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
-hydrogen, with base,
O
CH3 -C-H + NaOH

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'

Br

nucleophilic
substitution

R
An enolate A 1 haloalkane
anion
or sulfonate

Carbonyl
addition

O
R

R
An enolate
anion

R'

A ketone

R' + Br

R
R R

nucleophilic
addition

O
R +
R'

SN 2

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:

a -hydroxyaldehyde.

acid

OH
O
O
H
O

NaOH

+
CH3 -C-H
CH2 -C-H
CH3 -CH-CH2 -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

CH3-C-CH2-C-CH3
CH3
4-Hydroxy-4-methyl-2-pentanone
(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
pKa 20
(weaker acid)

H-O-H +

O
CH2 -C-H

pKa 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 tetrahedal carbonyl
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

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

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 ,unsaturated aldehydes or ketones.
OH

CH3 CHCH2 CH

warm in either
acid or base

CH3 CH=CHCH + H2 O
An -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
CH3CCH3 + HCH

acid

Nonacidic, no
alpha
hydrogens

O
CH3CCH2CH2OH
4-Hydroxy-2-butanone

19-11

Crossed Aldol Reactions

Crossed aldol reactions are most successful if

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

CHO
CHO
HCH

Formaldehyde Benzaldehyde

CHO
O
Furfural
2,2-Dimethylpropanal

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
+ H-CH2 -N
O

HO

Nitromethane
pKa 10.2
(stronger acid)

O
H-O-H + CH2 -N
Water
pKa 15.7
(weaker acid)

O
CH2 =N
O

Resonance-stabilized anion

Nitro groups can be reduced to 1 amines.

O

HO CH2 NO2
+ CH3NO2

Cyclohexanone

Nitromethane

NaOH

HO CH2 NH2
H2, Ni

(aldol)

1-(Nitromethyl)cyclohexanol

1-(Aminomethyl)cyclohexanol

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 -carbons.

-H2O

KOH

O
2,7-Octanedione

HO

(formed)

O
-H2O

KOH
OH
O

(not 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
2CH3COEt
Ethyl ethanoate
(Ethyl acetate)

1. EtO Na

CH3CCH2COEt + EtOH
2. H2O, HCl
Ethyl 3-oxobutanoate Ethanol
(Ethyl acetoacetate)

The product of a Claisen condensation is a ketoester.

O
O

Recognition
C C C C OR
Element
A -ketoester
19-18

Claisen Condensation
Claisen condensation of ethyl propanoate
O

O
OEt

Ethyl
propanoate

OEt
Ethyl
propanoate

1. EtO Na

2. H2O, HCl

O
OEt + EtOH

Ethyl 2-methyl-3oxopentanoate
(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.
O
EtO + H CH2-COEt
pKa = 22
(weaker acid)

O
O
EtOH + CH2-COEt
CH2=COEt
pKa 15.9 Resonance-stabilized 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

OO
CH3-C-CH2 -C-OEt
OEt
A tetrahedral carbonyl
addition intermediate

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

CH3-C-CH2 -C-OEt + EtO

OEt

Step 4: An acid-base reaction drives the reaction to

completion. This consumption of base must be
anticipated.
O
O
EtO + CH3-C-CH-C-OEt
H
pKa 10.7
(stronger acid)

O
O
CH3-C-CH-C-OEt + EtOH
pKa 15.9
(weaker acid)
19-21

Intramolecular Claisen condensation: Dieckman Condensation

O
EtO

OEt

O
Diethyl hexanedioate
(Diethyl adipate)

Acidic

1. EtO Na

2. H2 O, HCl
O

O
OEt

+ EtOH

Ethyl 2-oxocyclopentanecarboxylate

19-22

Crossed Claisen Condsns

Crossed Claisen condensations between two

different esters, each with -hydrogens, give
mixtures of products and are usually not useful.
But if one ester has no -hydrogens crossed
Claisen is useful.
OO

O
HCOEt

O
EtOCOEt

EtOC-COEt

Ethyl
formate

Diethyl
carbonate

Diethyl ethanedioate
(Diethyl oxalate)

O
COEt
Ethyl benzoate

No -hydrogens
19-23

Crossed Claisen Condsns

The ester with no -hydrogens is generally used in
excess.
O
Ph

OCH3

Methyl
benzoate

Used in
excess

1. CH3 O Na
OCH3 2. H2O, HCl

Methyl
propanoate

Ph

OCH3

Methyl 2-methyl-3-oxo3-phenylpropanoate
(racemic)

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. EtO Na
OEt2. H O, HCl
OEt + EtOH
2

Reactions 3 & 4: Saponification and acidification

O
O O
3. NaOH, H2 O, heat
OEt
4. H2 O, HCl

O
OH + EtOH

Reaction 5: Thermal decarboxylation.

