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Chapter 17
Carbonyl Alpha-Substitution and
Condensation Reactions
© 2006 Thomson Higher Education
a-Substitution and Carbonyl
Condensation Reactions
Alpha-substitution reactions
occur at the carbon next to
the carbonyl carbon – the a
position
• Involve substitution of ahydrogen by electrophile
• Proceed through enol or
enolate ion intermediate
Carbonyl condensation
reactions occur between two
carbonyl partners
• Combination of asubstitution and nucleophilic
addition steps
• Gives b-hydroxy carbonyl
compound
17.1 Keto-Enol Tautomerism
Carbonyl compounds with a-hydrogens rapidly
equilibrate with corresponding enol (ene + alcohol)
• Interconversion known as keto-enol tautomerism
•
Greek tauto, meaning “the same,” and meros, meaning
“part”
• Individual isomers called tautomers
Keto-Enol Tautomerism
Tautomers are constitutional isomers
• Isomers are different compounds with different structures
• Atoms arranged differently
• Different from resonance structures that differ only in the
position of their electrons
• Most carbonyl compounds exist almost exclusively in the keto
form at equilibrium
Keto-Enol Tautomerism
Mechanism of acid-catalyzed enol formation
•
Protonated intermediate
can lose H+, either from the
oxygen atom to regenerate
the keto tautomer or from
the a carbon atom to yield
an enol tautomer
Keto-Enol Tautomerism
Mechanism of base-catalyzed enol formation
•
The intermediate enolate
ion, a resonance hybrid
of two forms, can be
protonated either on
carbon to generate
the starting keto tautomer
or on oxygen to give an
enol tautomer
Keto-Enol Tautomerism
Only a-hydrogens are acidic
• a-Hydrogens are acidic because the enolate ion
that results from deprotonation is resonance
stabilized with the electronegative oxygen of the
carbonyl
• b-, g-, d-Hydrogens (and so on) are not acidic
because the ion that results from deprotonation is
not resonance stabilized
17.2 Reactivity of Enols:
a-Substitution Reactions
Enols are nucleophiles that react with electrophiles
• There is a substantial build-up of electron density on
the a carbon of the enol
Reactivity of Enols:
a-Substitution Reactions
Mechanism of carbonyl a-substitution reaction on an enol
•
•
•
Enol is formed with
acid catalysis
Electron pair from C=C
bond of enol attacks an
electrophile (E+), forming
new C-E bond and a
resonance stabilized
intermediate
Loss of H+ from oxygen
yields the neutral alphasubstitution product and
restores the C=O bond
Reactivity of Enols:
a-Substitution Reactions
Acid-catalyzed a-halogenation (Cl2, Br2, and I2) of
aldehydes and ketones is a common laboratory
reaction
a-Halogenation occurs in biological systems
• a-Halogenation of ketones in marine alga
Reactivity of Enols:
a-Substitution Reactions
Mechanism of acid-catalyzed
bromination of acetone
Reactivity of Enols:
a-Substitution Reactions
Isotopic labeling experiments support reaction
mechanism of acid-catalyzed halogenation
• For a given ketone, the rate of deuterium exchange is
identical to the rate of halogenation
• Enol intermediate involved in both processes
Reactivity of Enols:
a-Substitution Reactions
a-Bromoketones are dehydrobrominated by base to
yield a,b-unsaturated ketones
• E2 reaction mechanism
• 2-Methylcyclohexanone gives 2-methylcyclohex-2-
enone on heating in pyridine
17.3 Acidity of a Hydrogen Atoms:
Enolate Ion Formation
Presence of neighboring carbonyl
group increases the acidity of the
ketone over the alkane by a factor
of 1040
Proton abstraction from carbonyl occurs when the a C-H bond is
oriented parallel to the p orbitals of the carbonyl group
A carbon of the enolate ion has a p orbital that overlaps neighboring p
orbitals of the carbonyl group
Negative charge shared with oxygen atom by resonance
Acidity of a Hydrogen Atoms:
Enolate Ion Formation
Strong base required for enolate formation
•
•
If NaOCH2CH3 is used the extent of enolate formation is only
about 0.1%
If sodium hydride, NaH, or lithium diisopropylamide (LDA),
[LiN(i-C3H7)2], is used the carbonyl is completely converted to its
enolate conjugate base
• LDA is prepared by reaction of butyllithium with
diisopropylamine
Acidity of a Hydrogen Atoms:
Enolate Ion Formation
A C-H bond flanked by two carbonyl groups is even
more acidic
• Enolate ion is stabilized by delocalization of negative
charge over both carbonyl groups
• Pentane-2,4-dione has three resonance forms
Acidity of a Hydrogen Atoms:
Enolate Ion Formation
Acidity of a Hydrogen Atoms:
Enolate Ion Formation
Worked Example 17.1
Identifying Acidic Hydrogens in a Compound
Identify the most acidic hydrogens in each of the
following compounds, and rank the compounds in
order of increasing acidity:
Worked Example 17.1
Identifying Acidic Hydrogens in a Compound
Strategy
• Hydrogens on carbon next to a carbonyl group
are acidic.
