Chapter 22. Carbonyl
Alpha-Substitution
Reactions
Based on McMurry’s Organic Chemistry, 6th
edition
©2003 Ronald Kluger
Department of Chemistry
University of Toronto
The  Position
 The carbon next to the carbonyl group is designated
as being in the  position
 Electrophilic substitution occurs at this position
through either an enol or enolate ion
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
2
22.1 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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
3
Tautomers Are Not Resonance Forms
 Tautomers are structural isomers
 Resonance forms are representations of contributors
to a single structure
 Tautomers interconvert rapidly while ordinary isomers
do not
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
4
Enols
 The enol tautomer is usually present to a very
small extent and cannot be isolated
 However, since it is formed rapidly, it can
serve as a reaction intermediate
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
5
Acid Catalysis of Enolization
 Brønsted acids catalyze keto-enol tautomerization by
protonating the carbonyl and activating the  protons
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
6
Base Catalysis of Enolization
 Brønsted bases
catalyze keto-enol
tautomerization
 The hydrogens on
the  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 Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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Acid Catalyzed Enolization
 The addition of a
proton to the carbonyl
oxygen makes the 
C-H more acidic,
reducing the barrier to
the enol
 The enol then can
react with another
electrophile
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
8
22.2 Reactivity of Enols: The Mechanism of
Alpha-Substitution Reactions
 Enols behave as nucleophiles and react with
electrophiles because the double bonds are electronrich compared to alkenes
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
9
General Mechanism of Addition to
Enols
 When an enol reacts
with an electrophile the
intermediate cation
immediately loses the
OH proton to give a
substituted carbonyl
compound
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
10
22.3 Alpha Halogenation of Aldehydes
and Ketones
 Aldehydes and ketones can be halogenated at their 
positions by reaction with Cl2, Br2, or I2 in acidic
solution
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
11
Mechanism of Electrophilic
Substitution
 The enol tautomer reacts
with an electrophile
 The keto tautomer loses a
proton
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
12
Evidence for the Rate-Limiting Enol
Formation
 The rate of halogenation is independent of the
halogen's identity and concentration
 In D3O+ the  H’s are replaced by D’s at the same
rate as halogenation
 This because the barrier to formation of the enol goes
through the highest energy transiton state in the
mechanism
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
13
Elimination Reactions of
-Bromoketones
 -Bromo ketones can be dehydrobrominated by base
treatment to yield ,b-unsaturated ketones
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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22.4 Alpha 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
(Hell–Volhard–Zelinskii reaction)
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
15
Mechanism of Bromination
 PBr3 converts -COOH to –COBr, which can enolize
and add Br2
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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22.5 Acidity of Alpha Hydrogen
Atoms: 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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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Reagents for Enolate Formation
 Ketones are weaker acids than the OH of alcohols so
a a more powerful base than an alkoxide is needed to
form the enolate
 Sodium hydride (NaH) or lithium diisopropylamide
[LiN(i-C3H7)2] are strong enough to form the enolate
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
18
Lithium Diisopropylamide (LDA)
 LDA is from butyllithium (BuLi) and diisopropylamine
(pKa  40)
 Soluble in organic solvents and effective at low
temperature with many compounds (see Table 22.1)
 Not nucleophilic
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
19
b-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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
20
Table 22.1: Acidities of Organic
Compounds
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
21
22.6 Reactivity of Enolate Ions
 The carbon atom of an enolate ion is electron-rich
and highly reactive toward electrophiles (enols are
not as reactive)
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
22
Two Reactions Sites on Enolates
 Reaction on oxygen yields an enol derivative
 Reaction on carbon yields an -substituted carbonyl
compound
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
23
22.7 Halogenation of Enolate Ions:
The Haloform Reaction
 Base-promoted reaction occurs through an enolate
ion intermediate
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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Further Reaction: Cleavage
 Monohalogenated products are themselves rapidly
turned into enolate ions 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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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22.8 Alkylation of Enolate Ions
 Alkylation occurs when the nucleophilic enolate ion
reacts with the electrophilic alkyl halide or tosylate
and displaces the leaving group
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
26
Constraints on Enolate Alkylation
 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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
27
The Malonic Ester Synthesis
 For preparing a carboxylic acid from an alkyl halide
while lengthening the carbon chain by two atoms
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
28
Formation of Enolate and Alkylation
 Malonic ester (diethyl propanedioate) is easily
converted into its enolate ion by reaction with sodium
ethoxide in ethanol
 The enolate is a good nucleophile that reacts rapidly
with an alkyl halide to give an -substituted malonic
ester
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
29
Dialkylation
 The product has an acidic -hydrogen, allowing the
alkylation process to be repeated
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
30
Hydrolysis and Decarboxylation
 The malonic ester derivative hydrolyzes in acid and
loses CO2 (“decarboxylation”) to yield a substituted
monoacid
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
31
Decarboxylation of b-Ketoacids
 Decarboxylation requires a carbonyl group two atoms
away from the CO2H
 The second carbonyl permit delocalization of the
resulting enol
 The reaction can be rationalized by an internal acidbase reaction
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
32
Decarboxylation Involves Changes in
Hybridization
 The reaction involves formation of a zwitterionic
tautomer
 The carboxylate C is sp2 and becomes sp in CO2
 The -C goes from sp3 to sp2 in the key step
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
33
Reminder of Overall Conversion
 The malonic ester synthesis converts an alkyl halide
into a carboxylic acid while lengthening the carbon
chain by two atoms
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
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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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
35
The Acetoacetic Ester Synthesis
 Overall: converts an alkyl halide into a methyl ketone
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
36
Acetoacetic Ester (Ethyl
Acetoacetate)
  carbon is flanked by two carbonyl groups, so it
readily becomes an enolate ion
 This which can be alkylated by an alkyl halide and
also can react with a second alkyl halide
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
37
Decarboxylation of Acetoacetic Acid
 b-Ketoacid from hydrolysis of ester undergoes
decarboxylation to yield a ketone via the enol
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
38
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
Based on McMurry, Organic Chemistry, Chapter
22, 6th edition, (c) 2003
39