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Lecture 9
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-Alkylation of Carbonyl Compounds
-Alkylation of ketones - via the enolate anion - can be a useful
technique for extending or modifying the alkyl chain in aldehydes and
ketones at the -carbon:
O
O
LDA
C
C6 H 5
C
CH3
C6 H5
Acetophenone
O
_
CH2
C
C6 H5
CH2
CH3
I
The reaction is most useful with
1 alkyl halides - with 2
halides -elimination competes
significantly with alkylation.
_
O
C
C6 H5
C
H2
CH3
Propiophenone
As we saw earlier a problem here is that the intermediate enolate can be
a strong enough base to deprotonate the alkylated product at an carbon. This yields a new enolate which can then itself be alkylated hence mixtures which may be difficult to separate can be formed:
O
O
Base
H 3C
CH3
_
CH2
H3 C
O
CH3I
H3 C
CH3COCH2
O
H 3C
C
H2
C
H2
-
CH3
O
C
H2
CH3
CH3I
_
H2 C
C
H2
CH3
lkylation of -ketocarboxylic esters provides a clean alternative route
to direct -alkylation of ketones:
O
O
C
C
H3C
C
H2
Na+
1 Eq. NaOEt
O
[Quantitative]
C
OEt
H3C
Claisen condensation
of ethyl acetate
O
_ C
C
OEt
H
CH3CH2CH2Br
N.B. Mono-alkylation only - the
mono-alkylated product is less
acidic and more sterically
hindered than the -ketoester
starting material - cannot be
deprotonated by enolate.
O
C
C
H3C
CH
OEt
C3H7
H3O+
O
CH3CH2CH2Br
O
C
H3C
O
C
H3C
CH2
C3H7

- CO2
CH3
H3C
O
O
C
C
CH
OH
C3H7
The activating effect of the ester group increases the acidity of the
'doubly -' CH, directing alkylation to that carbon but di-alkylation is
sterically inhibited.
Following removal of the ester group by
hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.
yields the same product as - clean -monoalkylation of acetone.
The strategy of using a -ketoester as a synthetic 'stand-in' for a ketone
in alkylation reactions (in technical language, as a 'synthetic
equivalent' of a ketone) can also be applied to carry out effective
stepwise di-alkylation - to ketone carbonyl:
Na+
O
O
C
C
1 Eq. NaOEt
[Quantitative]
- H+
H3C
C
OEt
H2
Ethyl acetoacetate from
Claisen condensation of
ethyl acetate.
O
O
C
H3C
_
C
- H+
OEt
O
C
C
H3C
CH
OEt
C3H7
O
H3C
(i) C3H7I, EtO(ii) CH3I, EtO-
CH3
O
O
H3O+
C
C
OEt
Monoalkylation
O
C
C
H3C
C _ C
H3C
C
H
CH3CH2CH2Br
C
CH3I
O
O
1 Eq. NaOEt
C3H7
H3C
O
OEt
C3H7
, - CO2
C
H3C
H
C
H3C
C3H7
Although the reactions discussed above involve several steps, the ability
to exercise precise choice of mono- vs. di-alkylation and the ability to
attach two different alkyl groups to the -carbon makes them
significantly more useful than direct alkylation of the ketone enolate.
Revision: Indirect clean -monoalkylation of ketones via the Claisen
condensation:
O
O
C
C
H3C
C
H2
Na+
1 Eq. NaOEt
O
[Quantitative]
C
OEt
H3C
Claisen condensation
of ethyl acetate
O
_ C
C
OEt
H
CH3CH2CH2Br
N.B. Mono-alkylation only - the
mono-alkylated product is less
acidic and more sterically
hindered than the -ketoester
starting material - cannot be
deprotonated by enolate.
O
C
C
H3C
CH
OEt
C3H7
H3O+
O
CH3CH2CH2Br
O
C
H3C
O
C
H3C
CH2
C3H7

