4-Hydroxy-2-butanone
Nonacidic, no
alpha
hydrogens
19-11
Crossed Aldol Reactions
 Crossed
aldol reactions are most successful if
• one of the reactants has no a-hydrogen and, therefore,
cannot form an enolate anion,
O
•
CHO
CHO
HCH
Formald ehyde Benzaldehyde
CHO
O
Furfural
2,2-D imethylprop anal
• One reactant has a more acidic hydrogen than the
other (next slide)
• One reactant is an aldehyde which has a more reactive
carbonyl group.
19-12
Crossed Aldol Reactions, Nitro activation
 Nitro
groups can be introduced by way of an
aldol reaction using a nitroalkane.
O
O
+ H-CH2 -N
HO
O
H-O-H + CH2 -N
O
N itromethane
pK a 10.2
(stronger acid)
CH2 =N
O
Water
p Ka 15.7
(weaker acid)
O
Resonance-stabilized an ion
• Nitro groups can be reduced to 1° amines.
O
HO
+ CH3 NO2
Cyclohexan on e
N itrometh ane
NaOH
HO
CH2 NO2
CH2 NH2
H2 , Ni
( aldol)
1-(N itromethyl)cyclohexanol
1-(A min omethyl)cycloh exanol
19-13
Intramolecular Aldol Reactions
• Intramolecular aldol reactions are most successful for
formation of five- and six-membered rings.
• Consider 2,7-octadione, which has two a-carbons.
a
O
a
O
O
a
-H2 O
KOH
O
2,7-Octanedione
O
HO
(formed)
O
a
O
-H2 O
KOH
OH
O
(n ot formed)
19-14
Synthesis: Retrosyntheic Analysis
Two Patterns to look for
19-15
Synthesis: Retrosyntheic Analysis
Recognition
pattern
Analysis
19-16
Synthesis: Retrosyntheic Analysis
Example
Mixed
aldol
Benzaldehyde
No alpha
hydrogens
19-17
Claisen Condensation, Ester Substitution
 Esters
also form enolate anions which participate
in nucleophilic acyl substitution.
O
2 CH3 COEt
Ethyl ethan oate
(Ethyl acetate)
-
1 . EtO Na
+
O
O
+ EtOH
CH3 CCH2 COEt
2 . H2 O, HCl
Eth yl 3-oxobutanoate Ethanol
(Ethyl acetoacetate)
• The product of a Claisen condensation is a ketoester.
O
O
 a
Recognition
C C C C OR Element
A  -ketoest er
19-18
Claisen Condensation
• Claisen condensation of ethyl propanoate
O
O
OEt
Ethyl
propan oate
+
-
OEt
Ethyl
propan oate
1 . Et O Na
+
2 . H2 O, HCl
O
O
OEt + EtOH
Eth yl 2-methyl-3oxopen tan oate
(racemic)
Here the enolate part of one ester molecule has
replaced the alkoxy group of the other ester molecule.
19-19
Mechanism: Claisen Condensation
Step 1: Formation of an enolate anion.
Et O -
O
+ H CH -COEt
2
pK a = 22
(w eaker acid)
OO
EtOH + CH2 -COEt
CH2 =COEt
pK a 15.9 Res on ance-s tab ilized enolate anion
(stronger
acid )
Step 2: Attack of the enolate anion on a carbonyl carbon
gives a TCAI.
O
CH3 -C-OEt +
O
CH2 -COEt
O
-
O
CH3 -C-CH2 -C-OEt
OEt
A tetrahedral carbonyl
add ition in termediate
19-20
Mechanism: Claisen Condensation
Step 3: Collapse of the TCAI gives a -ketoester and an
alkoxide ion.
O
O
CH3 -C-CH2 -C-OEt
O
O
CH3 -C-CH2 -C-OEt + Et O
OEt
Step 4: An acid-base reaction drives the reaction to
completion. This consumption of base must be
anticipated.
