Reactions at

the a-Carbon
of Carbonyl
Compounds :
Enols and
Enolates
Lia Dewi Juliawaty
Sem.2-2020/2021
Reactions at the a Carbon of
Carbonyl Compounds:
Enols and Enolates

O Nu O

R  R' R Nu
R'
O
R'
R a Hydrogens are
H
weakly acidic
a (pKa = 19 – 20)
The Acidity of the a Hydrogens
of Carbonyl Compounds:
Enolate Anions
H
H C C H H2C C H
pKa 25 44

H O

H3C C H R'
R
H H
pKa 50 19-20
O H
C C
R

B:

O O
C C C C
R R

Resonance structures for

the delocalized enolates
 H+ O H+
C C
R
Enolate

HO O H
C C C
R R
Enol form Keto form
 Aldehyde or Ketone

When a proton is removed from an a-carbon, two factors combine to

increase the stability of the base that is formed.
(i) the electrons left behind when the proton is removed are
delocalized, electron delocalization increases stability
(ii) More importantly, the electrons are delocalized onto an oxygen, an
atom that is better able to accommodate them because it is more
electronegative than carbon.
Esters

The electrons left behind when a proton is removed from the a-carbon
of an ester are not as readily delocalized onto the carbonyl oxygen
(indicated by the red arrows) as they would be in an aldehyde or
a ketone.
 This is because the oxygen of the OR group of the ester also has a
lone pair that can be delocalized onto the carbonyl oxygen (indicated
by the blue arrows).
 Thus, the lone pair on carbon and the lone pair on oxygen compete for
delocalization onto the same oxygen.

Esters (pKa = 25) are less acidic than aldehydes and ketones
(pKa = 16–20)
2. Keto and Enol Tautomers

 Interconvertible keto and enol forms

are called tautomers, and their
interconversion is called
tautomerization
 Keto form Enol form
O OH
Acetaldehyde
H H
(~100%) (extremely small)

O OH
Acetone

(>99%) (1.5 X 10-4%)

O OH

Cyclohexanone

(98.8%) (1.2%)
 O O OH O

Pentane-2,4-dione Enol form

(24%) (76%)

Hydrogen bond

H H
:

:
:O :O: O :O:

Resonance stabilization of the enol

form
3. Reactions via Enols & Enolates
3A. Racemization
O OH
OH Enol
t
Et t
Et
Bu or Bu (achiral)
H3O
H Me Me
(chiral)
(s) H3O

Racemization at O O
an a carbon Et + Et
t t
takes place in Bu Bu
the presence of H Me Me H
acids or bases ( 1 : 1 ) racemate
 Base-Catalyzed Enolization
H OH

O O
Enolate
C C C C
(achiral)
H ion
HO Keto tautomer

O H
Enol
HO + C C
(achiral)
tautomer
  Acid-Catalyzed Enolization

O O H
H
C C + H O H C C +
O H
H H H
Keto tautomer

O H
H O H + C C
H
Tautomers are isomers that Enol tautomer
are in rapid equilibrium
(achiral)
Base-Promoted Halogenation

Mechanism:
Acid-Promoted Halogenation

Mechanism:
 ALKYLATION OF KETONES

NON-CATALYTIC BASES = NaH, LDA REACT ONCE .

one shot
CATALYTIC BASES = NaOH, KOH, NaOR REACT REPEATEDLY

It just keeps
on going and going
Alkylation of a Ketone .
NON-CATALYTIC BASES REACT ONCE one shot

O one mole O one mole

NaH _
..
C CH3 C CH2 + H
2
THF
a-hydrogens
LDA CH3-I
THF one mole
O _ O
.. CH3-I
C CH2 C CH2 CH3
monoalkylation

_ Sodium Hydride
+
: N : Li NaH
CH CH3
“LDA”
H3C CH
Lithium Diisopropyl Amide
CH3 CH3
a strong base
 ALKYLATION OF CYCLOHEXANONE
CATALYTIC BASES REACT REPEATEDLY

.. ..
O :O CH3CH2 I :O
CH2CH3
NaOH :-

enolate difficult to stop

ion at monoalkylation
.. - with NaOH or KOH
:O: (catalyst, not used up)

O
It just keeps
on going and CH3CH2 CH2CH3
going ….. CH3CH2 CH2CH3
Sequence of Alkylation - Cyclohexanone and Base
It is difficult to stop at monoalkylation
O even if one mole of CH3I is used.

