Alkylation of Carbanions
Carbanions
•
Negatively charged organic species in which carbon carries three bond p
airs and one lone pair, is known as cabanion. it is represented as
• Characteristic of carbanions
– Hybridization and geometry : Alkyl carbanion has three bond pairs and one lone pair. Thus
hybridization is sp3 and geometry is pryamidal.
– There are eight electrons in the outermost orbit of carbanionic carbon hence its octet is co
mplete.
– It behaves as charged nucleophile.
– It is diamagnetic in character because all eight electrons are paired.
– It is formed by heterolytic bond fission.
– It reacts with electrophiles.
Chemistry of carbanions
• Formation of C-C bond is fundamental to organic synthesis.
• Majority of reaction in organic synthesis involves carbanions
intermediates.
• Carbanions are formed when an hydrogen atom attached to
an a-carbon of a carbonyl compound moves to the carbonyl
oxygen
O
OH
KT
Carbonyl
Enol
KT = [enol]/[carbonyl]
Generation of Carbanions by
Deprotonation
• The rate of deprotonation and the stability of the
resulting carbanion are enhanced by the presence of
substituent groups that can stabilize negative charge.
• Several typical examples of proton abstraction equilibria
is shown in scheme 1.1
• The stability of these carbanions is shown in scheme 1.2
Enols and Enolates
O
E+
O
H
O
Enolate
E
carbonyl
O
H
E+
Enol
The acidic hydrogen (a-hydrogen) is abstracted by a base and through an intramo
lecular transfer of a hydrogen, thus an enol is form
Aldehyde, Ketone, and Ester Enolates
 The inductive effect of the carbonyl causes the a-protons to be more
acidic.
 The negative charge of the enolate ion (the conjugate base of the
carbonyl compound) is stabilized by resonance delocalization.
 The pKa of the a-protons of aldehydes and ketones is in the range of 1620
resonance effect
inductive
effect
d+
H
C C
O
ethane
pKa= 50-60
C C
O
acetone
pKa= 19
C C
O
ethanol
pKa= 16
pKa
19
acid
pKa
14
16
9
base
conjugate
base
19
-1.7
(weaker acid) (weaker base)
acid
pKa
base
conjugate
base
conjugate
acid
15.7
(weaker acid) (weaker base)
pKa
(stronger base) (stronger acid)
19
acid
conjugate
acid
base
9
(stronger acid) (stronger base)
(stronger base) (stronger acid)
_
conjugate
base
conjugate
acid
15.7
(weaker base) (weaker acid)
Lithium diisopropylamide (LDA): a super strong base
- +
N -H + H3CCH2CH2CH2 Li
diisopropylamine
pKa= 36
Li
+
H3CCH2CH2CH3
LDA
pKa= 60
pKa= 19
(stronger acid) (stronger base)
pKa= 25
(stronger acid)
N
(stronger base)
(weaker base)
pKa= 36
(weaker acid)
(weaker base)
pKa= 36
(weaker acid)
Strong base, but it is sufficiently bulky so as to be relatively nonnucleophilic.
Lithium, sodium, potassium of hexamethyldisilazane, [(CH 3)2Si]2NH
Aprotic solvent: ether, tetrahydrofurane (THF), dimethoxyethane (DME)
Regioselectivity and Stereoselectivity in
Enolate Formation
The products are isomers
of each other
Enolate Regiochemistry – deprotonation of unsymmetrical
ketones.
More substituted enolate:
thermodynamically more stable
Less substituted enolate: less
hindered, formed faster kinetic
ally
The more substituted (thermodynamic) enolate is formed under
reversible conditions (tBuO- K+, tBuOH).
The less substituted (kinetic) enolate is formed under irreversible
conditions (LDA, THF, -78°C).
 Ideal conditions for kinetic control of enolate formation are those in which
deprotonation is rapid, quantitative, and irreversible.
 Lithium is better counterion than sodium or potassium for regioselective
generation of the kinetic enolate, since lithium maintains a tighter coordination
at oxygen and reduces the rate of proton exchange.
 Aprotic solvents are essential because protic solvents permit
enolate equilibrium by reversible protonation-deprotonation,
which gives rise to the thermodynamically controlled enolate
composition.
 Excess ketone also catalyzes the eqiulibriation by proton
exchange.
 Conditions of kinetic control usually favor the less substituted
enolate.
 At equilibrium, thermodynamic controlled conditions, the more
substituted enolate is usually the dominant species.