O
O
Et O + CH3 -C-CH-C-OEt
H
pK a 10.7
(stron ger acid)
O
O
CH3 -C-CH-C-OEt + Et OH
p Ka 15.9
(w eaker acid)
19-21
Intramolecular Claisen condensation: Dieckman Condensation
O
Et O
-
1 . Et O Na
OEt
O
Diethyl hexanedioate
(Diethyl adipate)
+
2 . H2 O, HCl
O
O
OEt
Acidic
+
Et OH
Ethyl 2-oxocyclopentanecarboxylate
19-22
Crossed Claisen Condsns
 Crossed
Claisen condensations between two
different esters, each with a-hydrogens, give
mixtures of products and are usually not useful.
 But if one ester has no a-hydrogens crossed
Claisen is useful.
OO
O
HCOEt
O
EtOCOEt
EtOC-COEt
Eth yl
formate
D ieth yl
carbonate
D iethyl ethaned ioate
(D iethyl oxalate)
O
COEt
Ethyl ben zoate
No a-hydrogens
19-23
Crossed Claisen Condsns
• The ester with no a-hydrogens is generally used in
excess.
O
Ph
O
OCH3
Meth yl
benzoate
+
-
1 . CH3 O Na
OCH3 2 . H2 O, HCl
Meth yl
p ropan oate
O
+
Ph
O
OCH3
Methyl 2-meth yl-3-oxo3-ph enylprop anoate
(racemic)
Used in
excess
19-24
Synthesis: Claisen Condensation
 Claisen
condensations are a route to ketones via
decarboxylation
Reactions 1 & 2: Claisen condensation followed by acidification.
O
O O
+
1 . Et O Na
OEt 2 . H O, HCl
OEt + Et OH
2
Reactions 3 & 4: Saponification and acidification
O
O
O
OEt
3 . Na OH, H2 O, he a t
O
OH + Et OH
4 . H2 O, HCl
Reaction 5: Thermal decarboxylation.
O
O
5 . he at
OH
O
+
CO 2
19-25
Synthesis: Claisen Condensation
The result of Claisen condensation, saponification,
acidification, and decarboxylation is a ketone.
from the ester
furnish ing the
carbonyl group
s everal
O
O
steps
+
CH
-C-OR'
R-CH2 -C
2
OR' R
from the ester
furnish ing the
enolate anion
O
R-CH2 -C-CH2 -R + 2 HOR' + CO2
Note that in this Claisen (not crossed) the ketone is
symmetric. Crossed Claisen can yield non symmetric
ketones.
19-26
Synthesis: Retrosynthetic Analysis
Site of acidic
Site of
hydrogen,
substitution, nucleophile
electrophile
New
bond
19-27
Enamines (and imines, Schiff bases)
Recall primary amines react with carbonyl
compounds to give Schiff bases (imines), RN=CR2.
Primary
amine
But secondary amines react to give enamines
Secondary
Amine
19-28
Formation of Enamines
 Again,
enamines are formed by the reaction of a
2° amine with the carbonyl group of an aldehyde
or ketone.
• The 2° amines most commonly used to prepare
enamines are pyrrolidine and morpholine.
O
N
H
Pyrrolidine
N
H
Morpholine
19-29
Formation of Enamines
• Examples:
O
H
+
+
+
N
N
H
-H2 O
OH
H
An enamine
O
O
O
+
N
H
N
H
O
+
+
N
OH
H
-H2 O
N
An en amin e
19-30
Enamines – Alkylation at a position.
value of enamines is that the -carbon is
nucleophilic.
 The
• Enamines undergo SN2 reactions with methyl and
1° haloalkanes, a-haloketones, and a-haloesters.
• Treatment of the enamine with one equivalent of an
alkylating agent gives an iminium halide.
O
O
••
N
+
The morph olin e
en amin e of
cyclohexan on e
Br
SN 2
3-Bromopropene
(Allyl bromide)
N
Br
An iminiu m
bromid e
(racemic)
19-31
Compare mechanisms of acid catalyzed aldol and enamine
H
H
OH
O
O
CH3 -C-H + CH2 =C-H + :A
O
CH3 -CH-CH2 -C-H + H-A
(racemic)
O
O
••
N
+
The morph olin e
en amin e of
cyclohexan on e
Br
SN 2
3-Bromopropene
(Allyl bromide)
N
Br
An iminiu m
bromid e
(racemic)
19-32
Enamines - Alkylation
• Hydrolysis of the iminium halide gives an alkylated
aldehyde or ketone.