KOH Alkylation follows the sequence

shown below.
CH3I Large or bulky groups may follow a
different sequence than this one.

O O O O
CH3 CH3 H3C CH3 H3C CH3
CH3 CH3 H3C CH3

This enolate has O- O-

SAME lower energy -
SIDE the double bond is CH3 CH3
FIRSTmore substituted.
CH3-I This enolate has
Steric hindrance higher energy.
is not a problem.
ALKYLATION OF KETONES
NON-CATALYTIC BASES = NaH, LDA
 Monoalkylation is Obtained by Using
“Non-Catalytic Bases”
A “non-catalytic base” is used up, and not regenerated.

.. .. .. -
:O :H - :O
Na+
:O :
H
NaH - H
+ H2
H H
gone

one CH3I
mole
stoichiometric base
..
:O
.
one shot
CH3
+ NaI
H
 Lithium Diisopropyl Amide
.
one shot

_ +
: N : Li “LDA”
H3C CH CH CH3
Lithium Diisopropyl Amide
CH3 CH3
a strong base

LDA is also a non-catalytic base.

It is too strong a base to be regenerated after it is
used to remove a proton from an aldehyde or ketone.

.. - .. .. -
(iPr)2N:
+ a-H
(iPr)2NH X
difficult
(iPr)2N :

(need to add Lio)

ALKYLATION OF KETONES
ENAMINES
ALKYLATION OF CYCLOHEXANONE
ENAMINES ALSO GIVE MONOALKYLATION

SN2 -
.. I
+
O N CH3CH2 I N
CH2CH2

Alkylates once
and stops !
.
one shot
O
To perform a second alkylation CH2CH3
you must make the enamine all
over again!
STEPS IN THE ALKYLATION OF AN a-CARBON VIA
AN ENAMINE

the alkylation step is an SN2 reaction, only primary alkyl halides or

methyl halides should be used
STEPS IN THE ACYLATION OF AN a-CARBON VIA
AN ENAMINE
Sequence of Alkylation: Enamine
( pyrrolidine + CH3I )
O O Alkylations go one-at-a-time.
first CH3 You must make a new enamine
time each time.

Notice the different order of

O O methylation from that with base.

CH3 H3C CH3

Difficult to go beyond dialkylation
second because of steric hindrance.
time

Steric hindrance
N N This enamine
This enamine CH3 CH3 is not favored.
is favored.
yellow area
is planar
Halogenation at the a Carbon

H O X O
acid
C C + X2 C C + HX
or base

(racemic)

This is an a-substitution reaction because

one electrophile (Br+) is substituted for
another (H+) on the a-carbon
 Bromination
It just keeps
on going and
going …..
.. .. -
O :O .. .. :O:
: Br Br :
.. ..
KOH :-
Br2

O O O O
Br Br Br Br Br Br
Br Br Br Br

Difficult to stop at monobromination

The Haloform Reaction
O O

3 X2 CX3
+ 3X
3 OH
OH

O
CHX3 +
A haloform
(X = Cl, Br, I)
When hydroxide ion or an alkoxide ion is used to remove an
a-hydrogen from cyclohexanone, only a small amount of the
carbonyl compound is converted to the enolate ion
because the product acid (H2O) is a stronger acid than the
reactant acid (the ketone).