Other Means of Generating Enolates
Driving force: very strong Si-F bond energy (142 kcal/mol)
Alkylation of Nucleophilic Carbon
Intermediates
 C-C bond formation is the basis for the
construction of the molecular frame work of
organic molecules by synthesis.
 One of fundamental processes for C-C bond
formation is a reaction between a nucleophilic
carbon and an electrophilic one.
 Reaction of C-nucleophile (enolate ions, imine
anions, enamines) with alkylating agents
Alkylation of Enolates
SN2 Displacement
Primary halide, sulfonates, allyl benzyl > sec halide >> t-alkyl halide (only elimination)
The rate of cyclization: intramolecular cyclization for
w-haloalkyl malonate esters
3 : 4 : 5 : 6 = 650,000 : 1 : 6500 : 5
b-Ketoacid and malonic acid undergoes facile decarboxylation.
Therefore, ethyl acetoacetate and diethyl malonate are synthetic equivalents
of acetone and acetic acid.
Dilithium derivatives of acetoacetic acid is also a synthetic equivalent of
acetone enolate. Hydrolysis step is unnecessary, and decarboxylation can
be done directly.
Alkylation also can be carried out using silyl enol ethers by reaction with
fluoride ion such as tetraalkylammonium fluoride salts.
Generation and Alkylation of Dianions
Second deprotonation
First deprotonation
Medium Effect in theAlkylation of Enolates
DMF and DMSO are effective in enhancing the reactivity of enolate anions, polar aprotic solvent.
Oxygen versus Carbon as the Site ofAlkylation
Enolate anions are ambient nucleophile.
O-alkylation, when the enolate is dissociated.
HMPA
• Hexamethylphosphoramide, often abbreviated HMP
A,
• It is a phosphoramide (an amide of phosphoric acid)
with the formula [(CH3)2N]3PO.
• This colorless liquid is a useful reagent in organic sy
nthesis.
Leaving-group effects on the C- or O-alkylation: hard-soft-acid-base(HSAB)
Oxygen is harder than carbon.
Oxygen leaving group such as sulfonate and sulfate are harder: reacts at
the hard oxygen site of the enolate.
The amount of O-alkylation is maximized by use of an alkyl sulfate or alkyl
sulfonate in a polar aprotic solvent. And that of C-alkylation is maximized
by an alkyl halide in a less polar solvent such as THF or DME.
With 5-membered rings, colinearity cannot be achieved easily.. The
transition state for O-alkylation involves an oxygen lone-pair orbital
and is less strained than the transition state for C-alkylation.
Strong preference for O-alkylation in Phenoxide ions because C-alkylation
disrupts aromatic conjugation
Phenoxides undergo O-alkylation in solvent such as DMSO, DMF, ethers, and
alcohols. However, in water and trifluoroethanol, extensive C-alkylation
occurs.
Alkylation of Aldehyde, Esters, Amides, and Nitriles
Alkylation of aldehyde enolate is not very common because of facile adol condensation
by base. But rapid, quantitative formation of enolate avoids this: KNH2 in NH3, KH in THF.
Alkylation of simple esters requires a strong base: weak base such as alkoxide
promotes condensation reaction. Strong base: LDA, hesamethyldisilylamide (KHMDS).
Enolate of N-acyl oxazolidinones
Diastereomeric
Mixture: 95/5
Easily separated
Further
hydrolysis
or alcoholysis
Further
hydrolysis
or alcoholysis
Final product would be 99% enantiomeric purity.
The Nitrogen Analogs of Enols and EnolatesEnamines and ImineAnions
Imine is the nitrogen analog of ketone and aldehyde.
Removed by
azeotropic
distillation
From secondary amine, vinylamine or enamine is formed.
Strong dehydrating reagents to drive the reaction to completion: TiCl 4 or
Triethoxysilane. N-Timethylsilyl derivative: strong affinity of silicone for
oxygen than nitrogen.
The b-carbon atom of an enamine is a nucleophilic site because of conjugation
With the nitrogen atom.
Alkylation of enamine
Pyrrolidine enamine
Preferred enamine
Aserious nonbonded repulsion (A 1,3 strain) destabilizes isomer 7.
Because of the predominance of the less substituted enamine, alkylation
occur primarily at the less substituted a carbon.
trans
Imine can be deprotonated at the carbon by strong base to give the
nitrogen analog of enolates: imine anions or metalloenamines.
Isoelectronic and structurally analogous to both enolaes and allyl anions and
can also be called azaallyl anions.
In toluene it exists as dimeric form, but at high THF concentration, the monomer
Is favored.
Just as enamines are more nucleophilic than enols, imine anions are more
nucleophilic than enolates and react efficiently with alkyl halides.