O
+
N Br-
O
O
+
HCl/ H 2 O
2-Allylcyclohexanone
+
N ClH
H
Morpholinium
chloride
Overall process is to render the alpha carbonss of
ketone nucleophilic enough so that substitution
reactions can occur.
19-33
Enamines – Acylation at a position
• Enamines undergo acylation when treated with acid
chlorides and acid anhydrides.
N
Could this be made via a
crossed Claisen followed
by decarboxylation.
O
+
CH3 CCl
Acetyl ch loride
+
Cl N
-
O
O
HCl
O
+
H2 O
A n iminium
chlorid e
(racemic)
+
N ClH H
2-Acetylcyclohexan on e
(racemic)
19-34
Overall, Acetoacetic Ester Synthesis
 The
acetoacetic ester (AAE) synthesis is useful
for the preparation of mono- and disubstituted
acetones of the following types:
O
O
RX
CH3 CCH2 COEt
Ethyl acetoacetate
(Acetoacetic ester)
O
CH3 CCH2 R A mon os ubs tituted
acetone
O
CH3 CCHR
R'
A dis ubs tituted
acetone
Main points
1. Acidic hydrogen providing a nucleophilic center.
2. Carboxyl to be removed thermally
3. Derived from a halide
19-35
Overall, Malonic Ester Synthesis
 The
strategy of a malonic ester (ME) synthesis is
identical to that of an acetoacetic ester
synthesis, except that the starting material is a diester rather than a -ketoester.
O
O
RX
EtOCCH2 COEt
D iethyl malonate
(Malonic ester)
O
RCH2 COH A mon os ubs tituted
acetic acid
R O
RCHCOH
A dis ubs tituted
acetic acid
Main points
1. Acidic hydrogen providing a nucleophilic center
2. Carboxyl group removed by decarboxylation
3. Introduced from alkyl halide
19-36
Malonic Ester Synthesis
 Consider
the synthesis of this target molecule:
O
These tw o carbons
are from diethyl malon ate
MeO
OH
5-Methoxyp entanoic acid
Recognize as substituted acetic acid.
Malonic Ester Synthesis
19-37
Malonic Ester Synthesis Steps
1. Treat malonic ester with an alkali metal alkoxide.
Na+
COOEt
-
+ EtO Na
+
COOEt
+
COOEt
Sodiu m s alt of
dieth yl malonate
COOEt
D ieth yl malon ate Sodiu m
ethoxide
pK a 13.3
(s tronger acid)
EtOH
Eth anol
p Ka 15.9
(w eaker acid)
2. Alkylate with an alkyl halide.
Na+
MeO
Br
COOEt
+
COOEt
SN2
MeO
COOEt
+
Na+ Br-
COOEt
19-38
Malonic Ester Synthesis
3. Saponify and acidify.
MeO
COOEt
COOEt
3 . NaOH, H2 O
4 . HCl, H2 O
MeO
COOH + 2 EtOH
COOH
4. Decarboxylation.
MeO
COOH heat
COOH
COOH + CO2
MeO
5-Methoxypentanoic acid
19-39
Michael Reaction, addition to a,-unsaturated carbonyl
 Michael
reaction: the nucleophilic addition of an
enolate anion to an a,-unsaturated carbonyl
compound.