the equilibrium of an acid–base reaction favors

dissociation of the strong acid and formation of
the weak acid
When LDA (lithium diisopropylamide) is used to remove an
a-hydrogen, essentially all the carbonyl compound is
converted to the enolate ion because the product acid
(diisopropylamine, or DIA) is a much weaker acid than the
reactant acid (the ketone)

LDA is the base of choice for those reactions that require

the carbonyl compound to be completely converted to an
enolate ion before it reacts with an electrophile
Lithium Enolates
O O
+ EtO Na + EtOH

H weaker stronger stronger

weaker base base acid
acid (p K a = 16)
(p K a = 19)
Preparation of Lithium DiisopropylAmide (LDA)
(in THF at -78 °C  temperature of a dry ice/acetone bath.)

The two bulky isopropyl substituents attached to the nitrogen of LDA  difficult for the
nitrogen to get close enough to the carbonyl carbon to react with it.

LDA : a strong base but a poor it removes an a-hydrogen much faster than it adds to
a carbonyl carbon.
 Direct Enolate Alkylation

[1] Deprotonation: Base removes a proton from the a carbon to generate

an enolate.
The reaction works best with a strong non-nucleophilic base like LDA in
THF solution at low temperature(–78 °C).
[2] Nucleophilic attack: The nucleophilic enolate attacks the alkyl halide,
displacing the halide
(a good leaving group) and forming the alkylation product by an SN2
reaction.
Step [2] is an SN2 reaction, it works best with unhindered methyl and 1°
alkyl halides.
Hindered alkyl halides and those with halogens bonded to sp2 hybridized
carbons do not undergo substitution.
Treatment with LDA in THF solution at –78 °C gives the less
substituted kinetic enolate

Treatment of 2-methylcyclohexanone with NaOCH2CH3 in

CH3CH2OH solution at room temperature forms the more
substituted thermodynamic enolate,
Regioselective Formation of Enolates

 Formation of a Kinetic Enolate

O O Li
H
H3C Li N(iPr)2 H3C
H
DME
Kinetic
This enolate is formed faster enolate
because the hindered strong
base removes the less hindered
proton faster.
 Formation of a Thermodynamic Enolate
This enolate is more stable
because the double bond is
more highly substituted. It
is the predominant enolate
at equilibrium.
B
O O O
H H H
H3C H H3C
H3C H
weak
base in
Kinetic 2-Methylcyclo- a protic Thermodynamic
(less stable) hexanone solvent (more stable)
enolate enolate
Direct Alkylation of Ketones via
Lithium Enolates
O
CH3
H3C I

O Li O (- LiI)
(56%)
LDA
DME O

Br Ph Ph
(- LiBr)
(42-45%)
Aldol Reactions: Addition of
Enolates and Enols to
Aldehydes and Ketones

O OH O
10% NaOH
2
H H2O, 5 oC H

 contains both an
aldehyde and an alcohol
functional group
 ALDOL ADDITION
The Aldol Reaction
Aldol addition
Aldol Addition Reactions
 Mechanism of the aldol addition
O O O
H + H2O
H H H
HO O

OH O O O
HO H
H H
+ HO
The Retro-Aldol Reaction
OH O O
HO
2
H2O

 Mechanism
H
O O O O O
HO
+

O HO H O
HO +
 Aldol Condensation Reactions:
Dehydration of the Aldol Addition
Product
 Dehydration of the aldol addition
product Aldol condensation
OH O
O
H + H2O + OH
H
H
OH
In fact, under the basic reaction conditions
the initial aldol product is often not isolated.
Instead, it loses the elements of H2O from the from the a and b`
carbons to form an-unsaturated carbonyl compound.
When the a,b-unsaturated carbonyl compound is further conjugated with
carbon–carbon double bond or a benzene ring, as in the case of Reaction
[2], elimination of H2O is spontaneous and the bhydroxy carbonyl
compound cannot be isolated.

