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Organic synthesis via Enolates

1. Acidity of -hydrogens.
2. Alkylation of diethylmalonate.
3. Synthesis of ethyl acetoacetate by Claisen condensation (with mechanism).
4. Keto-enol tautomerism of ethyl acetoacetate.
5. Properties and synthetic applications of aceto acetic ester.
6. Synthesis of enamines.
7. Use of enamines in alkylation and acetylation.

1. Acidity of -hydrogens:
The  (alpha) - hydrogen is the hydrogen atom that is bound to the carbon (called as -
carbon atom) adjacent to the carbonyl carbon. The next carbon is the β-carbon and the
hydrogen atoms attached to it are called as β-hydrogen atoms and so on.
O

C C C

H H
β hydrogen α hydrogen
Aldehydes and ketones are weak acids and have remarkably low pKa values (between 15 and
20). Hence, they may act as a Bronsted acid in an acid-base reaction with a strong base. But,
aldehydes and ketones are much stronger acids than alkanes. Due to the only minor
difference in electronegativity between hydrogen and carbon, C-H bonds in alkanes are
hardly polarized. Thus, hydrogens of alkanes are in fact not acidic. The pKa values of alkanes
are around 50.

α hydrogen β hydrogen

H H H O Hα O H H

H C
α R C C C H
H C C H C C H

H H H H H H

pKa=40-50
The aciditypK -hydrogens ofpK
of a=50 a=20
aldehydes pKa=19-20
and ketones is much less than carboxylic acids,
which have pKa values around 3 to 4.
Reason for acidity: The - hydrogen of carbonyl compounds is acidic, as it is connected
with the -carbon that is directly bound to the electron withdrawing carbonyl group.
O
O O
α - H+
C C R
C C R C C R
αH
Acid α carbanion enolate anion
(conjugate base stabalised by resonance)
The relatively high acidity carbonyl compounds (as compared to alkanes) is explained by the
resonance stabilization of the conjugate base by the carbonyl group, or, in other words,
through the stabilization of the anion formed by deprotonation. This anion is called an enolate
anion.
The negative charge is mainly distributed among the -carbon and the carbonyl oxygen, by
resonance, which leads to the stabilization of the otherwise highly, energized carbanion.

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2. Alkylation of diethylmalonate: With sodium ethoxide, it forms a sodium derivative
called as sodiomalonic ester. This reacts with compounds containing a reactive
halogen atom, e.g., alkyl halides, acid chlorides, halogen-substituted esters, etc.
O H O O H O
C2H5ONa
C2H5O C C C OC2H5 C2H5O C C C OC2H5
Na
H (1) C2 H5 ONa
(2) RX

O R O O O
RX
C2H5O C C C OC2H5 + NaX C2H5O C C C OC2H5

H
H produces the disubstituted derivative of malonic
Na
The process on repetition ester.

O R O (1) C2 H5ONa O R O
(2) R1 X
C2H5O C C C OC2H5 C2H5O C C C OC2H5

These substituted derivatives


H of malonic ester can also be readily prepared
R1 in one step by
treating the ester with two equivalents of sodium ethoxide and then with two equivalents of
alkyl halide. This procedure is used only if two identical alkyl groups are to be introduced.

O H O O
(1) 2 C2 H5ONa R O
(2) 2 RX
C2H5O C C C OC2H5 C2H5O C C C OC2H5 + 2 NaX
As mentioned earlier, RHmay be alkyl, acetyl, acyl or halogen substituted ester.
R

When, R= methyl group i.e. -CH3, then reaction is expressed as-

O H O (1) C2H5ONa O H O
(2) CH3Br
C2H5O C C C OC2H5 C2H5O C C C OC2H5 + NaBr
When, R= acetyl group i.e. CH3CO-, then reaction is expressed as-
H CH3

