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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)
CO2CH2CH3
CH2
CO2CH2CH3
CO2CH2CH3
CH2
CO2CH2CH3
NaCO2CH2CH3
CH
CO2CH2CH3
+ 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.
CO2Et
CH
CO2Et
+ R-XSN2 CO2Et
CH
CO2Et
R
CO2Et
CH
CO2Et
RH2O, H+
heat
CO2H
CH
CO2H
R- CO2
heatCH2CO2HR
C
CH2
O
C
O
OEt
OEt
diethyl malonate
NaC
CH
O
C
O
OEt
OEtNa
RXC
CH
O
C
O
OEt
OEt
RH+,H2Oheat
C
CH
O
C
O
OH
OH
R
heat-CO2
CH2COOHNa
C
C
O
C
O
OEt
OEt
RR'X C
C
O
C
O
OEt
OEt
RH+,H2Oheat
C
C
O
C
O
OH
OH
R-CO2heat
R
CHCOOHR
R'R'R'
CH2COOHR CHCOOHR
R'
The malonate synthesis makes substituted acetic acidswith one or two alkyl groups on the alpha carbon.
for example: synthesis of 4-methylpentanoic acid
CH3CHCH2CH2COOH
CH3
start with diethyl malonate and isobutyl bromide
C
CH2
O
C
O
OEt
OEt
diethyl malonate
NaC
CH
O
C
O
OEt
OEtNa
C
CH
O
C
O
OEt
OEtH+,H2O
heat
heat-CO2
CH3CHCH2Br
CH3
CH3CHCH2
CH3 C
CH
O
C
O
OH
OH
CH3CHCH2
CH3
CH3CHCH2CH2COOH
CH3
Malonate synthesis of 2-methylpentanoic acid
Start with diethyl malonate and methyl bromide and n-propyl bromide.
CH3CH2CH2 CHCOOH
CH3
C
CH2
O
C
O
OEt
OEt
diethyl malonate
NaC
CH
O
C
O
OEt
OEtNa
C
CH
O
C
O
OEt
OEt
H3C
C
C
O
C
O
OEt
OEt
H3C
C
C
O
C
O
OEt
OEt
H3C CH2CH2CH3
CH3Br Na
CH3CH2CH2Br
H+,H2Oheat
-CO2heat
CH3CH2CH2 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.
CO2CH2CH3
CH2
COCH3
CH3CCH2CO2Et
O
C
CH2
O
C
O
CH3
OEt
ethyl acetoacetate
NaC
CH
O
C
O
CH3
OEtNa
RXC
CH
O
C
O
CH3
OEt
RH+,H2Oheat
C
CH
O
C
O
CH3
OH
R
heat-CO2
CH2CCH3
Na
C
C
O
C
O
CH3
OEt
RR'X C
C
O
C
O
CH3
OEt
RH+,H2Oheat
C
C
O
C
O
CH3
OH
R-CO2heat
R
CHCCH3R
R'R'R'
O
O
CH2CCH3R CHCH2CH3R
R'
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
C
CH2
O
C
O
CH3
OEt
ethyl acetoacetate
NaC
CH
O
C
O
CH3
OEtNa
C
CH
O
C
O
CH3
OEtH+,H2O
heat
heat-CO2
CH3CHCH2Br
CH3
CH3CHCH2
CH3 C
CH
O
C
O
CH3
OH
CH3CHCH2
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
C
CH2
O
C
O
CH3
OEtNa
C
CH
O
C
O
CH3
OEtNa
C
CH
O
C
O
CH3
OEt
H3C
C
C
O
C
O
CH3
OEt
H3C
C
C
O
C
O
CH3
OEt
H3C CH2CH2CH3
CH3Br Na
CH3CH2CH2Br
H+,H2Oheat
-CO2heat
CH3CH2CH2 CHCCH3
CH3
O
ethyl acetoacetate
Synthesis of 2,5-hexanedioneCH3CCH2CH2CCH3
O O
C
CH2
O
C
O
CH3
OEt
ethyl acetoacetate
NaC
CH
O
C
O
CH3
OEtNa
C
CH
O
C
O
CH3
OEtH+,H2Oheat
heat-CO2
CH3CCH2Br
O
CH3CCH2
O C
CH
O
C
O
CH3
OH
CH3CCH2
O
CH3CCH2CH2CCH3
O O
Synthesis of 2,4-pentanedioneCH3CCH2CCH3
O O
C
CH2
O
C
O
CH3
OEt
ethyl acetoacetate
NaC
CH
O
C
O
CH3
OEtNa
C
CH
O
C
O
CH3
OEtH+,H2Oheat
heat-CO2
CH3C
O C
CH
O
C
O
CH3
OH
CH3C
O
CH3CCH2CCH3
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 CH2CH2NHCCH2CH2NHCCHCCH2O
O O
OH
CH3
CH3
P O
O
O-P
O
O-
N
NN
N
NH2
O
HO
HHHH
PO
O-
O
O-
Coenzyme A
Acetyl CoA
CH3 C S
O
Malonyl CoA
O C
O
CH2 C
O
S
O
OHOH
HHHH
OP-O
NN
N N
NH2
OO
HO
H
H
H
H
O
P
O
HO O
-O N+
CNH2
O
nicotinamide adenine dinucleotide phosphate NADP+
N
C
O
NH2
H H
NADPH
P-O
O
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
SS
C C
CH3
OCH2
O
C
O-O
CO2
CE
AC
PSSHC
CH2
O
CO
CH3
2NADPH 2NADP+
CE
AC
P
SSHC
CH2
O
CH2
CH3
1
2 3
C
E
AC
P
SS
C C
CH3
OCH2
O
C
O-O
CO2
CE
AC
P
SSHC
CH2
O
CO
CH3
2
CE
AC
P
SS
C C
CH3
OCH
O
C
OH
O
CE
AC
P
SSHC
HC
O
CO
CH3
CO2H
->enolate
nucleo.acylsubstitution
decarboxylation
CE
AC
P
SSHC
CH2
O
CH2
CH3
CE
AC
P
SHS
C
CH2
CH2
CH3
O
malonyl CoA
CE
AC
P
SS
C
CH2
CH2
CH3
O C
CH2
C
O-O
O
CO2
CE
AC
P
SSHC
CH2
C
CH2
O
O
CH2
CH3
4 5 6
-> enolate
nucleophilicacyl substitution
-CO2
CE
AC
P
SSHC
CH2
C
CH2
O
O
CH2
CH3
7
CE
AC
P
SSHC
CH2
CH2
CH2
O
CH2
CH3
2NADPH 2NADP+
CE
AC
PSHS
C
CH2
CH2
CH2
CH2
CH3
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.