The aldol reaction may not stop at the beta-hydroxy aldehyde, but lose water
(dehydration) to form an alpha,beta-unsaturated aldehyde. Dehydration is much
faster under acidic conditions, but can happen under basic conditions too
 Mechanism
H
H OH2 O
O O
+ H O H
H
H
H
O

H
O O OH2 O OH

H2O:
+ H2O
H
+
+ H3O
 Synthetic Applications of Aldol
Reactions

 Aldol additions and aldol

condensations
● Important methods for carbon-
carbon bond formation
● Useful synthesis for
 b-hydroxyl carbonyl compounds
 a,b-unsaturated carbon
compounds
 R R
H H H
R R R
base NaBH4
O OH O OH OH
Aldehyde Aldol 1,3-diol
HA, -H2O
H2/Ni
high R R
pressure
H LiAlH 4
R R
a,b-unsaturated O
R aldehyde Allylic OH
H2, Pd-C alcohol
R
R
Saturated OH
H
alcohol R
Aldehyde
O
Crossed Aldol Condensations

O O O OH
HO
+ + H
H H H2O

OH O

OH O OH O
+ +
H H
Crossed Aldol Condensations
Using Weak Bases
O O

H + HO

aldol
addition

OH O
O
dehydration

H
Crossed Aldol Condensations Using
Strong Bases: Lithium Enolates and
Directed Aldol Reactions
 Directed Aldol Synthesis using a strong
base, iPr2NLi (LDA)

H
Crossed Aldol Condensations Using
Strong Bases: Lithium Enolates and
Directed Aldol Reactions
 Directed Aldol Synthesis using a strong
base, iPr2NLi (LDA)
O O
LDA, THF
-78 oC

H
O

O OH O O Li
H2O
Because LDA is a strong base, all of the carbonyl compound is
converted to an enolate ion, so none of that carbonyl compound is left
for the enolate ion to react with in an aldol addition

Aldol addition does not occur until the second carbonyl compound is
added to the reaction mixture.

• If the second carbonyl compound is added slowly, the chance that

it will form an enolate ion and then react with another molecule of
the same carbonyl compound will be minimized.
 The use of a weaker base under
protic conditions
● Formation of both kinetic and
thermodynamic enolates
● Results in mixture of crossed
aldol products
O O O
HO
+
protic
solvent
(Kinetic (Thermodynamic
enolate) enolate)
O

1. H O
O OH
2. H2O

OH
 Suggest a synthesis of the following
compound using a directed aldol
synthesis O OH

● Retrosynthetic analysis
O OH O
O

+
disconnection
 Synthesis

O O O Li

LDA

O OH O
1.
H

2. H2O
Cyclizations via Aldol
Condensations
 Intramolecular Aldol condensation
 Cyclizations via Aldol
Condensations
 Intramolecular Aldol condensation
● Useful for the synthesis of
five- and six-membered rings
● Using a dialdehyde, a keto
aldehyde, or a diketone
e.g. O O
HO

H
O
 ● Although three different enolates are
formed, cyclization usually occurs
with an enolate of the ketone adding
to the aldehyde

 
O O
<
R  R R  H
(Ketones are (Aldehydes are
less reactive more reactive
toward nucleophiles) toward nucleophiles)

 Path c is least favorable

● Path b is more favorable than path a
because six-membered rings are
thermodynamically more favorable to
form than eight-membered rings

● Likewise, five-membered rings form

far more readily than seven-
membered rings
 ● Aldol addition and condensation
O O OH O
Base
R' + R' R'
H H (addition) H
H R'
H
"condensation"

O
O + R'
H H H
R'
 Conjugate Additions of Enolates:
Michael Additions
O 1. NaOMe (cat.) O O
MeOH
O
2.
H

MeO H OMe

O
O O O

(Micheal
Addition)
 Other examples of Michael additions
O
MeOOC 1. NaOMe, MeOH
(1) MeOOC
O OEt
MeOOC
2. COOMe
OEt

O O O O
1. NaOMe, MeOH
(2)
OMe 2. COOMe OMe

COOMe
 ● Aldol addition and condensation
(additional information)

In this aldol addition reaction of acetone, the equilibrium favors

the ketone reactant rather than the addition product, diacetone
alcohol.