• In general, a b-dicarbonyl compound is most
acidic, a ketone or aldehyde is next most
acidic, and a carboxylic acid derivative is least
acidic.
• Remember that alcohols, phenols, and
carboxylic acids are also acidic because of
their –OH hydrogens
Worked Example 17.1
Identifying Acidic Hydrogens in a Compound
Solution
• The acidity order is (a) > (c) > (b). Acidic hydrogens
are shown in red:
17.4 Alkylation of Enolate Ions
Enolate ions are resonance
hybrides of two
nonequivalent
contributors
• Enolate ions are vinylic
alkoxides (C=C–O-)
•
•
Reaction on the
oxygen yields an
enol derivative
Enolate ions are a-keto
carbanions (-C–C=O)
•
Reaction on the
carbon yields an
a-substituted
carbonyl
compound
Alkylation of Enolate Ions
Enolate ions undergo alkylation by treatment with an
alkyl halide or tosylate
• Nucleophilic enolate ion reacts with the electrophilic
alkyl halide in an SN2 reaction
• Leaving group displaced by backside attack
Alkylation of Enolate Ions
• Alkylations are subject to all constraints that affect all
SN2 reactions
•
•
Alkyl group R should be primary or methyl and preferably
allylic or benzylic
Secondary alkyl halides react poorly and tertiary are
unreactive due to competing E2 reaction
Alkylation of Enolate Ions
The Malonic Ester Synthesis
• Preparation of carboxylic acids from alkyl halides
while lengthening the carbon chain by two atoms
Alkylation of Enolate Ions
Diethyl propanedioate, commonly known as diethyl
malonate, or malonic ester is more acidic than
monocarbonyl compounds (pKa = 13) because its a
hydrogens are flanked by two carbonyl groups
• Easily converted to enolate ion by sodium ethoxide in
ethanol
• “Et” is used as an abbreviation for –CH2CH3
Alkylation of Enolate Ions
Malonic ester contains two a hydrogens
• Product of a-alkylation can itself undergo alkylation
Alkylation of Enolate Ions
Alkylated of dialkylated malonic ester undergoes
hydrolysis to yield the diacid followed by
decarboxylation (loss of CO2) to yield the monoacid
Alkylation of Enolate Ions
Decarboxylation is unique to carboxylic acids with a
second carbonyl group located at the b position
Decarboxylation occurs via a cyclic mechanism
• Involves initial formation of an enol
Alkylation of Enolate Ions
Overall result of malonic ester synthesis is the
conversion of an alkyl halide into a carboxylic acid
while lengthening the carbon chain by two carbons
Alkylation of Enolate Ions
Malonic ester synthesis can be used to prepare
cycloalkane-carboxylic acids
• Three-, four-, five-, and six-membered rings can all
be prepared in this way
Worked Example 17.2
Using the Malonic Ester Synthesis to Prepare a
Carboxylic Acid
How would you prepare heptanoic acid using a
malonic ester systhesis?
Worked Example 17.2
Using the Malonic Ester Synthesis to Prepare a
Carboxylic Acid
Strategy
• The malonic ester synthesis converts an alkyl
halide into a carboxylic acid having two more
carbons.