Can we directly alkylate carbonyl compounds? Generally speaking, no!
Problems: 1) self-condensation
2) polyalkylation
3) in unsymmetric ketones, both sides or the wrong side!
Approach: place a group on the compound that prevents self-condensation, directs the substitution where wanted and then is easily removed.
Three such approaches:
1) 2-oxazoline synthesis of acids/esters
A. I. Meyers, Colorado State University
2) organoborane synthesis of acids/ketones
H. C. Brown, Purdue University
3) enamine synthesis of aldehydes/ketones
G. Stork, Colombia University
2-oxazoline synthesis of acids/esters
CH2 COH
OR +
H2N C CH3
CH3
CH2HO
2-amino-2-methyl-1-propanol
CH2RO
N+ 2 H2O
n-BuLi
CHRO
NR'XCHR
O
N
R'
EtOH
H2SO4CH C
OEt
OR
R'
2-oxazoline
CH3 COH
O+
H2N C CH3
CH3
CH2HOCH3
O
N+ 2 H2O
n-BuLi
CH2O
NCH2CH3CH2
O
N
H2SO4
CH3CH2Br
H2O
CH3CH2CH2CO2H
2-oxazoline synthesis of butyric acid from acetic acid
Organoborane synthesis of acids/ketones
R3B + BrCH2COCH3, base R—CH2COCH3
bromoacetone alkylacetone
R3B + BrCH2CO2Et, base R—CH2CO2Et
ethyl bromoacetate ethyl alkylacetate
Mechanism for organoborane synthesis
1) :base + CH2BrCOCH3 CHBrCOCH3 + H:base
2) R3B + CHBrCOCH3 R3BCHBrCH2OCH3
3) R B
R
R
CHCOCH3
Br
R B
R
CHCOCH3
R+ Br
4) R2B CHCOCH3
R+ H:base R CH2COCH3 + R2B:base
B-H
9-borabicyclo[3.3.1]nonane
+ RCH=CH2 B CH2CH2R
B-alkyl-9-borabicylo[3.3.1]nonane
R3B
B-H+
B
+ BrCH2CCH3, base CH3CHCH2
CH3
CH2CCH3
O
B
O
B-H+
B CH2CHCH3CH3C CH2
CH3 CH3
BrCH2CO2Et
CH3CHCH2CH2CO2Et
CH3
base
H2O, H+
CH3CHCH2CH2CO2H
CH3
organoborane synthesis of 4-methylpentanoic acid
Enamine synthesis of aldehydes and ketones
1) An aldehyde or ketone is reacted with a secondary amine to form an enamine.
2) The enamine reacts as the nucleophile in an SN2 reaction with an alkyl halide to form an iminium salt.
3) The iminium salt is hydrolyzed with H2O, H+ back to the carbonyl compound which has been alkylated at the alpha position.
C C O
H
+ R'2NH C C
H
OH
N R'
R'
C C N R'
R'
enamine
C C N R'
R'R X
C C N R'
R'RX
SN2
iminium ion
H2O
H+C C O
R
+ R'2NH
The secondary amines commonly used to form the enamine are pyrrolidine or morpholine:
N
H
pyrrolidine
N
O
H
morpholine
O N
HN
ClCH2CH=CH2N Cl
H2O,H+O
CH2CH=CH2
enamine synthesis of 2-allylcyclohexanone
Can we directly alkylate carbonyl compounds? Generally speaking, no!
Problems: 1) self-condensation
2) polyalkylation
3) in unsymmetric ketones, both sides or the wrong side!
Approach: place a group on the compound that prevents self-condensation, directs the substitution where wanted and then is easily removed.
Three such approaches:
1) 2-oxazoline synthesis of acids/esters
A. I. Meyers, Colorado State University
2) organoborane synthesis of acids/ketones
H. C. Brown, Purdue University
3) enamine synthesis of aldehydes/ketones
G. Stork, Colombia University
2-oxazoline synthesis of acids/esters
CH2 COH
OR +
H2N C CH3
CH3
CH2HO
2-amino-2-methyl-1-propanol
CH2RO
N+ 2 H2O
n-BuLi
CHRO
NR'XCHR
O
N
R'
EtOH
H2SO4CH C
OEt
OR
R'
2-oxazoline
Organoborane synthesis of acids/ketones
R3B + BrCH2COCH3, base R—CH2COCH3
bromoacetone alkylacetone
R3B + BrCH2CO2Et, base R—CH2CO2Et
ethyl bromoacetate ethyl alkylacetate
C C O
H
+ R'2NH C C
H
OH
N R'
R'
C C N R'
R'
enamine
C C N R'
R'R X
C C N R'
R'RX
SN2
iminium ion
H2O
H+C C O
R
+ R'2NH
enamine synthesis of aldehydes/ketones