O

O
OH

5. heat

O
+

CO2

19-25

Synthesis: Claisen Condensation

The result of Claisen condensation, saponification,
acidification, and decarboxylation is a ketone.
from the ester
furnishing the
carbonyl group
several
O
O
steps
+
CH
-C-OR'
R-CH2 -C
2
OR' R

from the ester

furnishing the
enolate anion

O
R-CH2-C-CH2 -R + 2HOR' + 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

N
H

OH

H
-H2 O

An enamine
O

O
+

N
H

O
+

H
N
OH -H2 O

An enamine
19-30

Enamines Alkylation at position.

The value of enamines is that the -carbon is

nucleophilic.
Enamines undergo SN2 reactions with methyl and
1haloalkanes, -haloketones, and -haloesters.
Treatment of the enamine with one equivalent of an
alkylating agent gives an iminium halide.
O

The morpholine
enamine of
cyclohexanone

Br

SN2

3-Bromopropene
(Allyl bromide)

Br

An iminium
bromide
(racemic)

19-31

Compare mechanisms of acid catalyzed aldol and enamine

OH

O
O
CH3 -C-H + CH2 =C-H + :A-

O
CH3-CH-CH2-C-H + H-A
(racemic)

The morpholine
enamine of
cyclohexanone

Br

SN2

3-Bromopropene
(Allyl bromide)

Br

An iminium
bromide
(racemic)

19-32

Enamines - Alkylation
Hydrolysis of the iminium halide gives an alkylated
aldehyde or ketone.
O
+

N Br-

O
+

HCl/ H2O
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 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 chloride
+

Cl N
-

HCl

H2 O
An iminium
chloride
(racemic)

N ClH H

2-Acetylcyclohexanone
(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
CH3CCH2 COEt
Ethyl acetoacetate
(Acetoacetic ester)

O
CH3CCH2 R A monosubstituted
acetone
O
CH3CCHR
R'

A disubstituted
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

RX

EtOCCH2COEt
Diethyl malonate
(Malonic ester)

O
RCH2COH A monosubstituted
acetic acid
R O
RCHCOH

A disubstituted
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 two carbons

are from diethyl malonate

MeO
OH
5-Methoxypentanoic acid

Recognize as substituted acetic acid.

Malonic Ester Synthesis

19-37

Malonic Ester Synthesis Steps

1. Treat malonic ester with an alkali metal alkoxide.
COOEt

Na+

+ EtO

Na

2. Alkylate with
Na+an alkyl halide.
MeO

Br +

COOEt

COOEt
Sodium salt of
diethyl malonate

COOEt
Diethyl malonate Sodium
ethoxide
pKa 13.3
(stronger acid)

COOEt

COOEt

SN2

MeO

EtOH

Ethanol
pKa 15.9
(weaker acid)

COOEt

+ Na+ Br-

COOEt

19-38

Malonic Ester Synthesis

3. Saponify and acidify.
MeO

COOEt 3. NaOH, H2 O
MeO
4. HCl, H2O
COOEt

COOH

+ 2EtOH

COOH

4. Decarboxylation.
MeO

COOH heat
COOH

COOH + CO2

MeO
5-Methoxypentanoic acid

19-39

Michael Reaction, addition to , -unsaturated carbonyl

Michael reaction: the nucleophilic addition of an

enolate anion to an ,-unsaturated carbonyl
compound.
Example:
EtOOC

O
+

COOEt
Diethyl
3-Buten-2-one
propanedioate
(Methyl vinyl
(Diethyl malonate)
ketone)

EtO Na
EtOH

O
EtOOC
COOEt

Recognition Pattern:
Nucleophile C C CO (nitrile or nitro)
19-40

Michael Reaction
These Types of -Unsaturated
Compounds are Nucleophile
Acceptors in Michael Reactions
O
CH2 =CHCH
O
CH2 =CHCCH3
O
CH2 =CHCOEt
O
CH2 =CHCNR2

