1.
2.
3.
The malonic ester synthesis
The acetoacetic ester synthesis
Direct alkylation of ketones, esters and nitriles

Relative acidity of selected organics
Structure
O
CH
3
C O H
O O
CH
3
CC H
2
CCH
3
O O
CH
3
CC H
2
COCH
3
O O
CH
3
OCC H
2
COCH
3 pKa
5
9
11
13
These compounds are MORE ACIDIC than CH
3
CH
2
OH (pKa = 16);
NaOCH
2
CH
3 can deprotonate them.

Relative acidity of selected organics
Structure
O
C H
3
CCl
O
C H
3
CH
O
C H
3
CC H
3 pKa
16
17
19
These compounds are SLIGHTLY LESS ACIDIC than CH
3
CH
2
OH;
NaOCH
2
CH
3 would result in only a small amount of deprotonation.

Relative acidity of selected organics
Structure
O
C H
3
COCH
3 pKa
25
C H
3
C N 25
N H
3
35
R
2
N H 40
These compounds are MUCH LESS ACIDIC than CH
3
CH
2
OH; to deprotonate the top two, a base such as the R
2
N anion must be used.

Acidity of b -dicarbonyl compounds
A base removes a proton a to both carbonyl groups:
O O
C
H
C
C
H
OCH
2
CH
3
O
C
O
C
C
H
+ CH
3
CH
2
O H
Resonance stabilizes the resulting anion:
O
C
O
C
C
H
O
C
O
C
C
H
O
C
O
C
C
H

General mechanism for alkylation
The anion attacks the carbon bearing a leaving group:
O
C
O
C
C
H
R X
R X
O O
C
R
C
C
H
+ X
A second equivalent of base can remove the second proton :
O O
C
C
R
C
H
OCH
2
CH
3
O
C
R
C
O
C
+ CH
3
CH
2
O H

Introduction of a second alkyl group:
This anion can be alkylated by a second alkyl halide
O O
C
R
C
C
R' X
R' X
O O
C
R
C
C
R'
+ X

Hydrolysis and Decarboxylation
O O
CH
3
CH
2
O
C
R
C
C
H
OCH
2
CH
3 a substituted malonic ester
HO
O O
C
R
C
C
H
OH
OH, heat followed by H
3
O or, H
3
O, heat
HO
O
H
O
C
R
C
C
H
O
H
3
O, heat
HO
O O
C
R
C
C
H
OH
O
HO
C
H
C
R
+
H
O
C
O
HO
O
C
H
C
R
H
O
C
H
HO C
H
R a substituted acetic acid

Hydrolysis and Decarboxylation
CH
3
O O
C
R
C
C
H
OCH
2
CH
3 a substituted acetoacetic ester
OH, heat followed by H
3
O or, H
3
O, heat
CH
3
O O
C
R
C
C
H
OH CH
3
O
H
O
C
R
C
C
H
O
H
3
O, heat
CH
3
O O
C
R
C
C
H
OH
CH
3
O
C
H
C
R
+
H
O
C
O
CH
3
O
C
H
C
R
H
O
C
H
CH
3
C
H
R a substituted acetone

Overall Process, single substitution, using abbreviations
O O
EtOCCH
2
COEt
O O
CH
3
CCH
2
COEt
1. Na OEt
2. R Br
3. H
3
O,
+ 
1. Na OEt
2. R Br
3. H
3
O,
+ 
O
R CH
2
COH
O
R CH
2
CCH
3

Overall Process, double substitution, using abbreviations
O O
EtOCCH
2
COEt
1. Na OEt
2. R Br
3. Na OEt
4. R' Br
5. H
3
O,
+ 
O
R CHCOH
R'
O O
CH
3
CCH
2
COEt
1. Na OEt
2. R Br
3. Na OEt
4. R' Br
5. H
3
O,
+ 
O
R CHCCH
3
R'

Forming a ring that includes the a -carbon
O O
CH
3
C C H
2
COEt
1. Na OEt
2. BrCH
2
CH
2
CH
2
CH
2
Br
3. Na OEt
4. H
3
O,
+ 
CH
2
CH
2
O
C HCCH
3
CH
2 CH
2
Substituted acetic acids having a ring that includes the a
-carbon can be synthesized similarly using diethyl malonate:
O O
EtOC C H
2
COEt
1. Na OEt
2. BrCH
2
CH
2
CH
2
CH
2
CH
2
Br
3. Na OEt
4. H
3
O,
+ 
CH
2
CH
2
O
C HCOH
CH
2
CH
2
CH
2
5- or 6-membered rings can be made using a 4- or 5-carbon alkyl dihalide

Direct alkylation of ketones, esters, and nitriles (but NOT aldehydes)
O
C
C H
3
1. Li N(CH(CH
3
)
2
)
2
(lithium diisopropylamide, LDA)
O
C
C H
2
CH
3
2. CH
3
I
O
CH
3
C H
2
COCH
3
1. Li N(CH(CH
3
)
2
)
2
(lithium diisopropylamide, LDA)
2. CH
3
CH
2
I
O
CH
3
C H COCH
3
CH
2
CH
3
CH
3
CH
2
C H
2
C N
1. Li N(CH(CH
3
)
2
)
2
(lithium diisopropylamide, LDA)
2. CH
3
I
CH
3
CH
3
CH
2
C H C N