Transcript Document

Carbanions II
Carbanions as nucleophiles in SN2 reactions with alkyl
halides.
a) Malonate synthesis of carboxylic acids
b) Acetoacetate synthesis of ketones
c) 2-oxazoline synthesis of esters/carboxylic acids
d) Organoborane synthesis of acids/ketones
e) Enamine synthesis of aldehydes/ketones
Malonate synthesis of carboxylic acids.
1. Diethyl malonate has acidic alpha-hydrogens
CO2CH2CH3
CH2
CO2CH2CH3
2. When reacted with sodium metal, the ester is converted
into its conjugate base (an enolate anion)
CO2CH2CH3
CH2
CO2CH2CH3
Na
CO2CH2CH3
+
+
Na
+ H2
CH
CO2CH2CH3
3. The enolate can be used as the nucleophile in an SN2
reaction with a 1o or CH3 alkyl halide.
CO2Et
SN2
+ R-X
CH
CO2Et
CO2Et
R CH
CO2Et
4. Upon hydrolysis, the substituted malonic acid will
decarboxylate when heated.
CO2H
CO2Et H O, H+
- CO2
2
R CH
R CH2CO2H
R CH
heat
heat
CO2H
CO2Et
5.
Product is a carboxylic acid derived from acetic acid.
O
C OEt
CH2
C OEt
O
Na
O
C OEt
Na CH
C OEt
O
RX
O
C OEt
R CH
C OEt
O
H+,H2O
heat
diethyl malonate
O
C OH
R CH
C OH
O
heat
-CO2
Na
R CH2COOH
O
C OEt R'X
R C
C OEt
O
O
C OEt
R C R'
C OEt
O
H+,H2O
heat
O
C OH
R C R'
C OH
O
-CO2
heat
R CHCOOH
R'
The malonate synthesis makes substituted acetic acids
with one or two alkyl groups on the alpha carbon.
R CH2COOH
R CHCOOH
R'
for example: synthesis of 4-methylpentanoic acid
CH3
CH3CHCH2CH2COOH
start with diethyl malonate and isobutyl bromide
O
C OEt
CH2
C OEt
O
Na
O
C OEt
Na CH
C OEt
O
CH3
CH3CHCH2Br
diethyl malonate
CH3
CH3CHCH2
O
C OEt
CH
C OEt
O
H+,H2O
heat
CH3
CH3CHCH2
O
C OH
CH
C OH
O
heat
-CO2
CH3
CH3CHCH2CH2COOH
Malonate synthesis of 2-methylpentanoic acid
CH3
CH3CH2CH2 CHCOOH
Start with diethyl malonate and methyl bromide and n-propyl
bromide.
O
C OEt
CH2
C OEt
O
Na
O
C OEt CH Br
3
Na CH
H3C
C OEt
O
O
C OEt
CH
C OEt
O
Na
O
C OEt
H3C C
C OEt
O
diethyl malonate
CH3CH2CH2Br
CH3
CH3CH2CH2 CHCOOH
-CO2
heat
H+,H2O
heat
O
C OEt
H3C C CH2CH2CH3
C OEt
O
Acetoacetate synthesis of ketones.
1. Ethyl acetoacetate has acidic alpha-hydrogens.
CO2CH2CH3
CH2
COCH3
O
CH3CCH2CO2Et
2. When reacted with sodium metal, the ester is converted
into its conjugate base (an enolate anion).
3. The enolate can be used as the nucleophile in an SN2
reaction with a 1o or CH3 alkyl halide.
4. Upon hydrolysis, the substituted acetoacetic acid will
decarboxylate when heated.
5. Product is a ketone derived from acetone.
O
C OEt
Na
CH2
C CH3
O
O
C OEt
RX
Na CH
C CH3
O
O
C OEt
R CH
C CH3
O
H+,H2O
heat
ethyl acetoacetate
heat
-CO2
O
R CH2CCH3
Na
O
C OEt R'X
R C
C CH3
O
O
C OEt
R C R'
C CH3
O
O
C OH
R CH
C CH3
O
H+,H2O
heat
O
C OH
-CO2
R C R'
heat
C CH3
O
O
R CHCCH3
R'
The acetoacetate synthesis makes substituted acetones
with one or two alkyl groups on the alpha carbon.
O
R CH2CCH3
O
R CHCCH3
R'
for example: synthesis of 5-methyl-2-hexanone
CH3
O
CH3CHCH2CH2CCH3
start with ethyl acetoacetate and isobutyl bromide
O
C OEt
Na CH
C CH3
O
O
C OEt
Na
CH2
C CH3
O
CH3
CH3CHCH2Br
ethyl acetoacetate
CH3
CH3CHCH2
O
C OEt
CH
C CH3
O
H+,H2O
heat
CH3
CH3CHCH2
O
C OH
CH
C CH3
O
heat
-CO2
CH3
O
CH3CHCH2CH2CCH3
Acetoacetate synthesis of 3-methyl-2-hexanone
CH3
CH3CH2CH2 CHCCH3
O
Start with ethyl acetoacetate and methyl bromide and npropyl bromide.
