Enolates Lithium in Organic Synthesis
The extent to which a carbonyl compound with an !-H is converted
to its enolate anion depends on the acidity of the !-H and the
strength of the base.
+ B:-
?
OC-C
:
=
=
OH
C-C
O
CH3CCH3 + HO-
=
OCH3C-CH2
pKa = 20
weaker acid
stronger base
weaker base
+ B-H
+
H2O
pKa = 15.7
stronger acid
Preparation of Stoichiometric Amounts of Enolate Anions
In the 1970s, it was found that nitrogen bases derived from highly
branched secondary amines are powerful bases but poor
nucleophiles. Stoichiometric amounts of enolate anions could be
prepared by reactions as shown below:
pKa = 20
stronger acid
Li+
OCH3C-CH2
:
=
O
CH3CCH3
Li+
CH3
-:
100%
N CH
+
CH
CH3
CH3
CH3
H
N:
+
i-Pr
Pr-i
pKa = 38
weaker base
weaker acid
enolate anion diisopropylamine
stronger base
lithium diisopropylamide
("LDA")
The lithium amides may be prepared by reacting the secondary
amine with a stoichiometric amount of an alkyl lithium (such as
butyl or methyl) in ethyl ether or tetrahydrofuran at -78oC.
100%
ether
-78oC
CH3CH2CH2CH2Li +
(CH3) 2CH CH(CH3)2
pKa = 38
-
:
H
N:
N: Li+
+ CH3CH2CH2CH3
(CH3) 2CH CH(CH3)2
LDA
pKa > 50
Note: The conjugate base of the amine is called an "amide." Do
not confuse this name with the acid derivative called an amide.
Other hindered secondary "amide" bases:
:
-
N: CH3
CH
CH3
CH3
Li+
N: CH3
CH3
:
Li+
CH3
lithium cyclohexylisopropylamide
lithium 2,2,6,6-tetramethylpiperidide
Note: Hindered "amides" are strong bases, but poor nucleophiles.
C-Alkylation
Reaction of an enolate anion with alkyl halides usually occurs by
way of c-alkylation.......reaction at the carbanionic (nucleophilic)
center of the enolate anion.
!R-C CHR' + R''CH2-X
enolate anion
O
RCCHCH2R'' + X
R'
=
!O
alkylated ketone
The bonding changes are seen more easily
with the resonance structure below:
:
=
via
HH
:O: RC CHR' + C X
R''
Note: All the usual limitations
of the SN2 reaction apply.
Regioselective Formation of Enolate Anions
Unsymmetrical ketones can form two possible enolate anions:
B:
- CH3
B-H
I
O
=
CH3
-O
B:
O-
CH3
-
B-H
2-methylcyclohexanone
II
Enolate anion I is thermodynamically more stable because of the
stabilizing influence of the methyl group on the carbon-carbon
double bond, as illustrated by the resonance structures below.
CH3
H
CH3
II
:O:
-H
:
I (more stable)
:O:
=
=
CH3 -
:
CH3
:O:
:
:
:O:
Thermodynamic versus Kinetic Control
of the C-Alkylation Reaction
B:- CH3
B-H
I
O
=
CH3
-O
B:
-
CH3
O-
B-H
2-methylcyclohexanone
II
Under reaction conditions that allow an equilibrium to be established
(HO-/H2O), enolated anion I dominates. But under nonequilibrating
conditions (powerful base in aprotic solvent), enolate anion II often
dominates because it is formed faster (kinetic control). The hydrogen
removed is sterically more accessible, and it is more acidic. Enolate
anion II is called the kinetic enolate.
Formation and Reaction of the Kinetic Enolate
The kinetic enolate is preferentially formed by reacting the ketone
with a sterically hindered base (such as lithium diisopropylamide,
LDA) in an ether solvent (dimethoxyethane, DME).
:O:
:
Li+
H + :N
CH(CH3)2
DME, 0o C
H
CH
CH3 CH3
:
=
H
CH3
O
CH3
H kinetic
enolate
Direct Alkylation of Kinetic Lithium Enolates
LDA
CH3
alkylation
C6H5CH2Br
CH3
O
=
=
CH3
O
- Li+
O
H
CH2C6H 5
DME, 0oC
Remember, one full equivalent
of anion enolate is formed.
kinetic enolate
C-alkylation product
(stereochemistry not shown)
Lithium Enolates in Intramolecular Condensations
LDA
=
=
=
O
O
CH3CCH2CH2CCH 3
-+
O Li
O
CH3CCH2CH2C=CH2
kinetic enolate
=
Intramolecular Condensation
- Li+
O
O
CH3CCH2CH2C=CH2
- Li+
O
CH3CCH2CH2
CH2 C=O
=O
HO
CH3
H3O+
=O
Li+ -O
CH3
=
=
!-Dicarbonyl Compounds:
O
O
-C-CH2-C!"