• Thus, a seven-carbon acid chain must be
derived from the five-carbon alkyl halide 1bromopentane
Worked Example 17.2
Using the Malonic Ester Synthesis to Prepare a
Carboxylic Acid
Solution
Alkylation of Enolate Ions
The Acetoacetic Ester Synthesis
• The acetoacetic ester synthesis converts an alkyl
halide into a methyl ketone having three more
carbons
Alkylation of Enolate Ions
Ethyl-3-oxobutanoate, commonly called ethyl acetoacetate
or acetoacetic ester, contains a hydrogens flanked by
two carbonyl groups
•
Enolate ion is readily formed and alkylated under SN2 reaction
conditions
• A second alkylation product can be derived from
monoalkylated product
Alkylation of Enolate Ions
Alkylated or dialkylated acetoacetic ester is hydrolyzed
in aqueous acid to a b-keto acid
b-Keto acid undergoes decarboxylation to yield ketone
product
Alkylation of Enolate Ions
Ketone product formed in three-step sequence:
1.
2.
3.
Enolate formation
Alkylation
Hydrolysis/decarboxylation
Sequence applicable to all b-keto esters with acidic a
hydrogens
Alkylation of Enolate Ions
• Cyclic b-keto esters such as ethyl 2-
oxocyclohexanecarboxylate can be alkylated and
decarboxylated to give 2-substituted cyclohexanones
Worked Example 17.3
Using the Acetoacetic Ester Synthesis to Prepare a
Ketone
How would you prepare pentan-2-one by an
acetoacetic ester synthesis?
Worked Example 17.3
Using the Acetoacetic Ester Synthesis to Prepare a
Ketone
Strategy
• The acetoacetic ester synthesis yields a methyl
ketone by adding three carbons to an alkyl halide:
• Thus, the acetoacetic ester synthesis of pentan-2-
one must involve reaction of bromoethane
Worked Example 17.3
Using the Acetoacetic Ester Synthesis to Prepare a
Ketone
Solution
Alkylation of Enolate Ions
Direct Alkylation of Ketones, Esters, and Nitriles
• A strong, sterically hindered base such as
LDA converts a ketone, ester, or nitrile to its
enolate ion
•
•
Use of a sterically hindered base avoids
nucleophilic addition
A nonprotic solvent such as THF is required
• Aldehydes rarely give high yields of alkylation
products because their enolate ions undergo
carbonyl condensation reactions
Alkylation of Enolate Ions
• Example alkylations
Alkylation of Enolate Ions
• Example alkylations
Alkylation of Enolate Ions
• Example alkylations
Worked Example 17.4
Using an Alkylation Reaction to Prepare a
Substituted Ester
How might you use an alkylation reaction to prepare
ethyl 1-methylcyclohexanecarboxylate?
Worked Example 17.4
Using an Alkylation Reaction to Prepare a
Substituted Ester
Strategy
• An alkylation reaction is used to introduce a
methyl or primary alkyl group onto the a
position of a ketone, ester, or nitrile by SN2
reaction of an enolate ion with an alkyl halide.
• Look at the target molecule and identify any
methyl or primary alkyl groups attached to an
a carbon.
• The target has an a methyl group, which
might be introduced by alkylation of an ester
enolate ion with iodomethane
Worked Example 17.4
Using an Alkylation Reaction to Prepare a
Substituted Ester
Solution
Alkylation of Enolate Ions
Biological
Alkylations
•
Alkylations are
not common in
biological
systems
• a-Methylation
occurs in the
biosynthesis of
the antibiotic
indolmycin from
indolylpyruvate
17.5 Carbonyl Condensations:
The Aldol Reaction
Carbonyl condensation
reactions occur
between an
electrophilic
carbonyl group of
one partner and the
nucleophilic enolate
ion of the other
partner
• Combination of asubstitution and
nucleophilic addition
steps
Carbonyl Condensations:
The Aldol Reaction
Aldehydes and ketones with an a hydrogen atom
undergo a base-catalyzed carbonyl condensation
reaction called the aldol reaction
• Treatment of acetaldehyde with sodium ethoxide
yields 3-hydroxybutanal (an aldol)
Carbonyl Condensations:
The Aldol Reaction
Position of the aldol equilibrium depends both on
reaction condition and substrate structure
• Equilibrium favors condensation product in the case
of aldehydes with no a substituent (RCH2CHO)
Carbonyl Condensations:
The Aldol Reaction
• Equilibrium favors reactant for disubstituted aldehydes
(R2CHCHO) and most ketones
Carbonyl Condensations:
The Aldol Reaction
Aldol reactions occur by
nucleophilic addition of
the enolate ion of the
donor molecule to the
carbonyl group of the
acceptor molecule
Resultant tetrahedral
intermediate is
protonated to give an
alcohol product
The reverse process occurs
when base abstracts the
–OH hydrogen from the
aldol to yield a b-keto
alkoxide ion, which
cleaves to give one
molecule of enolate ion
and one molecule of
neutral carbonyl
compound
Worked Example 17.5
Predicting the Product of an Aldol Reaction
What is the structure of the aldol product from
propanal?