The nitrogen substituent R’ is syn to the double bond are the more stable.
more stable
Lithiated ketimines  room temperature: thermodynamic composition
is established. less substituted isomer: the most stable structure.
Table 1.3 entry 2 : a) chelation of the methoxy group with the lithium ion
b) The interaction of the lithium with the bromide
c) the steric effect of the benzyl group
Hydrazones are more stable than alkylimines.
Kinetically deprotonated
Enantioselective synthesis of carboxylic acid derivative
Alkylation of Carbon Nucleophile by Conjugate
Addition (Michael reaction)
Acatalytic amount of base is use: thermodynamic control of enolate formation
W
Electrophile
W
Nucleophile: amine, alkoxide, sulfide anions
Common nucleophile: b-ketoester, maolonate esters.
Fluoride ion is an effective catalyst for Michael additions involving acidic
carbon compounds: excess use of fluoride because of formation of [F-H-F-]
Acetoacetic Ester Synthesis
The b-keto ester products of a Claisen condensation or Dieckmann cyclization
can be hydrolyzed to the b-keto acid and decarboxylated to the
Ketone.
Similarly, b-diesters can be hydrolyzed to the b-dicarboxylic acid
s and decarboxylated to the carboxylic acid (malonic acid synth
esis – Ch. 20.11).
Acetoacetic Ester Synthesis - The anion of ethyl acetoacetate ca
n be alkylated using an alkyl halide (SN2). The product, a b-keto
ester, is then hydrolyzed to the b-keto acid and decarboxylated to
the ketone.
O
H3C
C
EtO
C
CO2Et + RH2C-X
H H
ethyl acetoacetate
EtOH
alkyl
halide
Na+
O
C
CO2Et
H3C
C
RH2C H
_
EtO Na+,
EtOH
HCl, D
O
O
C
CO2H
H3C
C
RH2C H
- CO2
H3C
C
C
CH2R
H H
ketone
R'H2C-X
O
O
O
C
C
H3C
C
OEt
R'H2C CH2R
HCl, D
O
C
C
H3C
C
OH
R'H2C CH2R
O
- CO2
H3C
C
C
CH2R
H CH2R'
An acetoacetic ester can undergo one or two alkylations to give
an a-substituted or a-disubstituted acetoacetic ester
The enolates of acetoacetic esters are synthetic equivalents to
ketone enolates
acetone
pKa = 19
b-Keto esters other than ethyl acetoacetate may be used. The
products of a Claisen condensation or Dieckmann cyclization
are acetoacetic esters (b-keto esters)
20.11: The Malonic Acid Synthesis.
CO2Et
CO2Et
diethyl
malonate
Et= ethyl
Na+
EtO
+
RH2C-X
EtO2C
EtOH
C
CO2Et
HCl, D
HO2C
EtO Na+,
EtOH
C
HO2C
CO2Et
O
C
C
carboxylic
acid
C
CO2H
-CO2
CH2R
CH CO2H
CH2R'
RH2C CH2R'
RH2C CH2R'
H
RH2C-CH2-CO2H
R'H2C-X
HCl, D
EtO2C
-CO2
RH2C H
RH2C H
alkyl
halide
C
CO2H
carboxylic
acid
O
+ EtO
OEt
H H
H
C
C
+
OEt
EtOH
pKa= 16
H
ethyl acetate
pKa= 25
O
O
EtO
C
C
C
+ EtO
OEt
H H
diethyl malonate
pKa= 13
EtO
O
O
C
C
C
H
+
OEt
EtOH
pKa= 16
Summary:
Acetoacetic ester synthesis: equivalent to the alkylation of an
ketone (acetone) enolate
Malonic ester synthesis: equivalent to the alkylation of a
carboxylic (acetic) acid enolate
20.12: Alkylation of chiral Enolates (please read)
Chiral Auxiliaries
Enolization and Enol Content
Tautomers: isomers, usually related by a proton transfer,
that are in equilibrium.
Keto-enol tautomeric equilibrium lies heavily in favor of the
keto form.
C=C
C-O
O-H
DH° = 611 KJ/mol
380
426
C=O
C-C
C-H
DH° = -88 KJ/mol
Enolization is acid- and base-catalyzed
DH° = 735 KJ/mol
370
400
a Halogenation of Aldehydes and Ketones
 a-proton of aldehydes and ketones can be replaced with
a -Cl, -Br, or -I (-X) through the acid-catalyzed reaction
with Cl2 , Br2 , or I2 , (X2) respectively.
 The reaction proceeds through an enol.
