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 CO2CH2CH3
Na
CH2 CH + Na+ + H2
CO2CH2CH3 CO2CH2CH3
3. The enolate can be used as the nucleophile in an SN2
reaction with a 1o or CH3 alkyl halide.

CO2Et SN2 CO2Et

CH + R-X R CH
CO2Et CO2Et

4. Upon hydrolysis, the substituted malonic acid will

decarboxylate when heated.
CO2Et H O, H+ CO2H
2 - CO2
R CH R CH R CH2CO2H
heat heat
CO2Et CO2H

5. Product is a carboxylic acid derived from acetic acid.

 O O O O
C OEt C OEt C OEt C OH
Na RX H+,H2O
CH2 Na CH R CH R CH
heat
C OEt C OEt C OEt C OH
O O O O
diethyl malonate
heat
-CO2
Na
R CH2COOH

O O O
C OEt R'X C OEt C OH
H+,H2O -CO2
R C R C R' R C R' R CHCOOH
heat heat
C OEt C OEt C OH R'
O O O
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 O CH3
C OEt C OEt CH3CHCH2Br
Na Na CH
CH2
C OEt C OEt
O O
diethyl malonate

O O
CH3 C OEt CH3 C OH
H+,H2O
CH3CHCH2 CH CH3CHCH2 CH
heat
C OEt C OH
O 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 O O O
C OEt C OEt CH Br C OEt C OEt
Na 3 Na
CH2 Na CH H3C CH H3C C
C OEt C OEt C OEt C OEt
O O O O
diethyl malonate

CH3CH2CH2Br

O
CH3 C OEt
-CO2 H+,H2O
CH3CH2CH2 CHCOOH H3C C CH2CH2CH3
heat heat
C OEt
O
Acetoacetate synthesis of ketones.
1. Ethyl acetoacetate has acidic alpha-hydrogens.

CO2CH2CH3 O
CH2 CH3CCH2CO2Et
COCH3

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 O O O
C OEt C OEt C OEt C OH
Na RX H+,H2O
CH2 Na CH R CH R CH
heat
C CH3 C CH3 C CH3 C CH3
O O O O
ethyl acetoacetate
heat
-CO2
Na
O
R CH2CCH3
O O O
C OEt R'X C OEt C OH O
H+,H2O -CO2
R C R C R' R C R' R CHCCH3
heat heat
C CH3 C CH3 C CH3 R'
O O O
The acetoacetate synthesis makes substituted acetones
with one or two alkyl groups on the alpha carbon.

O O
R CH2CCH3 R CHCH2CH3
R'

for example: synthesis of 5-methyl-2-hexanone

CH3 O
CH3CHCH2CH2CCH3

start with ethyl acetoacetate and isobutyl bromide

 O O CH3
C OEt C OEt CH3CHCH2Br
Na Na CH
CH2
C CH3 C CH3
O O
ethyl acetoacetate

O O
CH3 C OEt CH3 C OH
H+,H2O
CH3CHCH2 CH CH3CHCH2 CH
heat
C CH3 C CH3
O 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 n-

propyl bromide.
O O O O
C OEt C OEt CH Br C OEt C OEt
Na 3 Na
CH2 Na CH H3C CH H3C C
C CH3 C CH3 C CH3 C CH3
O O O O
ethyl acetoacetate

CH3CH2CH2Br

O
CH3 C OEt
-CO2 H+,H2O
CH3CH2CH2 CHCCH3 H3C C CH2CH2CH3
heat heat
O C CH3
O
 O O
Synthesis of 2,5-hexanedione
CH3CCH2CH2CCH3

O O O
C OEt C OEt CH3CCH2Br
Na Na CH
CH2
C CH3 C CH3
O O
ethyl acetoacetate

O O
O C OEt O C OH O O
H+,H2O heat
CH3CCH2 CH CH3CCH2 CH CH3CCH2CH2CCH3
heat -CO2
C CH3 C CH3
O O
 O O
Synthesis of 2,4-pentanedione
CH3CCH2CCH3

O
O O H3C C using the carbanion
in a nucleophilic acyl
C OEt C OEt Cl
Na substitution
CH2 Na CH
C CH3 C CH3
O O
ethyl acetoacetate

O O
O C OEt O C OH O O
H+,H2O heat
CH3C CH CH3C CH CH3CCH2CCH3
heat -CO2
C CH3 C CH3
O O
Biological Synthesis of “Fatty” Acids.