This product can be isolated in good yield only if an apparatus is

used that allows the product to be removed from the base
catalyst as it is formed.
 ● Aldol addition and condensation
(additional information)

Under more severe conditions (higher base concentration,

or heat, or both), the product of aldol addition undergoes
a dehydration reaction.
 The Claisen–Schmidt condensation

The addition product cannot be isolated in this reaction;

the highly conjugated condensation product is formed as its
most stable stereoisomer—the trans isomer.

The reasons are as follows:

• First, because the aldehyde in the Claisen–Schmidt reaction
has no a-hydrogens, it cannot act as the enolate component of
the aldol condensation; consequently, two of the four possible
crossed aldol products cannot form
The other possible side reaction is the aldol addition reaction of
the ketone with itself;
why doesn’t this reaction occur?

The enolate ion from acetone can react either with another
molecule of acetone or with benzaldehyde.
Recall that addition to a ketone occurs more slowly than addition
to an aldehyde
Furthermore, even if addition to acetone does occur, the aldol
addition reaction of two ketones is reversible and addition to an
aldehyde has a more favorable equilibrium constant than addition
to a ketone
 Thus, both the rate and equilibrium for addition to
benzaldehyde are more favorable than they are for addition to a
second
molecule of acetone.
 Thus, the product is the only one formed.
The Claisen Condensation:
A Synthesis of b-Keto Esters
O O
R' + R'
OR OR 1. NaOR
H H 2. H3O+

O O
ROH + R'
OR
H R'
  Mechanism
● Step 1
O O
R' + OR R' + ROH
OR OR
H H
H

O
R'
OR
H
  Mechanism
● Step 2
O O O O
R' + R'
OR OR OR
H RO
H R'
R'

O O
RO + R'
OR
H R'
 Mechanism
● Step 3
O O O O
R' R'
OR OR
H R'
R'
+
OR
(pKa ~ 9) ROH
(pKa ~ 16)
 O O
R'
OR
R'

O O O O
R' R'
OR OR
R' R'
 Mechanism
● Step 4
O O H

R' + H O
OR
H (rapid)
R'

OH O O O
R' R'
OR OR
H R'
R'
(enol form) (keto form)
 Claisen condensation
● Esters that have only one a hydrogen
do not undergo the usual Claisen
condensation
e.g. O
H The a carbon has only
one a hydrogen
OMe  does not undergo
Claisen condensation

This is because an ester with only one hydrogen

will not have an acidic hydrogen when step 3 is
reached, and step 3 promotes the favorable
equilibrium that ensures the forward reaction
The importance of this strategy in the success of the
Claisen condensation is evident if the condensation is
attempted with an ester that has only one a-hydrogen:
No condensation product is formed.

In this case, the desired condensation product has

a quaternary a-carbon, and therefore it has no a-hydrogens
acidic enough to react completely with ethoxide.
 Claisen condensation

● An Acyl Substitution
(nucleophilic addition-elimination
reaction)

● Useful for the synthesis of

b-keto esters
These condensations are quite different and should not be
confused.
To compare:
1. The aldol condensation is an addition reaction of an enolate
ion or an enol with an aldehyde or ketone followed by a
dehydration.
The Claisen condensation is a nucleophilic acyl substitution
reaction of an enolate ion with an ester group.

2. The aldol condensation is catalyzed by both base and acid.

The Claisen condensation requires a full equivalent of base and
is not catalyzed by acid.

