Lecture Notes
Chemistry 342-2008
Lecture 31
Mukund P. Sibi
Reactions at the Alpha-Carbon of Carbonyl Compounds
Enolates are nucleophilic and undergo reaction with electrophiles. For example, one can
do halogenation under basic conditions. Even a weak base is sufficient for the reaction.
As soon as the enolate is formed, it reacts immediately with the electrophile forming the
product. It is not necessary to form the enolate completely.
O
C
O
NaOH
H
O
Br2
C
H2O
Br
C
+ Br-
carbon nucleophile
It is difficult to control halogenation of ketones under basic conditions. The product halo
compound is more reactive than the starting material. Thus one obtains products with
multiple halogen atoms. The final product in this reaction is a carboxylic acid and a
trihalomethane. The reaction is called the haloform reaction. One can use chlorine,
bromine and iodine as the halogen.
The Haloform Reaction
O
O
NaOH
H
C
H
H
O
Br2
C
H2O
O
Br
H
C
H
Br
Br
C
Br
O
HO
Br
Br
C
Br
OH
O
O
H
+
O
Br
Br
C
Br
Br
+ H C Br Bromoform
Br
O
Enolate Alkylation: Formation of C-C bonds
One of the important modes of reactivity for the enolate is the formation of C-C bonds by
alkylation. The enolate nucleophile can react with alkyl halides in an SN2 reaction. Here
the alkyl halides function as electrophiles.
Enolate Alkylation
O
C
Enolate Ion
+
C X
SN2
O
C
C
+ X-
Alkylating Agent
Since this is an SN2 reaction, there are only a few alkylating agents that can be used.
They need to be primary, allylic or benzylic. Reactions with secondary halides are not
Lecture Notes
Chemistry 342-2008
Lecture 31
Mukund P. Sibi
efficient and tertiary halides do not undergo SN2 substitution. Tosylates, iodides,
bromides, and chlorides can be used as a leaving group.
Relative reactivity of alkylating agents
X
R X
R
Tosylate > I > Br > Cl
allylic ~ benzylic > CH3 > RCH2-
Malonic Ester Synthesis
The hydrogens on alpha carbon of carbonyl compounds are only modestly acidic and
require a strong base for complete deprotonation. On the other hand, the methylene
groups of 1,3-dicarbonyl compounds have pKa from 9-13 and they can be deprotonated
readily using simple inorganic bases. Note from our previous discussion, methylenes
flanked by two carbonyl groups are quite acidic because the negative charge is highly
delocalized. Malonic esters, acetoacetic esters, and malononitriles can be used as the
nucleophile. Malonic esters (pKa = 13) can be alkylated readily using sodium alkoxide as
a base. The monoalkylated malonic ester can be further alkylated with a second
electrophile to provide dialkylated products.
Monoalkylation of malonic esters
H3CO
O
C
O
C
C
H
H
OCH3
NaOCH3
CH3OH
Dimethylmalonate
H3CO
O
C
C
O
C
Na+
OCH3
R X
H
O
O
R
C
C
C
OCH3
H3CO
H
Alkylated malonic ester
Sodio malonic ester
Dialkylation of malonic esters
O
O
R
C
C
H3CO
C
OCH3
H
NaOCH3
CH3OH
H3CO
O
C
C
O
C
Na+
OCH3
R
Sodio malonic ester
R1 X
O
O
R
C
C
C
OCH3
H3CO
R1
Dialkylated malonic ester
The malonic esters can be hydrolyzed readily under aqueous acidic conditions. The esters
are hydrolyzed to the corresponding acids. After this, the diacid undergoes
decarboxylation to furnish a monoacid.
O
O
R
C
C
C
OCH3
H3CO
H
O
O
R
C
C
C
OCH3
H3CO
R1
H3O+
heat
O
O
R
C
C
HO
C
OH
H
H3O+
O
O
R
C
C
HO
C
OH
heat
R1
O
H
C
C
OH
R
H
+ CO2 + 2 CH3OH
O
H
C
C
OH
R
1
R
+ CO2 + 2 CH3OH
Lecture Notes
Chemistry 342-2008
Lecture 31
Mukund P. Sibi
The decarboxylation occurs only with malonic and acetoacetic acids. These compounds
are β-keto acids. The decarboxylation occurs through a cyclic mechanism. For
decarboxylation to occur it is essential that there be a carbonyl group beta to the
carboxylic acid.