O H O (1) C2H5ONa O H O
(2) CH3COCl
C2H5O C C C OC2H5 C2H5O C C C OC2H5 + NaCl

3. Synthesis of ethylH acetoacetate by Claisen condensation (with COCHmechanism):


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Ethyl
acetoacetate is the ethyl ester of acetoacetic acid (CH3COOH) and is widely used as a
starting material for the synthesis of a variety of ketones and acids.
It can be prepared by Claisen condensation of ethyl acetate.
The condensation of two molecules of an ester (e.g. ethyl acetate), or of two molecules of
different esters, or of one molecule of an ester with one molecule of a ketone under the

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influence of sodium or sodium ethoxide, is termed Claisen condensation (1887), and is one of
the best methods for preparing beta-ketonic esters like ethyl acetoacetate.
Two molecules of ethyl acetate condense in the presence of sodium ethoxide to produce ethyl
acetoacetate. Claisen condensation may also be brought about by sodamide or tri-
phenylmethylsodium etc.

O O H O
C2H5 ONa
2 H3C C OC2H5 H3C C C C OC2H5
Mechanism: It involves following steps. It is similar to aldol H
condensation.
ethyl acetate ethyl acetoacetate
1) Dissociation of sodium ethoxide

2) Formation of α−carbanion
C2H5ONa C2H5 O + Na
O O
C2 H5O
H2C C OC2H5 H2C C OC2H5
3) Addition step
H
α carbanion

O O O H O
H3C
4) Elimination + H2C
C step C OC2H5 H3C C C C OC2H5

OC2H5 H
C2H5O

O H O O O
H
H3C C C C OC2H5 H3C C C C OC2H5 + C2H5O

C2H5O H H
4. Keto-enol tautomerism of ethyl acetoacetate: Acetic
ethyl ester or ethyl acetoacetate is
acetoacetate
the ethyl ester of acetoacetic acid CH3 . CO . CH2 . CO2H, a β-ketonic acid.
Acetoacetic ester was first discovered by Geuther (1863), who prepared it by the action of
sodium on ethyl acetate, and gave the formula as CH3 . C(OH) . CH . CO2C2H5 (β-
hydroxycrotonic ester). The same can written as-

OH O

H3C C C C OC2H5
In 1865, Frankland and Duppa, also prepared acetoacetic ester by the action of sodium on
ethyl acetate,but they proposed a different formula
H (β-ketobutyric ester).

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O H O
β-ketobutyric ester
H3C C C C OC2H5
Which of these is correct?
H
Evidence in favour of the Geuther formula (reactions of an unsaturated alcohol)

i) When acetoacetic ester is treated with sodium, hydrogen is evolved and the sodium
derivative is formed. This showed the presence of a hydroxyl group.
ii) When acetoacetic ester is treated with an ethanolic solution of bromine, it readily
decolourises. This indicates the presence of an olefinic double bond.
iii) When acetoacetic ester is treated with ferric chloride, a reddish-violet colour is
produced. This is characteristic of compounds containing the enolic group (
-C(OH)=C<) like phenols.

Evidence in favour of the Frandland-Duppa formula(reactions of a ketone).

(i) With sodium hydrogen sulphite, acetoacetic ester forms a bisulphate derivative.
(ii) With hydrogen cyanide, acetoacetic ester forms a cyanohydrin.

Thus, evidence for both the structure were there. The controversy continued until about 1910,
when chemists came to the conclusion that both formula were correct, and that the two
compounds existed together in equilibrium in solution (or in the liquid state):

O H O OH O
H3C C C C OC2H5 H3C C C C OC2H5
H H
5. Keto synthetic
Properties and f orm applications of acetoenolacetic
f orm ester: On reaction with
ethyl acetoacetate
sodium ethoxide, ethyl acetoacetate forms a sodium derivative called as
sodioacetoactic ester. This reacts with compounds containing a reactive halogen atom,
e.g., alkyl halides, acid chlorides, halogen-substituted esters, etc. However vinyl and
aryl halides do react.

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O H O O H O
C2H5ONa
H3C C C C OC2H5 H3C C C C OC2H5
Na
H (1) C2H5 ONa
(2) RX

O O
O R O RX
C C OC2H5 + NaX H3C C C C OC2H5
H3C C
H Na
H
The process on repetition produces the disubstituted derivative of acetoacetic ester.