Aldehyde
Ketone
Ester
Amide

CH2 =CHC N

Nitrile

CH2 =CHNO2

Nitro compound

These Types of Compounds

Provide Effective Nucleophiles
for Michael Reactions
O
O
CH3 CCH2 CCH3
O
O
CH3 CCH2 COEt
O
CH3 CCH2 CN
O
O
EtOCCH2 COEt
N
CH3 C=CH2

-Diketone
-Ketoester
-Ketonitrile
-Diester
Enamine

NH3 , RNH2 , R2 NH Amine

19-41

Michael Reaction in base

Example:O

O
-

EtOH

COOEt
Ethyl 3-oxobutanoate
(Ethyl acetoacetate)

EtO Na

O
O

2-Cyclohexenone

COOEt

The double bond of an ,-unsaturated carbonyl

compound is activated for attack by nucleophile.
O

O
+

More positive carbon

19-42

Mechanism: Michael Reaction

Mechanism
1: Set up of nucleophile; Proton transfer to the base.
Nu-H + :BBase

Nu:- + H-B

2: Addition of Nu:- to the carbon of the ,-unsaturated

carbonyl compound.
O
Nu

C C C

O
Nu C C

O
Nu 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

+ H-B

O-H

4 3 2

Nu C C C

+ B

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

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 enol form

More stable keto form

19-44

Michael Reaction, Cautions 1,4 vs 1,2

Resonance-stabilized enolate anions and
enamines are weak bases, react slowly with
,-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
Phenyllithium

+
4-Methyl-3penten-2-one

- +

Ph O Li

Ph OH

H2 O
HCl
4-Methyl-2-phenyl3-penten-2-ol

19-45

Michael Reaction: Thermodynamic vs Kinetic

fast

O
C C C

ROH

+ RO
C C C
Nu
1,2-Addition
(less stable product)

Nu

O
Nu: + C C C
slow

OH

O
Nu C C C

ROH

H O
Nu C C C

+ RO-

1,4-Addition
(more stable product)

Addition of the nucleophile is irrevesible for strongly basic

carbon nucleophiles (kinetic product)
19-46

Micheal-Aldol Combination
Carbanion site
O

O 1. NaOEt, Et OH

(Michael reaction)

COOEt
Ethyl 2-oxocyclohexanecarboxylate

unsaturated

3-Buten-2-one
(Methyl vinyl
ketone)
O
COOEt

2. NaOEt, Et OH
(Aldol reaction)

Dieckman

COOEt

19-47

Retrosynthesis of 2,6-Heptadione
these three
carbons from
acetoacetic ester
O

this bond formed

in a Michael reaction
O

O
+

this carbon
lost by
decarboxylation

COOH

COOEt
Ethyl
acetoacetate

Methyl vinyl
ketone

Recognize as substituted
acetone, aae synthesis
Recognize as Nucleophile C C CO
Michael
19-48

Michael Reactions
Enamines also participate in Michael reactions.
N

1. CH2=CHCN

O
CN

2. H2O, HCl
Pyrrolidine enamine
of cyclohexanone

+
N Cl
H H

(racemic)

19-49

Gilman Reagents vs other organometallics

Gilman reagents undergo conjugate addition to

,-unsaturated aldehydes and ketones in a
reaction closely related to the Michael reaction.
O

1. (CH3 )2 CuLi, ether, -78C

CH3

3-Methyl-2cyclohexenone

2. H2 O, HCl

CH3
CH3
3,3-Dimethylcyclohexanone

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 NH + CH3 (CH2 ) 3Li

Diisopropylamine
Butyllithium
(pK a 40
(stronger base)
(stronger acid)

[( CH3 ) 2 CH] 2 N-Li+ + CH3 (CH2 ) 2CH3

Lithium diisopropylamde
(weaker base)

LDA

Butane
pK a 50
(weaker acid)

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
-78C

O
O Li 1.C6H5CH2CH
-

OH O

Lithium
enolate

C6H5

2. H2O 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 hydrogens, 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.
slight excess
O

of base

+ LDA

O-Li+

O-Li+
0C

+ [( CH3 ) 2 CH] 2 NH

+
(racemic)
99%

1%

When 2-methylcyclohexanone is treated with LDA

where the ketone is in slight excess, the product is
richer in the more substituted enolate.
O

slight excess
of the ketone
+ LDA

O-Li+

O-Li+
0C

+ [( CH3 ) 2 CH] 2 NH

+
(racemic)
10%

90%

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 -hydrogen of an
unreacted ketone. Thus, equilibrium is established
between alternative enolate anions.
O Li+

O
H
CH3 +
(racemic)

O-Li+

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
-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