3. The aldol addition requires only one a-hydrogen. A second

a-hydrogen is required, however, for the dehydration step of
the aldol condensation.
In the Claisen condensation, the ester starting material must
have at least two a-hydrogens, one for each of the ionizations
  Examples of Claisen condensation

O O O
NaOMe
(1) 2
OMe OMe

+ MeOH

O O
H3O+

OMe
H
  Examples of Claisen condensation

O O O
NaOEt
(2) 2
OEt OEt

+ EtOH
O O
H3O+
OEt
H
Intramolecular Claisen Condensations:
The Diekmann Condensation

Ch. 18 - 88
Intramolecular Claisen Condensations:
The Diekmann Condensation
 Intramolecular Claisen condensation
● Diekmann condensation
● Useful for the synthesis of five- and
six-membered rings
6 4 2
MeO 7 1 OMe
5 3

O O O O

7 2 1
1. NaOMe 6 OMe
2. H3O+ 5 3

4
  Mechanism O
H 7
OMe
MeO
6 4
OMe OMe 6
7 2 1
5 3 OMe
5 1
2
O O
4 3
O
O O OMe O
H OMe OMe
7 2 1
OMe 6

5 3
O
4
(This
favorable O O H O O
equilibrium H O H
drives the OMe OMe
reaction)
Crossed Claisen Condensations
 Crossed Claisen condensations are
possible when one ester component
has no a hydrogens and, therefore,
is unable to form an enolate ion and
undergo self-condensation

O O O O
1. NaOMe
+
OMe OMe 2. H3O+ OMe

(no a-hydrogen)
 Mechanism
O O
+ OMe + MeOH
OMe OMe
H O

OMe

O O O O

OMe OMe
OMe
H
 Mechanism
(This favorable
equilibrium
drives the
O O O O
reaction)

OMe OMe
H
OMe H
O O H O H

OMe
  Other examples
(1) O O O
O
OEt 1. NaOEt OEt
+
OEt 2. H3O+

(no a hydrogen)

(2) O O O O
1. NaOMe
+
MeO OMe OMe 2. H3O+ MeO OMe
(no a carbon)
Recall: esters that have only
one ahydrogen cannot
undergo Claisen Condensation
by using sodium alkoxide

However, they can be converted to

the b-keto esters by reactions that
use very strong bases such as lithium
diisopropyamide (LDA)
O O

OMe LDA OMe

THF

O O Cl

OMe
The Robinson Annulation
NaOH, MeOH
O O O

(Michael O
O conjugate O
addition)

O Base
(Aldol (-H2O)
condensation)

O
 Mechanism of the Robinson Annulation
O O O O

H OH
O
(Micheal
O O addition) O

MeO H

O O

O O
O HO O
H
 Mechanism of the Robinson Annulation
O O

O (intramolecular
O Aldol O
O
condensation)

MeO H

O O

(dehydration)

O HO O
OH
H
CANNIZARO REACTION

Starting material

Aldehyde containing
No
a-hydrogen
Synthesis
 One molecule of aldehyde is reduced to
the corresponding alcohol,
while a second one is oxidized to
the carboxylic acid.
 Explanation
 The applicability of Cannizzaro reaction in
organic synthesis is limited as the yield is
not more than 50% for either acid or alcohol
formed.

 The a, a, a-Trihalo aldehyde undergo

haloform reaction in strongly alkaline
medium. E.g. Choral will give chloroform in
presence of an alkali.
Explanation
 Involves the base-induced disproportionation of an
aldehyde lacking a-hydrogen atom in the
a position.

 The overall order of the reaction is usually 3 or 4.

 The Cannizzaro reaction takes place very slowly

when electron-donating groups are present. But
the reaction occurs at faster rates when electron
withdrawing groups are present.
Mechanism
In case Dianion form
In Aromatic aldehyde
Argument ….

 hydrogen is transferred from the second

aldehyde molecule is from the solvent.