• Example:
EtOOC
O
+
COOEt
Dieth yl
3-Buten-2-one
prop anedioate
(Methyl vinyl
(D iethyl malonate)
k eton e)
-
Et O Na
EtOH
O
+
EtOOC
COOEt
Recognition Pattern:
Nucleophile – C – C – CO (nitrile or nitro)
19-40
Michael Reaction
These Types of a -Unsaturated
Compounds are Nucleophile
Acceptors in Michael Reactions
O
CH2 = CHCH
O
CH2 = CHCCH 3
O
CH2 = CHCOEt
O
CH2 = CHCNR 2
Aldehyde
Ketone
Ester
Amide
CH2 = CHC N
Nitrile
CH2 = CHN O2
Nitro compound
These Types of Compounds
Provide Effective Nucleophiles
for Michael Reactions
O
O
CH3 CCH2 CCH 3
O
O
CH3 CCH2 COEt
O
CH3 CCH2 CN
O
O
Et OCCH2 COEt
N
CH3 C= CH2
-Diketone
-Ketoester
-Ketonitrile
-Diester
Enamine
N H3 , RNH2 , R2 NH Amine
19-41
Michael Reaction in base
Example:O
O
-
EtO Na
+
O
+
O
EtOH
COOEt
Eth yl 3-oxobutanoate
(Ethyl acetoacetate)
2-Cyclohexen on e
COOEt
• The double bond of an a,-unsaturated carbonyl
compound is activated for attack by nucleophile.
O
O
O
+
+
More positive carbon
19-42
Mechanism: Michael Reaction
 Mechanism
1: Set up of nucleophile; Proton transfer to the base.
Nu-H + :BBas e
Nu:- + H- B
2: Addition of Nu:- to the  carbon of the a,-unsaturated
carbonyl compound.
O
Nu
+
C C C
O
Nu C C
C
O
Nu C C
C
Resonance-stabilized enolate anion
19-43
Michael Reaction
Step 3: Proton transfer to HB gives an enol.
1
O
Nu C C C
O-H
+
4
H-B
3 2
Nu C C C
+
B
A n enol
(a p rodu ct of 1,4-ad dition)
Step 4: Tautomerism of the less stable enol form to the
more stable keto form.
H O
O-H
Nu C C C
Nu C C C
Less stable en ol form
More stab le keto form
19-44
Michael Reaction, Cautions 1,4 vs 1,2
• Resonance-stabilized enolate anions and
enamines are weak bases, react slowly with
a,-unsaturated carbonyl compounds, and
give 1,4-addition products.
• Organolithium and Grignard reagents, on the
other hand, are strong bases, add rapidly to
carbonyl groups, and given primarily 1,2addition.
O
PhLi +
Phenyl4-Methyl-3lithiu m pen ten-2-one
-
+
Ph O Li
Ph OH
H2 O
HCl
4-Methyl-2-phen yl3-penten -2-ol
19-45
Michael Reaction: Thermodynamic vs Kinetic
O
C C C
fast
-
ROH
-
+ RO
C C C
Nu
1,2-Add ition
(les s stab le prod uct)
Nu
O
Nu: + C C C
s low
OH
-
O
Nu C C C
ROH
H
O
Nu C C C
+ RO-
1,4-Add ition
(more stable p rodu ct)
Addition of the nucleophile is irrevesible for strongly basic
carbon nucleophiles (kinetic product)
19-46
Micheal-Aldol Combination
a  unsaturated
Carbanion site
O
O 1 . Na OEt , Et OH
+
(Michael reaction)
COOEt
Ethyl 2-oxocyclohexanecarboxylate
3-Buten-2-one
(Methyl vinyl
ketone)
O
COOEt
O
O
2 . Na OEt , Et OH
(Aldol reaction)
COOEt
Dieckman
19-47
Retrosynthesis of 2,6-Heptadione
thes e three
carbons from
acetoacetic ester
O
O
this b on d formed
in a Mich ael reaction
O
O
O
O
+
this carb on
los t by
decarboxylation
COOH
COOEt
Eth yl
acetoacetate
Meth yl vinyl
k eton e
Recognize as substituted
acetone, aae synthesis
Recognize as Nucleophile – C – C – CO
Michael
19-48
Michael Reactions
• Enamines also participate in Michael reactions.
O
N
1 . CH2 =CHCN
CN
2 . H2 O, HCl
Pyrrolidin e enamine
of cycloh exanone
+
N
+
H
ClH
(racemic)
19-49
Gilman Reagents vs other organometallics
 Gilman
reagents undergo conjugate addition to
a,-unsaturated aldehydes and ketones in a
reaction closely related to the Michael reaction.
