carbanions ii carbanions as nucleophiles in s n 2 reactions with alkyl halides
DESCRIPTION
Carbanions II Carbanions as nucleophiles in S N 2 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 - PowerPoint PPT PresentationTRANSCRIPT
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
2. When reacted with sodium metal, the ester is converted into its conjugate base (an enolate anion)
CO2CH2CH3CH2CO2CH2CH3
CO2CH2CH3CH2CO2CH2CH3
Na CO2CH2CH3CHCO2CH2CH3
+ Na+ + H2
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 malonic acid will decarboxylate when heated.
5. Product is a carboxylic acid derived from acetic acid.
CO2EtCHCO2Et
+ R-XSN2 CO2Et
CHCO2Et
R
CO2EtCHCO2Et
RH2O, H+
heat
CO2HCHCO2H
R- CO2
heatCH2CO2HR
CCH2
O
CO
OEt
OEt
diethyl malonate
NaCCH
O
CO
OEt
OEtNa RX
CCH
O
CO
OEt
OEtR
H+,H2Oheat
CCH
O
CO
OH
OHR
heat-CO2
CH2COOHNa
CC
O
CO
OEt
OEtR
R'X CC
O
CO
OEt
OEtR H+,H2O
heat
CC
O
CO
OH
OHR
-CO2heat
R
CHCOOHRR'
R'R'
CH2COOHR CHCOOHRR'
The malonate synthesis makes substituted acetic acidswith one or two alkyl groups on the alpha carbon.
for example: synthesis of 4-methylpentanoic acid
CH3CHCH2CH2COOHCH3
start with diethyl malonate and isobutyl bromide
CCH2
O
CO
OEt
OEt
diethyl malonate
NaCCH
O
CO
OEt
OEtNa
CCH
O
CO
OEt
OEtH+,H2Oheat
heat-CO2
CH3CHCH2BrCH3
CH3CHCH2
CH3 CCH
O
CO
OH
OHCH3CHCH2
CH3
CH3CHCH2CH2COOHCH3
Malonate synthesis of 2-methylpentanoic acid
Start with diethyl malonate and methyl bromide and n-propyl bromide.
CH3CH2CH2 CHCOOHCH3
CCH2
O
CO
OEt
OEt
diethyl malonate
NaCCH
O
CO
OEt
OEtNa
CCH
O
CO
OEt
OEtH3C
CC
O
CO
OEt
OEtH3C
CC
O
CO
OEt
OEtH3C CH2CH2CH3
CH3Br Na
CH3CH2CH2Br
H+,H2Oheat
-CO2heatCH3CH2CH2 CHCOOH
CH3
Acetoacetate synthesis of ketones.
1. Ethyl acetoacetate has acidic alpha-hydrogens.
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.
CO2CH2CH3CH2COCH3
CH3CCH2CO2EtO
CCH2
O
CO
CH3
OEt
ethyl acetoacetate
NaCCH
O
CO
CH3
OEtNa RX
CCH
O
CO
CH3
OEtR
H+,H2Oheat
CCH
O
CO
CH3
OHR
heat-CO2
CH2CCH3
Na
CC
O
CO
CH3
OEtR
R'X CC
O
CO
CH3
OEtR H+,H2O
heat
CC
O
CO
CH3
OHR
-CO2heat
R
CHCCH3RR'
R'R'O
O
CH2CCH3R CHCCH3RR'
The acetoacetate synthesis makes substituted acetoneswith one or two alkyl groups on the alpha carbon.
for example: synthesis of 5-methyl-2-hexanone
CH3CHCH2CH2CCH3
CH3
start with ethyl acetoacetate and isobutyl bromide
O O
O
CCH2
O
CO
CH3
OEt
ethyl acetoacetate
NaCCH
O
CO
CH3
OEtNa
CCH
O
CO
CH3
OEtH+,H2Oheat
heat-CO2
CH3CHCH2BrCH3
CH3CHCH2
CH3 CCH
O
CO
CH3
OHCH3CHCH2
CH3
CH3CHCH2CH2CCH3
CH3 O
Acetoacetate synthesis of 3-methyl-2-hexanone
Start with ethyl acetoacetate and methyl bromide and n-propyl bromide.