 * When the reaction is carried out with

D2O as solvent, the resulting alcohol does
not show carbon bonded deuterium.
It indicates the hydrogen is transferred
from the second aldehyde molecule, and
not from the solvent.
In case of aldehydes that do have α-hydrogens, the aldol
condensation reaction takes place preferentially.
Enolates of b-Dicarbonyl
Compounds

O O O

H H
pKa = 9-11 pKa = 18-20
(more acidic)
 Recall
O O
+ EtO + EtOH

 a-hydrogens of b-dicarbonyl compounds

are more acidic
O O O O
+ EtO + EtOH

H
 Contributing resonance structures

O O O O O O
C C C C C C
C C C


 
O O Resonance
C C hybrid
C

b-Dicarbonyl Compounds by
Acylation of Ketone Enolates
O O O
NaNH 2
Et2O
O (kinetic
H H enolate)
Ph OMe

slightly O O
more
acidic
  Intramolecular example
a b O
H H O O
1. NaOMe
7 6 5 4 3 2 1 1 6
+
OMe 2. H3O 2 5 7
c 3 4
O H

● The product was formed by

deprotonation of Hb, the enolate
formed at C5 and then adding to C1
Questions

i. Give the structure of the product by

deprotonation of Ha, and adding the
resulting enolate (at C7) to C1. Explain
why this product is not formed.

i. Give the structure of the product by

deprotonation of Hc, and adding the
resulting enolate (at C2) to C6. Explain
why this product is not formed.
Synthesis of Methyl Ketones:
The Acetoacetic Ester Synthesis
O O O O
EtO Na
Na
OEt OEt

O O t O O R X
BuO K

OEt OEt
R R
O O
R' X (R, R' = 1o
OEt alkyl groups)
R R'
Synthesis of monosubstituted methyl
ketones
O O O O
1. EtO Na , EtOH

OEt 2. Ph Br OEt

Ph

1. NaOH
O
heat
O O 2. H3O+

(- CO2) OH

Ph (Decarboxylation Ph
of b-keto acid)
Synthesis of disubstituted methyl ketones

O O O O
1. EtO Na , EtOH
OEt 2. MeI OEt
Me
1. tBuOK, tBuOH
O O O O 2. Et-Br
1. NaOH

OH 2. H3O+ OEt
Me Et Me Et
O
heat
Et
(- CO2)

Me
Decarboxylation of b-keto acid
 O O is the synthetic O
equivalent of

Ethyl acetoacetate ion Acetate enolate

 Synthesis of g-keto acids and g-diketones
O O O O
EtO Na
OEt OEt O
Br
X

O O O O
1. NaOH (aq)

OH 2. H3O+ OEt
O O

X O X
a
X
heat g
b X=OH: g-keto acid
(- CO2) X=R: g-diketone
O
6A. Acylation
 Synthesis b-diketones
O O NaH
O O
DMF
OEt (cannot use EtOH OEt O
because it will react
with acid chloride) R Cl

O O O O
1. NaOH (aq)

OH 2. H3O+ OEt

R O R O
O O

heat R
(- CO2)
7. Synthesis of Substituted Acetic
Acids: The Malonic Ester Synthesis

O O

EtO OEt
Diethyl malonate

O O O O
is the synthetic
and
equivalent of:
EtO OEt OEt O
 O
R
O O OH

EtO OEt O
R
OH
R'
 Synthesis of monoalkylacetic acid
O O O O
OEt

EtO OEt EtO OEt

R X
H
O O O O
1. NaOH (aq)

HO OH 2. H3O+ EtO OEt

heat
R R

H
O O OH O
R R
HO O HO HO
R
 Synthesis of dialkylacetic acid
O O O O
1. EtONa

EtO OEt 2. RX EtO OEt

R
1. tBuOK, tBuOH
2. R'X

O O O O
1. NaOH (aq)

HO OH 2. H3O+ EtO OEt

R R' R R'
O
heat
R
(- CO2) HO
R'
  Example 1
O O O O
1. EtONa, EtOH

EtO OEt 2. EtO OEt

Br

1. 50% KOH, reflux

2. dil. H2SO4, reflux

O O O
(-CO2)