Enzyme = ‘fatty acid synthase”

(multifunctional enzyme)

Condensing Enzyme (CE)

Acyl Carrier Protein (ACP)
 NH2
Coenzyme A
N N

O O CH3 O O N N
HS CH2CH2NHCCH2CH2NHCCHCCH2O P O P O O
OHCH3 O- O- H H
H H
O H
O P O-
O-
Acetyl CoA

O
CH3 C S

Malonyl CoA

O O
O C CH2 C S
biological oxidation/reduction

O H H O
C C
NH2 NH2

-O N+ N
-O P O O
O H H
HO P O HOH OH H
O NADPH
H
HO H
O O
-O P O H NADPH is a biological reducing agent
H N N
O-
NADP+ is a biological oxidizing agent
N NH2
N

nicotinamide adenine dinucleotide phosphate

NADP+
 ACP = acyl carrier protein
ACP CE = condensing enzyme
CE

SH SH
acetyl CoA
malonyl CoA
1
CO2 2NADPH 2NADP+

ACP

ACP
ACP

CE

CE
CE

2 3
S S SH S SH S
O C C O C O C O
CH3 CH2 CH2 CH2
C O O C CH2
O- CH3 CH3
 CO2

ACP
ACP

CE
CE
2
S S SH S
O C C O C O
CH3 CH2 CH2
C O O C
O- CH3

->enolate decarboxylation
ACP
CE

ACP
S S
nucleo.acyl CE
SH S
O C C O substitution C O
CH3 CH HC CO2H
C O O C
OH CH3
 malonyl CoA
CO2

ACP
ACP

ACP

ACP
CE
CE

CE

CE
4 5 6
SH S S SH S S SH S
C O O C O C C O C O
CH2 CH2 CH2 CH2 CH2
CH2 CH2 CH2 C O C O
CH3 CH3 CH3 O- CH2
CH2
CH3
-> enolate

-CO2
nucleophilic
acyl substitution
 2NADPH 2NADP+
malonyl CoA
ACP

ACP

ACP
CE

CE

CE
7 8 9
SH S SH S S SH
C O C O O C
CH2 CH2 CH2
C O CH2 CH2
CH2 CH2 CH2
CH2 CH2 CH2
CH3 CH3 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.
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

CH3
O
H2N C CH3 N
R CH2 C + R CH2 + 2 H2O
OH HO CH2
O
2-amino-2-methyl-1-propanol 2-oxazoline
n-BuLi

O EtOH N R'X N
R CH C R CH R CH
R' OEt H2SO4 R' O O
2-oxazoline synthesis of butyric acid from acetic acid

CH3
O
H2N C CH3 N
CH3 C + CH3 + 2 H2O
OH HO CH2
O

n-BuLi

N CH3CH2Br N
CH3CH2 CH2 CH2
O O

H2SO4 H2O

CH3CH2CH2CO2H
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

R R
3) R B CHCOCH3 R B CHCOCH3 + Br
R Br R

R
4) R2B CHCOCH3 + H:base R CH2COCH3 + R2B:base
 R3B

+ RCH=CH2
B-H B CH2CH2R
9-borabicyclo[3.3.1]nonane B-alkyl-9-borabicylo[3.3.1]nonane

+
B-H B

O CH3 O
B + BrCH2CCH3, base CH3CHCH2 CH2CCH3
organoborane synthesis of 4-methylpentanoic acid

CH3 CH3
+
B-H CH3C CH2 B CH2CHCH3

BrCH2CO2Et
base

CH3 H2O, H+ CH3

CH3CHCH2CH2CO2H CH3CHCH2CH2CO2Et

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 + R'2NH C C OH C C N R'
H H N R' R'
R' enamine

C C N R'
R' H2O
C C N R' C C O
R X +
SN2 H R
R R'
X
iminium ion + R'2NH
The secondary amines commonly used to form the
enamine are pyrrolidine or morpholine:

N
N
H
H
pyrrolidine
morpholine
enamine synthesis of 2-allylcyclohexanone

O N N Cl
N
H ClCH2CH=CH2

O
H2O,H+
CH2CH=CH2
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

CH3
O
H2N C CH3 N
R CH2 C + R CH2 + 2 H2O
OH HO CH2
O
2-amino-2-methyl-1-propanol 2-oxazoline
n-BuLi

O EtOH N R'X N
R CH C R CH R CH
R' OEt H2SO4 R' O O
Organoborane synthesis of acids/ketones

R3B + BrCH2COCH3, base  R—CH2COCH3

bromoacetone alkylacetone

R3B + BrCH2CO2Et, base  R—CH2CO2Et

ethyl bromoacetate ethyl alkylacetate
enamine synthesis of aldehydes/ketones

C C O + R'2NH C C OH C C N R'
H H N R' R'
R' enamine

C C N R'
R' H2O
C C N R' C C O
R X +
SN2 H R
R R'
X
iminium ion + R'2NH