CHAPTER 17
Enolates and
Carbanions: Building
Blocks for Organic
Synthesis
1
The Acidity of the α Hydrogens
of Carbonyl Compounds
• Hydrogens on carbons α to carbonyls are
unusually acidic.
2
Why α hydrogen is acidic
(enolate ion)
Extremely strong bases are needed to form the
enolate ion. Such as :
NaNH2
NaH
CH3CH2CH2CH2Li [(CH ) CH] NLi
3 2
2
sodamide Sodium Butyllithium
Lithium
hydride
diisopropylamide
3
(LDA)
A hydrogen alpha to a single carbonyl is
less acidic than a hydroxyl hydrogen
H
CH3CH2
pKa 50
H
O
CH2CCH3
20
H
O
CH2COCH2CH3 CH3CH2O H
16
25
Thus, alkoxide ion is not a good base to form the
enolate ion from acetone or ethyl acetate.
O
CH3COCH2CH3 + -OCH2CH3
-
O
CH2COCH2CH3 + CH3CH2OH
pKa=16
O
CH3COCH2CH3
4
+
-
NH2
-
O
CH2COCH2CH3 +NH3
favored
pKa=35
The α hydrogen of an ester is
less acidic than that of a ketone
O
CH3
C OCH2CH3
O
CH3
+
C OCH2CH3
Ethyl acetate
Major contributor
The ester carbonyl is less able to delocalize the
negative charge of the enolate because the carbonyl
oxygen already carries a partial negative charge.
5
Protons on the α-carbon of β-dicarbonyl
compounds are acidic (pKa = 9-13)
O
O
CH3CCHCCH3
H
acetylacetone
pKa=9
O O
CH3CCCOCH2CH3
HR
Acetoacetic ester
pKa=13
6
O
O
CH3CCHCOCH2CH3
H
Ethyl acetoacetae
pKa=11
O
O
CH3CH2OCCHCOCH2CH3
H
diethyl malonate
pKa=13
The acidity can be explained by resonance
stabilization of the corresponding enolate by
two carbonyl groups
pKa=16
7
Alkoxide is a good base to
form the enolate- no need
for a stronger base.
Nitro and cyanide groups enhance
the acidity of α hydrogen
CH2NO2
H
pKa=9
O
CH3CH2OCCHCN
H
pKa=13
8
NCCHCN
H
pKa= 13
CHCN
H
Alkylation of Malonic Ester
General: Synthesis of Substituted Acetic Acids
++
)
Na
OC
H
H
, H2O
2 5
CH2(CO2C2H5)2 1
RCH(CO2C2H5)2
heat RCH2CO2H
2) RX
Diethyl malonate
CO2
α substituted
acid
(malonic ester)
Example
++
)
Na
OC2H5
H
, H2O
1
CH2(CO2C2H5)2
CH3CH2CH(CO2C2H5)2 heat
2) CH3CH2Br
CO2
9
From RX
CH3CH2CH2CO2H
Mechanism
• Step1: formation of the enolate
10
11
• Step 3: Hydrolysis and Decarboxylation
12
Summary of alkylation of malonic
ester
CH (CO C H )
2
2 2 5 2
malonic ester
1) NaOC2H5
2) RX
H+, H2O
CO
2
RCH(CO2C2H5)2
RCH(CO
H)
RCH2CO2H
2
2
heat
heat
1) NaOC2H5
2) R'X
RC(CO2C2H5)2
R'
13
a diester
a diacid
H+, H2O
RC(CO
H)
2
2
heat
R'
a diacid
An acid
-
CO2
RCHCO2H
heat
R'
An acid
Examples
14
15
• By using two molar equivalents of malonate
anion and a dihalide, the dicarboxylic acid is
obtained
16
• C2 through C5 terminal dihalides can react to
form rings by dialkylation of one molar
equivalent of malonate
17
Alkylation of Acetoacetic ester
• Synthesis of Methyl Ketones
18
• Hydrolysis of the ester and heating of the
resultant β-ketoacid causes decarboxylation
– The product is a substituted acetone derivative
19
• A second alkylation can be performed
20
Summary of alkylation of acetoacetic ester
O
CH3CCH2CO2C2H5
acetoacetic ester
1) NaOC2H5
2) RX
O
+
O
-
O