CH3CH2CH2 CHCCH3
CH3
O
CCH2
O
CO
CH3
OEtNa
CCH
O
CO
CH3
OEtNa
CCH
O
CO
CH3
OEtH3C
CC
O
CO
CH3
OEtH3C
CC
O
CO
CH3
OEtH3C CH2CH2CH3
CH3Br Na
CH3CH2CH2Br
H+,H2Oheat
-CO2heat
CH3CH2CH2 CHCCH3
CH3
O
ethyl acetoacetate
Synthesis of 2,5-hexanedioneCH3CCH2CH2CCH3
O O
CCH2
O
CO
CH3
OEt
ethyl acetoacetate
NaCCH
O
CO
CH3
OEtNa
CCH
O
CO
CH3
OEtH+,H2Oheat
heat-CO2
CH3CCH2BrO
CH3CCH2
O CCH
O
CO
CH3
OHCH3CCH2
OCH3CCH2CH2CCH3
O O
Synthesis of 2,4-pentanedioneCH3CCH2CCH3
O O
CCH2
O
CO
CH3
OEt
ethyl acetoacetate
NaCCH
O
CO
CH3
OEtNa
CCH
O
CO
CH3
OEtH+,H2Oheat
heat-CO2
CH3CO C
CH
O
CO
CH3
OHCH3C
OCH3CCH2CCH3
O
H3C CCl
O
O
using the carbanionin a nucleophilic acylsubstitution
Biological Synthesis of “Fatty” Acids.
Enzyme = ‘fatty acid synthase”
(multifunctional enzyme)
Condensing Enzyme (CE)
Acyl Carrier Protein (ACP)
HS CH2CH2NHCCH2CH2NHCCHCCH2OO O
OH
CH3
CH3
P OO
O-PO
O-
N
NN
N
NH2
O
HO
HHHH
POO-
O
O-
Coenzyme A
Acetyl CoA
CH3 C SO
Malonyl CoA
O CO
CH2 CO
S
O
OHOH
HHHH
OP-O
NN
N N
NH2
OO
HO
H
H
H
HOPO
HO O
-O N+
CNH2
O
nicotinamide adenine dinucleotide phosphate NADP+
N
CO
NH2
H H
NADPH
P-OO
O-NADPH is a biological reducing agent
NADP+ is a biological oxidizing agent
biological oxidation/reduction
CE
AC
P
SHSH
ACP = acyl carrier proteinCE = condensing enzyme
acetyl CoAmalonyl CoA
CE
AC
P
SSC C
CH3
OCH2
O
CO-
O
CO2
CE
AC
PSSHCCH2
O
COCH3
2NADPH 2NADP+
CE
AC
P
SSHCCH2
O
CH2CH3
1
2 3
C
E
AC
P
SSC C
CH3
OCH2
O
CO-
O
CO2
CE
AC
P
SSHCCH2
O
COCH3
2
CE
AC
P
SSC C
CH3
OCH
O
COH
O
CE
AC
P
SSHC
HCO
COCH3
CO2H
->enolate
nucleo.acylsubstitution
decarboxylation
CE
AC
P
SSHCCH2
O
CH2CH3
CE
AC
P
SHSCCH2CH2CH3
O
malonyl CoA
CE
AC
P
SSC
CH2CH2CH3
O CCH2CO-
O
O
CO2
CE
AC
P
SSHCCH2CCH2
O
O
CH2CH3
4 5 6
-> enolate
nucleophilicacyl substitution
-CO2
CE
AC
P
SSHCCH2CCH2
O
O
CH2CH3
7
CE
AC
P
SSHCCH2CH2CH2
O
CH2CH3
2NADPH 2NADP+
CE
AC
PSHS
CCH2CH2CH2CH2CH3
O
8 9
malonyl CoA
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.