Malonic The Ester Synthesis of Substituted Acetic Acids
By a similar sequence of alkylation, hydrolysis, and decarboxylation,
substituted acetic acids may be prepared from diethyl malonate.
malonic ester synthesis
=
=
O
O
EtOCCH2COEt
diethyl malonate
R-CH2COOH
alkylated acetic acid
The Malonic Ester Synthesis
+ R-X
=
OO
EtOCCHCOEt + NaX
R
alkylated malonic ester
OO
HOCCHCOH
R
=
(i) dil. NaOH, heat
(ii) H3O+
=
=
=
hydrolysis
OO
EtOCCHCOEt
R
pKa = 16
enolate anion
(stoichiometric amount)
=
=
=
alkylation
Na+
O- O
EtOCCHCOEt
=
diethyl malonate
(pKa = 12.9)
Na+
O- O
EtOCCHCOEt + EtOH
=
=
=
formation of enolate anion
O
O
EtOCCH2COEt + NaOEt
alkylated malonic acid
decarboxylation
=
=
OO
HOCCHCOH
R
heat (-CO2)
R-CH2COOH
"alkylated acetic acid"
An Example of a Two-Stage Alkylation Scheme
=
OO
EtOCCHCOEt
CH3
=
=
EtOH
=
=
=
O
O
1 eq. NaOEt
EtOCCH2COEt
alkylation
Na+
OO
CH3I
EtOCCHCOEt
=
=
=
=
alkylation
Na+
CO2Et
OO
1 eq. NaOEt
C6H5CH2Cl
O
OC6H5CH2C-CO2Et
EtOCCHCOEt
EtOCCCOEt
EtOH
CH3
CH3
CH3
hydrolysis
CO2H
CO2Et
(i) dil. NaOH, heat
C6H5CH2C-CO2H
C6H5CH2C-CO2Et
+
(ii) H3O
CH3
CH
3
CO2H decarboxylation
180o C
C6H5CH2C-CO2H
(-CO2)
CH3
dialkylated malonic acid
H
C6H5CH2CCO2H
CH3
2-methyl-3-phenylpropanoic acid
Synthesis and Reaction of Enamines:
Alkylation and Acylation
Aldehydes and ketones with enolizable H may be alkylated and
acylated by way of their enamine derivatives.
Imines
Primary amines react with aldehydes and ketones to form imines:
dehydration
OH
R
R-C-NHR''
C=NR'' + H2O
R'
R'
imine
nucleophilic addition
R
R'
C=O + R''-NH 2
1o -amine
tautomerization
If there is an enolizable H in R
or R', an equilibrium exists:
H
=
However, the imine isomer is
more stable than the enamine
just as the ketone isomer is
more stable than the enol.
N
C
R''
R
CH2R'
imine
R
N
C
R''
CHR'
enamine
Secondary Amines Give Only Enamines
nucleophilic addition
2o-amine
O
C
R
R''
R''
=
When a
reacts
with an aldehyde or
ketone with enolizable H:
+
CH2R'
N
R-C-OH
CH2R'
NH
R'''
2o -amine
dehydration in the addition product can only yield an enamine.
R''
R'''
N
R-C-OH
CH2R'
R''
R'''
N
R C=CHR'
R'''
+ H2O
enamine
Enamine formation is catalyzed by acid and promoted
by removing the water as it is formed.
Typical secondary amines used in synthesis enamine are:
O
N
H
N
H
pyrrolidine
piperidine
N
H
morpholine
Enamines are Nucleophiles
Enamines and enols are nucleophiles via the !-position:
:
H-O:
R-C=CHR
+
H-O: R-C CHR
!"
:
=
enamine
R
R-N+ R-C CHR
!"
:
=
R
R-N:
R-C=CHR
enol
Synthetic Applications of Enamines
Examples: the Alkylation and Acylation of Cyclohexanone
enamine formation
=
O
+
H+
N
H
pyrrolidine
N
+ H2O
N-(1-cyclohexenyl)pyrrolidine
Reaction with Benzyl Chloride (C-Alkylation)
:
+
N
N
+ C6H 5CH2Cl
-
Cl
H
CH2C6H 5
an iminium salt
hydrolysis of iminium salt
+
-
O
Cl
N
H
CH2C6H 5
O+
H3
H
CH2C6H 5
+
+
H
H2O
2-benzylcyclohexanone
O Overall C-Alkylation O
CH2C6H 5
N
Cl
H
-
Reaction with Propanoyl Chloride (C-Acylation)
:
N
+
-
Cl
N
H
CCH2CH3
O
O
+ CH3CH2CCl
iminium salt
+
-
Cl
N
H
CCH2CH3
O
O+
H3
H2O
O
H
+ Cl
CCH2CH3 +
N
O
HH
O Overall C-Acylation O
O
CCH2CH3
Chapter 16 and Chapter 18 Key Concepts!
Nucleophilic Additon vs. Acid-Base Reactions!
O
Nu:
O
O
and/or
Nu
1. With Grignard reagents (RMgX) the nuceophilic addition
pathway will dominate.!
2. With alkyl lithium reagents (RLi) a mixture of products can
result.!
3. With LDA and related, strong, non-nucleophilic nitrogen bases,
enolate formation will dominate.!
4. Weakly basic nucleophiles, such as cyanide, favor the addition
product.!
Nucleophilic Additon vs. Acid-Base Reactions!
O
Nu:
O
O
and/or
Nu
1. With hydroxide bases both pathways can occur. Addition
leads to an unstable hydrate (in an unfavorable equilibrium),
so the predominant useful intermediate is the enolate.!
2. With alkoxide bases, both pathways can occur. Addition leads
to an unstable hemiacetal (in an unfavorable equilibrium), so
the predominant useful intermediate is the enolate.!
Nucleophilic Additon vs. Acid-Base Reactions!
O
NuH
H
OH
OH
and/or
Nu
1. Under acidic conditions, the keto-enol tautomerization will
always yield a low concentration of enol form.!
2. Under acidic conditions there will always be some acidactivated carbonyl.!
3. The enol form is a nucleophile and can react with electrophiles
such as Br2 or another equivalent of aldehyde or ketone (aldol).!
4. The acid-activated carbonyl is a great electrophile and can react
with neutral nucleophiles such as alcohols (acetals) and
primary amines (imines).!