CH3CCHCO2C2H5 H , H2O CH CCHCO H CO2
3
2
heat
heat CH3CCH2
R
R
R
1) NaOC2H5
a keto acid
a ketone
)
R'X
2
O
O
O
+
CO2
CH3CCCO2C2H5 H , H2O CH3CCCO2H
CH3CCHR'
heat
heat
R R'
R R'
R
21a keto ester
a keto acid
a ketone
example
22
Syntheses Using Alkylation
Reactions
From
malonic ester
From CH3X
CO2H
CH3CH
CO2H
From
malonic ester
From
CH3X
CCH3
CH3CH2CH
CO2C2H5
23
CHCO2H
CH3CH2
From CH3CH2X
O
From CH3CH2X
CH3
From acetoacetic
ester
From
acetoacetic
ester
O
CH2CHCCH3
CH3
From C6H5CH2X
From
CH3X
Example
From
C6H5CH2X
O
From diethyl malonate
CH2CHCOH
From CH3CH2X
CH2CH3
CH2(CO2C2H5)2
1)
-
2)
CH3CH2I
OC2H5
CH3CH2CH(CO2C2H5)2
O
CH2CHCOH
CH2CH3
24
H+, H2O
heat - CO2
)
1 OC2H5
CH2Br
2)
CH3CH2C(CO2C2H5)2
CH2C6H5
Alkylation of a Ketone
NON-CATALYTIC BASES REACT ONCE
one mole
NaH
O
C CH3
THF
α-hydrogens
one mole
_
..
C CH2 + H
O
2
CH3-I
one mole
LDA
THF
O
_
..
C CH2
CH3-I
O
C CH2 CH3
monoalkylation
_
+
: N : Li
CH CH3
H3C CH
25
CH3
CH3
Sodium Hydride
NaH
“LDA”
Lithium Diisopropyl Amide
a strong base
EXAMPLE
26
Alkylation of esters
27
Alkylation and Acylation of
Enamines
• Aldehydes and ketones react with
secondary amines to form enamines.
28
Enamines have a nucleophilic carbon and
are the equivalent of ketone and aldehyde
enolates
29
C-Acylation leads to β-diketones
H2O
30
Enamine alkylation steps
O
1) Enamine
formation
R2CHCR
2) Substitution
+
HN
H+
R
R2C C N
R
R
R'X
R2C C N
+
R2C C N
R'
3) Hydrolysis
R
+
R2C C N
R'
31
R
+
H , H2O
R2C C O
R'
α to C=O
Summary
of enamine
Reactions
α methyl ketone
O
CHC
CHC
1)
CH3I
+
)
H
O,H
2
2
a ketone
1)
NR'2
O
R'2NH
O
CH C
enamine
1)
RCCH2X
+
)
H
O,H
O
2
2
ArCH2X
+
)
H
O,H
2
2
O
1) RCCl
+
2) H , H 2O
32
O
β- diketone
O
CHC
CR
O
CHCH2X
1) CH2
+
)
H
O,H
2
2
O
CHC
CH2CR
α benzyl ketone
CH2Ar
CH3
CH2C
O
CHC
γ- diketone
α allyl ketone
CH2CH CH2
How would you synthesis the following
compound
O
CCHCHO
From propanal
CH3
HN
CH3CH2CHO
CH3CH CH N
+
H
1)
O
CCHCHO
CH3
33
+
O
)
H
O,H
2
2
Cl
ALDOL CONDENSATION
34
The Aldol Condensation
ald
+
ol
O
R CH2 C H
+
base
O
OH
R CH2 C CH C H
H R
an aldol
(β-hydroxyaldehyde)
R CH2 C H
H3O+
aldols easily lose
water to form a
double bond
35
O
- H2O
O
R CH2 CH C C H
R
α,β-unsaturated aldehyde
The Aldol Reaction: The Addition of Enolate
Anions to Aldehydes and Ketones
• Acetaldehyde dimerizes in the presence of
dilute sodium hydroxide at room
temperature
36
Mechanism
37
Examples
O
O
CH3CH2CH2CH + CH3CH2CH2CH
OH
-
OH
O
CH3CH2CH2CHCHCH
CH2CH3
O
O
O
CH
38
+
CH
OH-
OH
CH
CH
Dehydration of the Aldol Product
•The aldol product easily undergo dehydration to an α,βunsaturated aldehyde
•Dehydration is favorable because the product is
stabilized by conjugation of the alkene with the carbonyl
group
β-hydroxy aldehyde
39
Dehydration is Spontaneous if the double
bond is in conjugation with aromatic ring
O
OH
O
CH CH2CH
3-hydroxy-3phenylpropanal
40
spontaneous
CH CHCH
3-phenylprpenal
Ketones Also Give Aldol Condensations
O
OH
C CH
3
C
..