O
C OEt
Na
CH2
C CH3
O
O
C OEt CH Br
3
Na CH
H3C
C CH3
O
O
C OEt
CH
C CH3
O
Na
O
C OEt
H3C C
C CH3
O
ethyl acetoacetate
CH3CH2CH2Br
CH3
CH3CH2CH2 CHCCH3
O
-CO2
heat
H+,H2O
heat
O
C OEt
H3C C CH2CH2CH3
C CH3
O
Synthesis of 2,5-hexanedione
O
C OEt
Na
CH2
C CH3
O
O
C OEt
Na CH
C CH3
O
O
O
CH3CCH2CH2CCH3
O
CH3CCH2Br
ethyl acetoacetate
O
CH3CCH2
O
C OEt
CH
C CH3
O
H+,H2O
heat
O
CH3CCH2
O
C OH
O
O
heat
CH
CH3CCH2CH2CCH3
-CO2
C CH3
O
Synthesis of 2,4-pentanedione
O
C OEt
Na
CH2
C CH3
O
O
C OEt
Na CH
C CH3
O
O
O
CH3CCH2CCH3
O
H3C C
Cl
using the carbanion
in a nucleophilic acyl
substitution
ethyl acetoacetate
O
O C OEt
CH3C CH
C CH3
O
H+,H2O
heat
O
CH3C
O
C OH
O
O
heat
CH
CH3CCH2CCH3
-CO2
C CH3
O
Biological Synthesis of “Fatty” Acids.
Enzyme = ‘fatty acid synthase”
(multifunctional enzyme)
Condensing Enzyme (CE)
Acyl Carrier Protein (ACP)
NH2
Coenzyme A
N
O
O CH3
O
O
HS CH2CH2NHCCH2CH2NHCCHCCH2O P O P O
OHCH3
OO-
N
H
O
H
H
H
O
H
O P OO-
N
N
Acetyl CoA
CH3
O
C S
Malonyl CoA
O
O
O C CH2 C S
biological oxidation/reduction
O
C
NH2
N+
-O
-O P O
O
H
H
O
H
HO P O HOH OH
O
H
HO H
O
O
-O P O H
H
N
N
ON
H O
C
H
NH2
N
nicotinamide adenine dinucleotide phosphate
NADP+
NH2
N
NADPH
NADPH is a biological reducing agent
NADP+ is a biological oxidizing agent
ACP
CE
ACP = acyl carrier protein
CE = condensing enzyme
SH SH
1
acetyl CoA
malonyl CoA
3
ACP
SH S
C O
CH2
O C
CH3
CE
ACP
CE
ACP
CE
2
S S
O C C O
CH3 CH2
C O
O-
2NADP+
2NADPH
CO2
SH S
C O
CH2
CH2
CH3
CO2
ACP
CE
ACP
CE
2
SH S
C O
CH2
O C
CH3
S S
O C C O
CH3 CH2
C O
O->enolate
nucleo.acyl
substitution
ACP
CE
ACP
CE
S S
O C C O
CH3 CH
C O
OH
decarboxylation
SH S
C O
HC CO2H
O C
CH3
malonyl CoA
CO2
S
O C
CH2
CH2
CH3
S
C O
CH2
C O
O-
ACP
S SH
O C
CH2
CH2
CH3
CE
ACP
SH S
C O
CH2
CH2
CH3
CE
ACP
CE
ACP
CE
5
4
6
SH S
C O
CH2
C O
CH2
CH2
CH3
-> enolate
-CO2
nucleophilic
acyl substitution
2NADPH
2NADP+
malonyl CoA
ACP
CE
ACP
CE
ACP
CE
SH S
C O
CH2
C O
CH2
CH2
CH3
9
8
7
SH S
C O
CH2
CH2
CH2
CH2
CH3
S SH
O C
CH2
CH2
CH2
CH2
CH3
Overall:
step 1) malonyl CoA and acetyl CoA transfer the acetyl
and malonate to the carrier enzyme (CE) and acyl carrier protein
(ACP) respectively.
step 2) enolate carbanion from malonate (ACP)
nucleophilic acyl substitution on the acetyl (CE) followed by
decarboxylation.
step 3) reduction of the ketone to a hydrocarbon.
step 4) transfer of the carboxylate from CE ACP to CE.
step 5) malonyl CoA transfers malonate to the carrier
enzyme.
step 6) enolate from malonate…etc.
Biological synthesis of fatty acids is analogous to the
malonate synthesis of carboxylic acids. The enolate
carbanion from malonate acts as a nucleophile in a
nucleophilic substitution on the acetyl-CE followed by
decarboxylation. Each series puts the three carbon malonate
on the ACP and then decarboxylates the substitution product
resulting in lengthening the carbon chain by two carbons at a
time. Naturally occuring fatty acids are even numbered
carboxylic acids.