H
O
O
!
"
C
C
O
C
OH
H R
H
O
O
!
"
C
C 1
O
C
R
H R
malonic acid
!-Keto acid
Decarboxylation of malonic esters
H
O
C
H3CO
C
H
O
C
R
OCH3
O+
H3
heat
O
O
C
H
Decarboxylation of !-Keto esters
O
C
H3CO
H
C
O
C
H3O+
heat
R1
R
C
O
O
C
OH
-CO2
OH
C
R
C
OH
H
-CO2
OH
R
C 1
C
R
H
R
O
C
R
C
OH
H
H
Carboxylic acid
H
O
C
C
H
O
C
R1
R
R
C
H
H
O
C
R1
Ketone
By applying the malonic ester reaction, one can convert an alkyl halide to a carboxylic
acid. Overall the process adds two extra carbon atoms to the alkyl halides. This reaction
provides a convenient method for the preparation of carboxylic acids from alkyl halides.
H
CO2CH3
C
H
CO2CH3
NaOCH3
+ CH3Br
H
H 3C
C
CO2CH3
H
H3O+
H3C
CO2CH3
C
H 3C
CO2CH3
Br
+
H
CO2H
3 carbon
acid
1 carbon
halide
H
C
NaOCH3
CO2CH3
C
H 3C
CO2CH3
H3O+
C
H 3C
CO2CH3
Br
H
H
C
CO2CH3
NaOCH3
+
CO2CH3
C
CO2CH3
CO2CH3
Br
H3O+
C
H
CO2H
H
CO2H
Lecture Notes
Chemistry 342-2008
Lecture 31
Mukund P. Sibi
Acetoacetic Ester Synthesis
Acetoacetic ester (a β-keto ester) undergoes alkylation similar to malonates. The
alkylated product can be hydrolyzed to furnish a methyl ketone.
Alkylation of Acetoacetic ester
H3CO
O
C
C
H
O
C
H
CH3
NaOCH3
R-X
H3CO
O
C
C
H
O
C
R
CH3
H3O+
heat
!-Keto ester
R
C
H
H
O
C
CH3
Methyl Ketone
Similar to malonic esters, acetoacetic esters can also be dialkylated. The product β-keto
esters can also be hydrolyzed under acidic conditions to produce methyl ketones. As
noted before, alkylation of ketones requires a strong base and anhydrous conditions. In
contrast, the acetoacetic ester method allows for a clever way of enhancing the acidity of
alpha C-H bonds in ketones and the ability to alkylate under simple conditions. Once, the
product is formed, simple hydrolysis gives the alkylated ketones. One important
characteristic of β-ketoester synthesis is its generality. Any β-keto ester with an alpha CH bond can be used. Over all it is a three step process involving (1) enolate formation (2)
alkylation and (3) hydrolysis and decarboxylation.
Alkylation of Acetoacetic ester
H3CO
O
C
C
O
C
H
H
O
H O
CH3
NaOCH3
CH3CH2Br
H3CO
O
C
H
O
NaOCH3
OCH3
C
O
C
CH3
CH2CH3
O
H 3O +
heat
H3O+
OCH3
O
H3CH2C
C
C
CH3
H
H
O
heat
Br
Direct Alkylation of Ketones, Esters, and Nitriles
As illustrated earlier, one can generate an enolate completely by the use of a strong nonnucleophilic base. For example, LDA will deprotonate cyclohexanone readily. LDA is a
strong enough base that it can deprotonate the alpha C-H bonds of esters, lactones, and
nitriles. The resulting enolates can be alkylated with alkylating agents. Aldehydes are too
reactive and the enolate will react with the starting aldehyde very rapidly. The direct
alkylation has some advantage over the acetoacetic ester reaction in that it takes only one
Lecture Notes
Chemistry 342-2008
Lecture 31
Mukund P. Sibi
step. Controlling regiochemistry is an issue with ketones. In the cyclohexanone example
the major product is the 2,6-disubstituted cyclohexanone.
Ketone
O
O
O
H
LDA
CH3
CH3I
THF
O
O
H
CH3
Br
CH3
O
CH3
LDA
O
THF
O
Br
CH3
CH3
Ester
H
H
O
O
O
OCH3
LDA
I
OCH3
H
H
THF
Lactone
O
H
H
O
O
LDA
O
O
Br
H
O
THF
Nitrile
H
C N
LDA
H
THF
C N
H
OCH3
I
C N