This group of compounds includes:
=
!-keto esters
O
O
ROCCH2COR
=
=
=
O
O
RCCH2COR'
malonic esters
These compounds are widely used in organic synthesis because of
the stability of the anion formed by loss of the relatively acidic
enolizable H:
=
=
=
:O: :O:
-C-C-Cresonance stabilized enolate anion
:
pKa~ 9-11
~
+
B:-
=
=
=
:O: :O:
-C-C-CH
:O: :O:
-C=C-C:
:
:O: :O:
-C-C=C-
Bases such as alkoxides react completely with
!-dicarbonyl compounds to produce stoichiometric
quantities of enolate anions in solution.
!" O
-C
O !"
C-
C
!"
enolate anion hybrid
The synthetic importance of these enolate anions derives
from the participation of the nucleophilic carbanion in a
variety of carbon-carbon bond forming condensation reactions.
Facile Decarboxylation of !-keto Acids
A second feature built into many synthetic applications of !-keto
esters is the facile decarboxylation of the corresponding !-keto acids:
O
-C-C-CO2H
!-keto acid
heat
O
-C-C-H + CO2
=
!-keto ester
hydrolysis
=
=
O
-C-C-CO2R
ketone
The Acetoacetic Ester Synthesis of Substituted Acetones
A synthetic sequence starting from ethyl acetoacetate is a standard
way to prepare methyl ketones (substituted acetones). It is called
the acetoacetic ester synthesis.
Synthetic Overview
=
=
=
OR
OR
OH
hydrolysis
alkylation
CH3C-C-CO2C2H5
CH3C-C-CO2H
CH3C-C-CO2C2H5
H
H
H
alkylation
=
OR
CH3C-C-H
R'
dialkylated methyl
ketone
OR
CH3C-C-H
H
=
decarboxylation
OR
CH3C-C-CO2C2H5
R'
=
=
OR
hydrolysis
CH3C-C-CO2H
R'
decarboxylation
alkylated methyl
ketone
A More Detailed General Synthetic Scheme
+
O - Na
CH3C-CH-CO2C2H 5 + EtOH
=
:
=
O
CH3C-CH2-CO2C2H 5 + NaOEt
(one full equivalent)
pKa = 10.7
RX
alkylation
O
CH3C-CH-CO2C2H 5 + NaX
R
=
=
O
CH3C-CH2R + CO2
decarboxylation
dilute NaOH/H2O
hydrolysis
100oC
acidification
H3O +
O
CH3C-CH-CO2- Na+
R
=
=
O
CH3C-CH-CO2H
R
CH
=
3
CH3
Decarboxylation of
OH
C=O
(-CO2)
C
H
the !-keto acid
H
C
C
occurs by way of the
CO
R
R
H
enol:
O
enol
CH3
C=O
CH2 R
ketone
Two-Stage Alkylation: An Example
NaOEt
EtOH
CH3I
decarboxylation
OCH3
CH3CCCO2H
CH2CH3
hydrolysis
(i) dil NaOH/heat
(ii) H3O+
acidification
OCH3
CH3CCCO2C2H 5
CH2CH3
=
3-methyl-2-pentanone
100o C
alkylation
=
=
O
CH3CCHCH2CH3
CH3
O Na+
CH3CCCO2C2H 5
CH2CH3
=
=
=
O
O
(i) NaOEt/EtOH
CH3CCH2CO2C2H5
CH3CCHCO2C2H5
(ii) CH3CH2Br
CH2CH3
alkylation
Acylation of Enolate Anions
The enolate anions derived from acetoacetic esters react with acylating
reagents such as acyl chlorides and acid anhydrides. Because these
reagents react with ethanol and ethoxide ion, the syntheses typically use
sodium hydride (NaH) as a base to form the enolate anions in aprotic
sovents such as dimethylformamide (DMF) or dimethyl sulfoxide
(DMSO).
The Acylation of Ethyl Acetoacetate
=
pKa = 10.7
=
=
=
O
O
CH3CCH2COC 2H5 + NaH DMF or DMSO
Na+
O-O
CH3CCHCOC2H5
+ H2
=
O
RCCl acylation
=
(iii) heat, -CO2
OO
CH3CCHCOC2H5 + NaCl
CR
O
=
a !-diketone
(i) dil. NaOH, heat
(ii) H3O+
=
=
=
O
O
CH3CCH2CR
acylation product