- CH2
NaOH
CH3
CH2
CH
C O
C O
C O
“aldol”
41
C
CH3
-H2O
“CROSSED” ALDOL
CONDENSATIONS
42
• Crossed Aldol Reactions
• Crossed aldol reactions (aldol reactions
involving two different aldehydes) are of little
use when they lead to a mixture of products
43
Practical Crossed Aldol Reactions
• Crossed aldol reactions give one predictable
product when one of the reaction partners has
no α hydrogens
44
Crossed-aldol reactions in which
one partner is a ketone
45
Formation of Rings
α1
α2
O
O
H3C C CH2CH2CH2 C CH3
NaOH
CH3
CH3
OH
CH3
O
- :CH2
O
46
Why don’t α2 hydrogens react ?
O
O
Syntheses Pattern
HO
R CH2 C
(H)
R
β-hydroxy to C=O
O
CH C R
R
(H)
3-hydroxyaldehyde or
ALDOL
3-hydroxyketone
-H2O
R CH2 C
C
R
R
47
O
α,β-unsaturated C=O
C R
2-propen-1-al or
2-propen-1-one
ALDOL
(with loss of H2O)
Syntheses Using Aldol Condensation
O
C6H5C CHCC6H5
CH3
From acetophenone
48
OH
O
CH3CH2CHCHCH
CH3
From prpanal
Knoevenagel Condensation
• Reaction of an aldehyde or a ketone with a
compound hat has a hydrogen α to two activating
groups (C=O or CN). Amine is a catalyst.
O
CH3(CH2)3CH
piperidine
+
CH2(CO2C2H5)2
heat
CH3(CH2)3CH C(CO2C2H5)2
49
+ H2O
More examples
CN
NH4+-O2CCH3
CH2
CO2C2H5
O
+
CN
C
H2O
CO2C2H5
+
O
CH
+
CH2(CO2H)2
NH3
heat
CH CHCO2H
+
50
H2O
+CO2
CLAISEN CONDENSATIONS
51
The Claisen Ester Condensation
General:
The overall reaction involves loss of an a
hydrogen from one ester and loss of ethoxide
from another
Notice that
the base, the solvent and the leaving group
CH3CH2O- Na+, CH3CH2OH, CH3CH2Oall match (this is required in most cases).