O R O (1) C2 H5 ONa O R O
(2) R1 X
H3C C C C OC2H5 H3C C C C OC2H5

H R1
As mentioned earlier, R may be alkyl, acetyl, acyl or halogen substituted ester.

When, R= methyl group i.e. -CH3, then reaction is expressed as-

O H O (1) C2H5ONa O H O
(2) CH3Br
H3C C C C OC2H5 H3C C C C OC2H5 + NaBr
The process on repetition produces the dimethyl derivative of acetoacetic ester
H CH3

O H O (1) C2H5ONa O CH3 O


(2) CH3Br
H3C C C C OC2H5 H3C C C C OC2H5 + NaBr
When, R= acetyl group i.e. CH3CO-, then reaction is expressed as-
CH3 CH3

O H O (1) C2H5ONa O H O
(2) CH3COCl
H3C C C C OC2H5 H3C C C C OC2H5 + NaCl
Acetoacetic ester and its alkyl derivatives can undergo two types of hydrolysis with
potassium hydroxide:H COCH3

(a) Ketonic hydrolysis: It is so called because a ketone is the chief product. It is carried
out by boiling with dilute aqueous or ethanolic potassium hydroxide solution, e.g.,

The ketone obtained is acetone or its derivatives, and the latter always contain the group .
CH3CO-
Mechanism of decarboxylation:

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H R
O R O O R O H3C O
dil KOH
H3C C C C OC2H5 H3C C C C OH

H O O
H
H
H
O R
H3C - CO2
R
H3C C C H
Ketone
H
(b) Acid hydrolysis: It is so called because an acid is the
O chief product, is carried out by
H e.g.,
boiling with concentrated ethanolic potassium hydroxide solution,

The acid obtained is acetic acid or its derivatives as the potassium salt. The free acid is
readily obtained from these salts by treatment with inorganic acids.
Mechanism of the cleavage:
O O O R O
R
H3C C C C OC2H5 + KOH H3C C C C OH + K + C2H5O

H H
O O R O
R O

H3C C C C OH + KOH H3C C C C OK + H2 O

H H

O O R O
R O

H3C C C C OK + C2H5O H3C C C C OK

H C2H5O H

R O O
R O C2H5OH
C C OK + H3C C OC2H5
C2 H5O + H C C OK

Applications: These alkylation Hreactions followed by ketonicH hydrolysis or acidic hydrolysis


are used for the synthesis of various ketones and acids.

1.Synthesis of Ketones: The formula of the ketone is written down, and provided it contains
the group, the ketone can be synthesized via acetoacetic ester as follows. The acetone nucleus
is picked out, and the alkyl groups attached to it are then introduced into acetoacetic ester one
at a time; this is followed by ketonic hydrolysis. –CO.CH3
It is usually better to introduce the larger group before the smaller (steric effect).

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O O O
1. NaOEt
2. R-X R
H3C C OC2H5 H3C C + CO2 + C2H5OH
3. Aq. H+or HO-
H H H H
4. ∆
Reaction type: Nucleophilic substitution, then ester hydrolysis & finally
decarboxylation

For example, For Butanone. CH3COCH2 CH3 R= -CH3

CH 3COCH CH 2CH 3 R= -CH3 and R1 = -C2H 5

CH3
O O O
1. NaOEt
2. CH3Br CH3
H3C C OC2H5 H3C C + CO2 + C2H5OH
3.Aq. H+or HO-
H H H H
4. ∆
For example,
For 3-methylpentan-2-one.

