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A library of the enol and enolate mediated carbonyl
compound reactions:
O
Intermolecular a-alkylation
and acetoacetic and malonic ester
synthesis
via enolate anions
Chapters 22 and 23
Intramolecular a-alkylation
Favorskii rearrangement
via enolate anions
extra
O
CH3X
a
CO2H
OH-
O
X
a
CO2CH3
CH3OO
Intermolecular a-halogenation
and haloform reaction
via enols and enolate anions
Chapters 22
a
O
a
X2
X
a
A library of the enol and enolate mediated carbonyl
compound reactions:
Self-condensation
Self and mixed Aldol and Claisen
via enols and enolate anions
Chapter 23
O
OH
-
O
OH
H
a
H
O
O
O
H
OH-
+
O
OHa
+ H3CH2CO
O
OCH3
O
OCH2CH3
O
OCH3
O
a
H
H
a
O
OHOCH2CH3
H3CH2CO
O
OCH2CH3
A library of the enol and enolate mediated carbonyl
compound reactions:
Intramolecular condensation
Dieckmann
via enolate anions
Chapter 23
O
O
a
O
O
O
OH-
CO2Et
The α Position
 The carbon next to the carbonyl group is designated
as being in the α position
 Electrophilic substitution occurs at this position
through either an enol or enolate ion
Enols and enolate anions behave as nucleophiles
and react with electrophiles because the double
bonds are electron-rich compared to alkenes
Part A: Keto–Enol Tautomerism
 A carbonyl compound with a hydrogen atom on its a carbon rapidly
equilibrates with its corresponding enol
 Compounds that differ only by the position of a moveable proton are
called tautomers
 The enol tautomer is usually present to a very small extent and cannot
be isolated, but is formed rapidly, and serves as a reaction
intermediate
1H-NMR
spectrum of neat 2,4-pentanedione
H
O
O
O
3.61 ppm
2.22 ppm
O
5.52 ppm
2.05 ppm
Acid Catalysis of Enolization
 Brønsted acids catalyze keto-enol tautomerization by
protonating the carbonyl and activating the α protons
Base Catalysis of Enolization
 Brønsted bases
catalyze keto-enol
tautomerization
 The hydrogens on
the α carbon are
weakly acidic and
transfer to water is
slow
 In the reverse
direction there is
also a barrier to the
addition of the
proton from water to
enolate carbon
General Mechanism of Addition to Enols
 When an enol reacts with an
electrophile the intermediate
cation immediately loses the -OH
proton to give an a-substituted
carbonyl compound.
O
O
a
a
O
a
O
a
a
H
a-Halogenation of Aldehydes and
Ketones
 Aldehydes and ketones can be halogenated at their α
positions by reaction with Cl2, Br2, or I2 in either the
acidic or basic solutions.
Mechanism of AcidCatalyzed Electrophilic
Substitution
Mechanism of Acid-Catalyzed Electrophilic Substitution
O
O
Br
CF3CO2H
H
O
O
1.
CF3CO2-
+
HO2CCF3
+
fast
H
2.
H
O
O
H
+
C
H
H
H
CF3CO2-
C
fast
enol
H
+
CF3CO2H
3.
H
O
OH
+
Br
Br
CH2Br
+
Br
slow
H
4.
O
O
Br
CH2Br
+
Br
fast
+ HBr
α-Bromoketones Undergo Facile Elimination
Reaction to Yield α,b-unsaturated Carbonyl
Compounds for 1,4-addition Reactions.
a-Bromination of Carboxylic Acids:
The Hell–Volhard–Zelinskii Reaction
 Carboxylic acids do not react with Br2.
 Unlike aldehydes and ketones, they are
brominated by a mixture of Br2 and PBr3
Mechanism of the Hell–Volhard–Zelinskii Reaction
 PBr3 converts -CO2H to –COBr, which can enolize
and add Br2
Part B: Enolate Ion Formation
 Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa
of ethane = 60)
 The conjugate base of a ketone or aldehyde is an enolate ion - the
negative charge is delocalized onto oxygen
Two Reactions Sites on Enolates
 Reaction on oxygen yields an enol derivative
 Reaction on carbon yields an a-substituted carbonyl
compound
Reagents for Enolate Formation
 Ketones are weaker acids than the OH of alcohols but can be
deprotonated to a small extent by an alkoxide anion (RO-) to form the
enolate. This is sufficient in reactions with strong electrophiles such as
Br2.
 Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C3H7)2] are
strong enough to form large amounts of the enolates required for aalkylation reactions.
 LDA is generated from butyllithium (BuLi) and diisopropylamine (pKa = 40)
and is soluble in organic solvents.
Mechanism of Base-Promoted
Electrophilic Halogenation
1. The base abstracts the a-H from the keto tautomer.
2. The resulting enolate anion reacts with an electrophile.
O
O
X
Br2
a
a
CH3O-Na+
Mechanism
O
O
H
CH3O-
C
H
H
H
fast
+
CH3OH
H
O
O
slow
H
+
H
Br
Br
Br
+
Br-
The Haloform Reaction
 Base-promoted reaction occurs through an enolate anion intermediate.