52
The Claisen Condensation:
Synthesis of β-Keto Esters
53
Mechanism of Claisen Condensation
54
β-Keto ester
55
Crossed Claisen Condensations
• Crossed Claisen condensations can lead to one
major product when one of the two esters has no
α hydrogen
56
Crossed Claisen Condensation
Between Ketones and Esters
O
COC2H5
+
57
O
CH3CCH3
)
1 OC2H5
+
2) H
O
O
C
CH2CCH3
O
O
O
O
CCH3
)
1 OC2H5
+ C2H5OC(CH2)3CH3
+
)
H
2
CCH2
C(CH2)3CH3
β-diketone
Dieckmann Condensation
A CYCLIC CLAISEN CONDENSATION
58
Syntheses Using Ester
Condensation
Claisen Pattern
2 RCH2CO2C2H5
O
base
RCH2CCHCO2C2H5
R
H+, H2O
heat
a β-keto ester
O
O
RCH2CCHCO2H heat
-
R
a β-keto acid
59
CO2
RCH2CCH2R
a Ketone
Syntheses problems
O
From ethyl
benzoate
O
CH3CH2CH2CCHCO2C2H5
CCHCO2H
CH2CH3
CH2CH3
From ethyl butanoate
From ethyl butanoate
O
From ethyl
benzoate
60
CCH2CH2CH3
From ethyl butanoate
Dieckmann Condensation Pattern
O
O
base
H+, H2O
heat
CO2C2H5
O
CO2H
heat
CO2
CO2C2H5
(CH2)3 or 4
CH2CO2C2H5
base
61
O
O
O
CO2C2H5
H+, H2O
heat
CO2H
heat
CO2
Michael Additions
• A Michael addition involves conjugate addition of
the anion derived from an active hydrogen
compound (e.g., an enolate) to an α,βunsaturated carbonyl compound
62
63
64
Examples
O
O
CH2
CHCH
+
CH2(CO2C2H5)2
1)
NaOC2H5
+
)
H
, H2O
2
O
CH3CH CHCOC2H5
+
CH2(CO2C2H5)2
1)
NaOC2H5
2)
H+, H2O
CH2
CH2CH
CH(CO2C2H5)2
O
CH3CH CH2COC2H5
CH(CO2C2H5)2
H+,H2O
heat
CH3CHCH2CO2H
CH2CO2H
65
-
CO2
heat
CH3CHCH2CO2H
CH(CO2H)2
Michael addition products of malonic
ester and α,β,-unsaturated ester
O
O
RCH CHCOC2H5 + R'CH(CO2C2H5)2 NaOC2H5 RCH CH2COC2H5
R'C(CO2C2H5)2
a triester
H+,H2O
heat
RCHCH2CO2H
R'CHCO2H
66
a diacid
-
CO2
heat
RCHCH2CO2H
R'C(CO2H)2
a triacid
ROBINSON ANNULATION
FORMING RINGS BY COMBINING
CONJUGATE ADDITION WITH AN ALDOL CONDENSATION
METHYL VINYL KETONE (MVK)
67
Michael Addition of Cyclopentanone to MVK
enolate
weak base
MVK
methyl vinyl ketone
..
..
:O
:
-
H
H
C
CH3
- ..
: O-CH
3
..
H
C
C
H
H
NaOCH3
CH3OH
O
:O
O:
.. : O:
..
CH3
H
H-OCH3
..
:O
..
O:
C
CH2 CH2 CH3
- ..
+ : O-CH
3
..
68
can continue
ROBINSON ANNULATION
USES MVK TO BUILD A RING
FROM PREVIOUS SLIDE
O
O
H
C
H
CH3
H
O
NaOCH3
H3O+
(workup)
O
C
CH2 CH2 CH3
CH3OH
Michael
addition
NaOCH3
O
-O
69
O
O
-: CH
2
C
CH2 CH2 O
Annelation
(ring formation)
internal aldol condensation
ANOTHER EXAMPLE
MICHAEL ADDITION + ALDOL CONDENSATION
2
O
ALDOL
C O
1
O
70
O
H3 C
CH
CH2
NaOEt
EtOH
Most acidic set
of hydrogens
MICHAEL
reacts first.
O
Another Example of Robinson
Annulation
71
Summary of Synthesis of
Dicarbonyl Compouds
1. 1,3- dicarbonyl compounds (β)
a. From enamine + acid chloride
O
O
H+, HN
2) RCCl
1)
R
O
+
3) H , H2O
O
b. From Claisen Condensation.
O
RCOR'
72
O
+
1) base
R''CH2COR'
+
2) H
O
O
RCCHCOR'
R''
2. 1,4- Dicarbonyl compounds.
a. From enamine + α-haloketone
O
O
+ HN
)
H
,
1
R''CCH2R'
2) RCCH2Cl
O
R''CCHCH2CR
R'
O
3) H , H2O
+
b. From acetoacetic ester + α-haloketone
O
O
O
R'
C2H5O
73
O
1)
base
2)
RCCH X
OR'
R'
R
C2H5O
O
O
H+, H2O
heat
R
O
3. 1,5-Dicarbonyl compounds
from Michael Addition
O
RCCH CHR'
+
CH2(CO2C2H5)2
O
1)
base
+
)
H
2
RCCH2 CHCH(CO2C2H5)2
R'
4. 1,6-Dicarbonyl componds
By Oxidation of cycolhexene
KMnO4
CO2H
CO2H
74