O O O O O O
1. NaOEt 3. NaOEt
2. CH3Br C 4. C2H5Br C
H3C C OC2H5 H3C C OC2H5 H3C C OC2H5
H H H3C H H3C C2H5

O O O
5. Aq. H+or HO-
CH3
C 6. ∆
H3C C OC2H5 H3C C C2H5 + CO2 + C2H5 OH
H
H3C C2H5
3-methylpentan-2-one
2. Synthesis of fatty acids: Here, the acetic acid nucleus is picked out, and the acetoacetic
ester derivatives are subjected to acid hydrolysis. The acetoacetic ester acid synthesis is
usually confined to the preparation of straight-chain acids or branched-chain acids where the
branching occurs on the α-carbon atom. For example,

For Synthesis of n-Butyric acid


CH 3CH2 CH2COOH R= -C 2H5
O O
1. NaOEt O O
2. C2H5I 3. acid hydrolysis
H3C C OC2H5 C CH3CH2 CH2COOH
H3C C OC2H5
H H
3. Other synthesis: Sodioacetoacetic esterH reacts
C2H5with many other halogen compounds
besides alkyl halides, and so may be used to synthesise a variety of compounds.

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(i) 1, 3-Diketones. Here, the halogen compound used is an acid chloride. As acid chlorides
react with ethanol, the reaction is not carried out in this solvent in the usual way. The reaction
is thus carried out by treating acetoacetic ester in benzene solution with magnesium and the
acid chloride.
For example synthesis of pentane-2,4-dione

O O O O
1. Mg
2. CH3COCl C 3. ketonic hydrolysis
H3C C OC2H5 H3C C OC2H5 CH 3COCH2COCH 3
H H H COCH3
(ii) Dicarboxylic acids: These may be prepared by interaction of sodioacetoacetic ester and a
halogen derivative of an ester. e.g., preparation of succinic acid from ethyl chloroacetate:

1. NaOEt
CH3COCH 2CO2 C2H5 CH 3COCHCO 2C2H5 Na 2. BrCH2COOC2H 5 CH3COCHCO 2C 2H5

3. acid hydrolysis CH2CO2C 2H5

CH2CO 2C 2H 5

CH2CO 2C 2H 5
6. Synthesis of enamines: Primary amines react with aldehydes and ketones to produce
imines. For example, the reaction of acetophenone with methyl amine.

O NCH3
OH
CH3 CH3
+ H2NCH3 CH3
NHCH3 + H2O

A
In this reaction the initially formed tetrahedral intermediate, A, undergoes dehydration. The
loss of the OH group in A could be accompanied by loss of a proton from either the NH
group or the CH3 group. The former alternative is preferred because the C-N double bond is
more stable than the C-C double bond that would be produced via the latter route, i.e. the
more stable product is preferred. Also the hydrogen attached to nitrogen is more acidic as
compared to carbon and in acid catalysed dehydration, the hydrogen attached to nitrogen gets
lost.
Note that the amine has to be primary, i.e. have two hydrogen atoms attached to the nitrogen,
for the imine to form. On the other hand, reaction of a secondary amine initially follows the
same course as that of a primary amine, but now the tetrahedral intermediate, B, cannot form
an imine because the nitrogen does not have a second hydrogen atom to lose:

O N(CH3)2
OH
CH3 CH3
+ HN(CH3)2 CH2
N(CH3)2 + H2O

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Consequently, intermediate B undergoes dehydration to form an alkene. (Note that the
starting material must have at least one hydrogen attached to the α-carbon in order for this
reaction to occur.) But this type of alkene is special and is called as an enamine.

H+
O + HN N + H2O
C6H6

N
H+
+
C6H6 + H2O
N
H

H+
O +
N + H2O
HN
C6H6

A less substituted f orm will be major


Alkylation of Enamines
Enamines are alkylated by treating them with alkyl halide. Benzene is used as a solvent and
the water that is formed is removed by azeotropic distillation.

N N
C6H6 N

Cl

Acylation of Enamines
Similar to alkylation, acylation can be done using acetyl chloride. For example,

N N
C6H6 N
Cl

O Cl O
O
The alkylated and acylated enamine are hydrolyzed to get alkylated and acylated aldehyde or
ketone. Thus sequence of this reactions can shown as

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N N
C6H6 H2O/H+ O

Cl

N N
C6H6 H2O/H+ O
∆ O
O Cl O

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