O
O
X2, H-X
H
H
X
H
X= Cl, Br, I
+ H-X
a,b-unsaturated ketones and aldehydes:
a -bromination followed by elimination
O
O
CH3 Br2, CH3CO2H
CH3
Br
O
(H3C)3CO- K+
E2
CH3
Why is one enol favored over the other?
OH
O
OH
CH3
H+
CH3
CH3
The Haloform Reaction. In the base promoted reaction, the produ
ct is more reactive toward enolization and resulting in further a-ha
logenation of the ketone or aldehyde. For methyl ketone, an a,a,
a -trihalomethyl ketone is produced.
a-Halogenation of Carboxylic Acids:
The Hell-Volhard-Zelinsky Reaction.
Mechanism of a-halogenation goes through an acid bromide
intermediate. An acid bromide enolizes more readily than a
carboxylic acid. Mechanism is analogous to the a-halogenation
of aldehydes and ketones
The a-halo carboxylic acid can undergo
substitution to give a-hydroxy and a amino acids.
Some Chemical and Stereochemical Consequences
of Enolization (please read)
Effects of Conjugation in ab-Unsaturated Aldehydes
and Ketones. ab-Unsaturated carbonyl have a
conjugated C=C
R= H, ab-unsaturated aldehyde= enal
R H, ab-unsaturated ketone= enone
Conjugation of the -electrons of the C=C and C=O is a
stabilizing interaction
Conjugate Addition to ab-Unsaturated Carbonyl Compounds.
The resonance structures of an ab-unsaturated
ketone or aldehyde suggest two sites for nucleophilic addition;
the carbonyl carbon and the b-carbon
1,2 vs 1,4-addition ab-unsaturated ketone and aldehydes
Organolithium reagents, Grignard reagents and
LiAlH4 react with ab-unsaturated ketone and
aldehydes at the carbonyl carbon. This is referred
to as 1,2-addition.
Organocopper reagents, enolates, amines, thiolates, and cyani
de react at the b-carbon of ab-unsaturated ketone and aldehyd
es. This is referred to a 1,4-addition or conjugate addition.
 When a reaction can take two possible path, it is said to be
under kinetic control when the products are reflective of the
path that reacts fastest.
 The reaction is said to be under thermodynamic control
when the most stable product is obtained from the reaction
 In the case of 1,2- versus 1,4 addition of an abunsaturated carbonyl, 1,2-addition is kinetically favored and
1,4-addition is thermodynamically favored.
NOTE: conjugation to the carbonyl activates the b-carbon tow
ards nucleophilic addition. An isolated C=C does not normally
react with nucleophiles
Addition of Carbanions toab-Unsaturated Carbonyl
Compounds: The Michael Reaction.
The conjugate addition of an enolate ion to an ab-unsaturated
carbonyl. The Michael reaction works best with enolates of
b-dicarbonyls.
electrophile
nucleophile
This Michael addition product can be decarboxylated.
The product of a Michael reaction is a 1,5-dicarbonyl compound,
which can undergo a subsequent intramolecular aldol reaction
to give a cyclic ab-unsaturated ketone or aldehyde. This is
known as a Robinson annulation.
Conjugate Addition of Organocopper Reagents to
ab-Unsaturated Carbonyl Compounds
Recall from the preparation of organocopper reagents
2 Li(0)
R-X
R-Li
+
Dialkylcopper lithium: (H3C)2CuLi
LiX
pentane
Divinylcopper lithium: (H2C=CH)2CuLi
ether
2 R2Li +
CuI
R2CuLi + LiI
diorganocopper reagent
(cuprate, Gilman's reagent)
O
H3C
(H3C)2CuLi
O
C6H13
C6H13
O
O
O
O
(H2C=CH)2CuLi
O
O
O
O
Ph2CuLi
H3C
H3C
H 3C
CH3
H3C
Diarylcopper lithium: Ar2CuLi
Ph
CH3
ab-unsaturated ketones and
aldehydes react with diorganocopper
reagents to give 1,4-addition products
(C-C bond forming reaction)
Synthetic Applications of Enamines
Reaction of a ketone with a 2°amines gives an enamine
Enamines are reactive equivalents of enols and enolates and
can undergo a-substituion reaction with electrophiles. The enami
ne (iminium ion) is hydrolyzed to the ketone after alkylation.
Reaction of enamine with ab-unsaturated ketones (Michael
reaction).
Enamines react on the less hindered side of unsymmetrical ketones
Organic Synthesis
Robert B. Woodward (Harvard): 1965 Nobel Prize in Chemistry
"for his outstanding achievements in the art of organic synthesis"