- CO2
CH3
H3C
O
O
C
C
CH
OH
C3H7
The activating effect of the ester group, increases the acidity of the
'doubly -' CH, directing alkylation to that carbon but sterically
inhibiting di-alkylation.
Following removal of the ester group by
hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.
yields the same product as - clean -monoalkylation of acetone.
Some further examples of indirect ketone monoalkylation:
O
O
CO2Et
_
NaOEt
- H+
O
CO2Et
O
_
CO2Et
CO2Et
Br
3-Bromopropene
Allyl bromide
H3O+
O
O
CO2H
, - CO2
[Equivalent to -allylation of
cyclohexanone]
O
O
C
C
H3C
C
H2
O
(i) NaOEt
OEt
(ii) BrCH2CO2Et
C
H3C
O
H
C
C
OEt
CH2CO2Et
Ethyl Bromoacetate
H3O+
O
H3C
C

O
, - CO2
CH2CH2CO2H
C H
H3C  C
O
C
OH
[Equivalent to alkylation of acetone by BrCH2CO2H] CH2CO2H
Malonic Ester Synthesis - A synthesis of -substituted carboxylic
acids - equivalent to clean indirect mono- or di- -alkylation of acetic
acid:
CO2H
CO2Et
H2C
H2C
CO2H
CO2Et
Malonic Acid
CO2Et
H2C
R 1X
HC
CO2Et
R1
C
CO2H
(iii) H3O+, 
Diethylmalonate
aka Malonic Ester
EtO-
R
(i) Base, RX
(ii) Base,
H
CO2Et
_
RR1CHCO2H
CO2Et
MeBr
Me
CH
CO2Et
EtO-
CO2Et
-2
CH CO2H
(i) MeBr; (ii) EtBr
Me
Et
C CO2H
H
O+
(i) H3
(ii) ,
- CO2
CO2Et
Me
C
Et
EtBr
Me
CO2Et
C
CO2Et
_
CO2Et
The CH2 hydrogens in diethylmalonate are 'doubly -' to the two ester
carbonyl groups and therefore have enhanced acidity.
One or two
deprotonation/alkylation steps leads cleanly to monoalkylated or
dialkylated products (compare the -ketoester chemistry just studied)
Hydrolysis of both ester groups gives a -dicarboxylic acid which - like
a -keto carboxylic acid - undergoes rapid decarbonylation to a
monocarboxylic acid. The overall reaction is equivalent (i.e. gives the
same product as) the clean indirect di--alkylation of acetic acid. 
The Knoevenagel Condensation - The 'doubly -' enolate anion of
diethyl malonate behaves as the nucleophile in an aldol-like reaction
with an aldehyde or ketone forming an ,-unsaturated diester.
Following hydrolysis and decarboxylation, the final product is an ,unsaturated carboxylic acid.
Here diethyl malonate acts as a
synthetic equivalent of the enolate anion of acetic acid.
H2C(CO2Et)2 + PhCHO
Mild base
PhCH
C(CO2 Et)2
(i) H3 O+ (ii) , - CO2
PhCH
Piperidine
H2C(CO2 Et)2
H
C
Piperidine =
_
O
H
CO2Et
Ph
OH
H
Š
HC(CO2 Et)2
CO2Et
HC _
O
C
_
C
H
Base
C
Ph
CO2Et
CH
H
C
Ph
CO2Et
CH
CO2Et
-
CO2Et
C
OH
CO2Et
- OH
C
N
H
CO2Et
Ph
H 2O
CO2Et
Ph
CHCO2H
CO2Et
(i) H3 O+
(ii) , - CO2
PhHC
CHCO2H
Tutorial Question:
In the base-catalysed Aldol-Claisen Condensation of a ketone and an
ester the ketone behaves as the nucleophile and the ester behaves as the
electrophile:
O
C
H3C
O
_
CH2 H3C
O_
O
C CH2 C
C
OEt
H3 C
CH
3
OEt
-
- OEt
O
O
C CH2 C
H3C
CH3
Etc.
In the base-catalysed Knoevenagel Condensation of malonic ester and a
ketone the ester behaves as the nucleophile and the ketone behaves as
the electrophile:
CH3
O
C
Ph
CO2 Et
HC _
_
O
H
CO2 Et
C
CO2Et
CH
CO2Et
Ph
H2O
OH
H
C
CO2Et
CH
CO2Et
Ph
Etc.
How do you explain the difference?
Enamines - nitrogen analogues of enols:
OH
C
O
C
H
Enol
C
C
Carbonyl
NH2
C
NH
C
H
C
Enamine
C
Imine
NR2
C
C
Isolable because tautomerism is now impossible
Preparation of 3° enamines - acid-catalysed addition of a secondary
amine to an enolisable ketone:
+
OH
O
HO
H3O+
+
NHMe2
Me2NH
TsOH
Methylene imminium cation
Me
Me
N
Me + Me
N
H
H
O
H
- H2O
Reactivity of enamines:
+
H2O
NMe2
NR2
C
_
C
C
+
NR2
C
Nucleophilic
carbon
-Alkylation of enamines - another synthetic equivalent of clean monoalkylation of ketones:
+
Me2N
Me2N
+
Me2N
_
CH
CH3
3
I
The neutral enamine - unlike the anionic
enolate - is a weak base and does not de-
I
-
H2 O
protonate the mono-alkylated product.
Hence no di-alkylation occurs.
O
CH3
O
Me2NH +
Base/CH3I
Poor control - mono & di-alkylation
Although a multi-step process, ketone alkylation via enamines may be
more efficient than direct alkylation via the enolate.
Special properties of conjugated carbonyl compounds:
Carbonyl compounds in which other multiple bonds are conjugated with
the C-O double bond are significantly more stable than their nonFor this reason ,-unsaturated carbonyl
conjugated isomers.
compounds readily isomerise to the more stable conjugated ,unsaturated isomers via enol (acidic conditions) or enolate (basic
conditions) intermediates:

H2 C
O

C C
H2
H

C
H

H3 C
Catalysis by
-
H+ or OH

C
H

C
H
O
C
H
Acid catalysis:
:
O
H2C
C
H
C C
H2
H2C
H
+
OH
H3C
C
H
C
H
C
H
O
C
H
C
H
H+
C
H
C
H
C
H
C
H
+
OH
_
H2C
- H+
H3C
:OH
H+
C
H
C
H
C
H
-Unsaturated carbonyl compounds have two electrophilic carbon
sites - the carbonyl carbon and the -carbon:
H3 C
C
H
O C +
H
C
H
H3C
Electrophilic
carbon

C C
H
+
C
H
_
O
H
Electrophilic
carbon
Addition reactions tto the C=C or C=O double bond alone are called
'normal' or 1,2 additions:
Y
O
O
2
O
1
C
1
C
C
C
+ X
C
Y
C
X
2
C
or
C
C
C
C
C
X
Y
Addition reactions that involve the conjugated system as a whole are
called 'conjugate additions' or 1,4 additions:
1
Y
O
O
4
C
+
C
C
C
X
Y
C
X
C
C
2
C
3
Note that here '1,2' and '1,4', do not refer to the numbering system for
identifying carbon atoms in the systematic naming of the molecules.
Examples of 1,4 (i.e. conjugate) addition:
O
H2 C
C
H
C
CH3 + HCl
O
ClH2C
CH C
H
CH3
This reaction looks like a 'normal' or 1,2 - although anti-Markownikov addition of HCl to the C-C double bond. However the mechanism
involves acid-catalysed 1,4-addition:
+
OH
O
H 2C
C
H
C
CH3 + H3O+
H2 C
C
H
C
H
C
CH3
OH
OH
ClH2 C
C
CH3
+
H 2C
Cl
C
H
C
CH3
-
O
ClH2C
H
C
H
C
CH3
This apparent contradiction arises because 1,4-addition of HZ to the
C=C-C=O structure yields an enol which then tautomerises to the
corresponding keto form which has the same structure as would be
produced by anti-Markovnikov 1,2-addition to the C=C bond.