HO HO OH
(Heptanoic acid)
 Example 2
O O O O
1. EtONa, EtOH

EtO OEt 2. MeI EtO OEt

Me
1. tBuOK, tBuOH
2. Ph Br
O O O O
1. NaOH (aq)

HO OH 2. H3O+ EtO OEt

Me Ph Me Ph
O
180oC
(- CO2) HO Ph
Me
8. Further Reactions of Active
Hydrogen Compounds
Z Z'

Active hydrogen compound

(Z and Z' are electron withdrawing groups)

Z, Z':
O O O O
N NO2
R H OR NR2

O O O O
S S R S OR or S NR2
R
O O O
 Example
O O
1. EtONa, EtOH
NC NC
OEt 2. OEt
Br

O
NC t t
1. BuOK, BuOH
OEt
2. Ph Br

Ph
9. Synthesis of Enamines:
Stork Enamine Reactions
O
OH
C R
C + HN R C C N
H R R
H

Aldehyde 2o Amine
R
or ketone
N R
C C + H2O

Enamine
 2° amines most commonly used to
prepare enamines O

N N N
H H H
Pyrrolidine Piperidine Morpholine
● e.g.
O N
N
H
p-TsOH, H2O
 N R
(a) N-alkylated
(a) product
+X

(b) N heat
+R X

(b) N
R = H2C CH C-alkylated
R product
or Ph
+X
O
H2O
N + R
H
 Synthesis of b-diketones

O N O N O
N Cl
H R Cl R
p-TsOH
(enamine)

O O N O

R H2O R
 Synthesis of g-keto esters

O N OEt
Br
N
H O
p-TsOH
(enamine)

O N
OEt OEt
H2O
O O
 Enamines can also be used in Michael
additions

N EtOH N
+ CN
reflux CN

O
CN H2O
10. Summary of Enolate Chemistry
1. Formation of an Enolate
O O
+ :B
R R
H Resonance-
stabilized
enolate
O
H:B +
R
2. Racemization

R' O R' OH R' O

OH OH
R H
H Ph or H3O R Ph or H3O R Ph
Enol
(achiral)

Enantiomers
3. Halogenation of Aldehydes & Ketones
O O
R' acid R'
R + X2 R
or base
H X
 Specific example: haloform reaction
O O
H OH X
Ph + 3 X2 Ph
H H2O X
H X
O
CHX3 +
Ph O
4. Halogenation of Carboxylic Acids: The
HVZ Reaction
O
O 1. X2, P R
R OH
OH 2. H2O
X
5. Direct Alkylation via Lithium Enolates
O O O
LDA, THF R'' X
R o R R
H(R') -78 C H(R') H(R')
(formation of the R''
kinetic enolate)

 Specific example:
O O Li O

LDA, THF CH3I

-78oC
6. Direct Alkylation of Esters

O O
LDA
R R
OEt THF OEt

O R' Br

R
OEt

R'
7. Acetoacetic Ester Synthesis
O O O O
1. NaOEt

OEt 2. RBr OEt

1. OH, heat R
O
2. H3O+
R
3. heat, ( CO2)

O O t O O
1. BuOK

OEt 2. R'Br OEt

R R'
R
O
1. OH, heat
R
2. H3O+
R' 3. heat, ( CO2)
8. Malonic Ester Synthesis
O O O O
1. NaOEt

EtO OEt 2. RBr EtO OEt

1. OH, heat R
O
2. H3O+
R
HO 3. heat, ( CO2)

O O t O O
1. BuOK

EtO OEt 2. R'Br EtO OEt

R R'
R
O
1. OH, heat
R
HO 2. H3O+
R' 3. heat, ( CO2)
9. Stork Enamine Reaction
O NR' 2
R R + R' NH R
2

R
Enamine
O
1. R'' Br
R R
2. heat
3. H2O
R''