O
O
1 . ( CH3 ) 2 CuLi, eth er, -78°C
CH3
3-Methyl-2cyclohexenone
2 . H2 O, HCl
CH3
CH3
3,3-D imethylcyclohexanone
• Gilman reagents are unique among organometallic
compounds in that they give almost exclusively 1,4addition.
• Other organometallic compounds, including Grignard
reagents, add to the carbonyl carbon by 1,2-addition.
19-50
Crossed Enolate Reactions using LDA
 With
a strong enough base, enolate anion
formation can be driven to completion.
 The base most commonly used for this purpose
is lithium diisopropylamide , LDA.
 LDA is prepared by dissolving diisopropylamine
in THF and treating the solution with butyl
lithium.
[ ( CH3 ) 2 CH] 2 N H + CH3 ( CH2 ) 3 Li
Diisopropylamine
(pK a 40
(stronger acid)
Butyllithium
(stronger base)
[ ( CH3 ) 2 CH] 2 N - Li + + CH3 ( CH2 ) 2 CH 3
Butane
Lithium diis opropylamde
pK a 50
(weaker base)
(weaker acid)
LDA
19-51
Crossed Enolate Reactions using LDA
 The
crossed aldol reaction between acetone and
an aldehyde can be carried out successfully by
adding acetone to one equivalent of LDA to
completely preform its enolate anion, which is
then treated with the aldehyde.
O
Acetone
LDA
O
O Li 1.C6 H5 CH2 CH
-
OH O
+
-78°C
Lithium
enolate
C6 H5
2. H 2O 4-Hydroxy-5-phenyl-2-pentanone
(racemic)
19-52
Examples using LDA
Crossed aldol
Michael
Alkylation
Acylation
19-53
Crossed Enolate Reactions using LDA
Question: For ketones with nonequivalent ahydrogens, can we selectively utilize the
nonequivalent sites?
Answer: A high degree of regioselectivity exists
and it depends on experimental conditions.
19-54
Crossed Enolate Reactions using LDA
• When 2-methylcyclohexanone is treated with a slight
excess of LDA, the enolate is almost entirely the less
substituted enolate anion.
O
slight excess
of base
+ LDA
O - Li +
O - Li +
0°C
+
+
(racemic)
99%
[ ( CH3 ) 2 CH] 2 N H
1%
• When 2-methylcyclohexanone is treated with LDA
where the ketone is in slight excess, the product is
richer in the more substituted enolate.
slight excess
of the ketone
O - Li +
O - Li +
O
+ LDA
0°C
+
+
(racemic)
10%
90%
[ ( CH3 ) 2 CH] 2 N H
19-55
Crossed Enolate Reactions using LDA
 The
most important factor determining the
composition of the enolate anion mixture is
whether the reaction is under kinetic (rate) or
thermodynamic (equilibrium) control.
 Thermodynamic Control: Experimental
conditions that permit establishment of
equilibrium between two or more products of a
reaction.The composition of the mixture is
determined by the relative stabilities of the
products.
19-56
Crossed Enolate Reactions using LDA
• Equilibrium among enolate anions is established when
the ketone is in slight excess, a condition under which
it is possible for proton-transfer reactions to occur
between an enolate and an a-hydrogen of an
unreacted ketone. Thus, equilibrium is established
between alternative enolate anions.
O Li+
O
O - Li +
H
CH3 +
(racemic)
O
+
Less stable
enolate anion
(racemic)
More stable
enolate anion
(racemic)
19-57
Crossed Enolate Reactions using LDA
 Kinetic
control: Experimental conditions under
which the composition of the product mixture is
determined by the relative rates of formation of
each product. First formed dominates.
• In the case of enolate anion formation, kinetic control
refers to the relative rate of removal of alternative
a-hydrogens.
• With the use of a bulky base, the less hindered
hydrogen is removed more rapidly, and the major
product is the less substituted enolate anion.
• No equilibrium among alternative structures is set up.
19-58
Example
1. 1.01 mol LDA, kinetic control
1. 0.99 mol LDA, thermodynamic
control
19-59