 Monohalogenated products are themselves rapidly turned into enolate
anions and further halogenated until the trihalo compound is formed
from a methyl ketone.
 The product is cleaved by hydroxide with -CX3 as a leaving group.
a-Alkylation of Enolate Ions via Lithium
Enolate Salts
 Even unreactive ketones will be easily
deprotonated with LDA to give stable, isolable
lithium enolate salts.
a-Alkylation of Enolate Ions
 Alkylation occurs when the nucleophilic enolate ion reacts with the
electrophilic alkyl halide or tosylate and displaces the leaving group
 SN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate
 R should be primary or methyl and preferably should be allylic or benzylic
 Secondary halides react poorly, and tertiary halides don't react at all because of
competing elimination
Mechanism of Base-Promoted
Electrophilic Alkylation
O
O
1. THF / [(CH3)2CH]2N-Li+
a
2. CH3OTs
Mechanism
O
O
H
H
O
[(CH3)2CH]2N-
H
fast
Li+
Li+
+
[(CH3)2CH]2NH
+
OTs-Li+
O
slow
H
+
H3C
OTs
O
O
allylic bromide
a
1.
BrCH2CH
+
LDA
THF
CH2
O
a
O
CH2
H
+
fast
N
+ H
2.
O
H
H
C
+
Br
CH2
N
allylic
O
C
H
a
+ Br
Intramolecular a-alkylation reaction:
Favorskii rearrangement.
Intramolecular a-alkylation in the Favorskii rearrangement proceeds via enolate
anion generated within the molecule. The molecule must contain a leaving
group, usually a halide. The purpose of the reaction is two fold: 1. Molecular
rearrangements of ketones to carboxylic acids and 2. Ring contraction
reaction to make high energy small size and/or fused rings.
3
CO2H
OH-
O
1
2
a
3
4
X
1
2
5
4
CO2CH3
5
CH3O-
OH-
Mechanism
O
O
Br
a
+
H
H
Br
H
O
O
Br
+
Br-
H
O
OH-
HO
O
+
HO
O
CO2H
H2O
CO2H
+
OH-
Intramolecular a-alkylation reaction: Favorskii
rearrangement resulting in ring contractions.
3
O
a
2
3
4
CO2H
Br
OH-
2
1
4
5
1
6
6
O
Br
CH3O-
5
CO2CH3
O
O
1.
H
a
H
CH3O
Br
Br
fast
CH3OH +
2.
O
O
slow
Br
+
Br
3.
O
O
OCH3
slow
+
CH3O
5.
4.
OCH3
O
O
OCH3
C
OCH3
fast
O
fast
+ CH3OH
β-Dicarbonyls Are More Acidic
 When a hydrogen atom is flanked by two carbonyl groups,
its acidity is enhanced (Table 22.1)
 Negative charge of enolate delocalizes over both carbonyl
groups
Relative acidities are dictated by the
substituents on the carbonyl group.
acidity reduced due to the
inductive effect of the alkyl group
O
H
a
pKa
pKa
17
O
O
O
a
a
19
OCH3
OCH3
a
25
acidity reduced due to the
resonance effect of the alkoxy group
O
O
O
O
a
a
a
a
19
9
19
11
O
OCH3
H3CH2CO
O
a
13
OCH2CH3
Ethyl Acetoacetate Ester
O
pKa
Diethyl Malonate Ester
O
a
a
19
11
O
OCH2CH3
H3CH2CO
O
a
OCH2CH3
13
Acetoacetic and malonic esters are easily
converted into the corresponding enolate anions
by reaction with sodium ethoxide in ethanol. The
enolates are good nucleophiles that react rapidly
with alkyl halides to give an a-substituted
derivatives. The product has an acidic αhydrogen, allowing the alkylation process to be
repeated.
Formation of Enolate and Alkylation
Formation of Enolate and Alkylation
2. The Malonic Ester Synthesis
 For preparing a carboxylic acid from an alkyl halide
while lengthening the carbon chain by two atoms
3. The Acetoacetic Ester Synthesis
 Overall: converts an alkyl halide into a methyl ketone
Synthesis of ketones using acetoacetic ester via
the decarboxylation of acetoacetic acid
 b-Ketoacid from hydrolysis of ester undergoes
decarboxylation to yield a ketone via the enol
Synthesis of carboxylic acids using malonic ester
via the decarboxylation of malonic acid
 The malonic ester synthesis converts an alkyl halide into a
carboxylic acid while lengthening the carbon chain by two
atoms
Decarboxylation of b-Ketoacids
 Decarboxylation requires a carbonyl group two atoms away from the β
CO2H
 The second carbonyl permit delocalization of the resulting enol
 The reaction can be rationalized by an internal acid-base reaction
Generalization: b-Keto Esters
 The sequence: enolate ion formation, alkylation,
hydrolysis/decarboxylation is applicable to b-keto esters in
general
 Cyclic b-keto esters give 2-substituted cyclohexanones
Preparation Cycloalkane Carboxylic Acids
 1,4-dibromobutane reacts twice, giving a cyclic product
 Three-, four-, five-, and six-membered rings can be prepared
in this way