Worked Example 17.5
Predicting the Product of an Aldol Reaction
Strategy
• An aldol reaction combines two molecules of
reactant, forming a bond between the a
carbon of one partner and the carbonyl
carbon of the second partner
Worked Example 17.5
Predicting the Product of an Aldol Reaction
Solution
Carbonyl Condensations:
The Aldol Reaction
Carbonyl Condensations versus a-Substitutions
Carbonyl condensation reactions and a substitutions take place
•
under basic conditions and involve enolate-ion intermediates
Alpha-substitution reactions require a full equivalent of strong
base and are carried out so that the carbonyl compound is
rapidly and completely converted into its enolate ion at low
temperature before addition of the electrophile
Carbonyl Condensations:
The Aldol Reaction
• Carbonyl condensation reactions require only a
catalytic amount of a relatively weak base
• Enolate ion is generated in the presence of unreacted
carbonyl compound
17.6 Dehydration of Aldol Products
b-Hydroxy aldehydes or ketones formed in aldol
reactions can be easily dehydrated to yield a,bunsaturated products, or conjugated enones
• Aldol reactions were named condensation reactions
due to the loss of water
Dehydration of Aldol Products
Aldol products dehydrate easily because of carbonyl group
• Under basic conditions, an acidic a hydrogen is removed,
yielding an enolate ion that expels the –OH leaving group in an
E1cB reaction
• Under acidic conditions an enol is formed, the –OH group is
protonated, and water is expelled in an E1 or E2 reaction
Dehydration of Aldol Products
Reaction condition needed for aldol dehydration are often
only slightly more vigorous than conditions for aldol
formation
•
•
Conjugated enones are often obtained directly from aldol
reactions without isolating the intermediate b-hydroxy carbonyl
compounds
Conjugated enones are more stable than nonconjugated enones
• Interaction between p electrons of C=C bond and the p
electrons of the C=O bond
Dehydration of Aldol Products
Removal of water from reaction mixture drives the aldol
equilibrium toward product
Worked Example 17.6
Predicting the Product of an Aldol Reaction
What is the structure of the enone obtained
from aldol condensation of acetaldehyde?
Worked Example 17.6
Predicting the Product of an Aldol Reaction
Strategy
• In the aldol reaction, H2O is eliminated and a
double bond is formed by removing two
hydrogens from the acidic a position of one
partner and the carbonyl oxygen from the
second partner.
Worked Example 17.6
Predicting the Product of an Aldol Reaction
Solution
17.7 Intramolecular Aldol Reactions
Some dicarbonyl compounds react when treated
with base in an intramolecular aldol reaction
•
Leads to formation of cyclic product
Intramolecular Aldol Reactions
Intramolecular aldol reactions may lead to product mixtures
• Most thermodynamically stable product formed selectively
•
•
All reaction steps are reversible
Most thermodynamically stable product predominates at
equilibrium
17.8 The Claisen Condensation
Reaction
Reversible condensation reaction between two esters is
called the Claisen condensation reaction
• Esters have weakly acidic a hydrogens
• When an ester with an a hydrogen is treated with 1
equivalent of a base a b-keto ester is formed
The Claisen Condensation
Reaction
Claisen condensation
mechanism proceeds
through a tetrahedral
intermediate
•
•
•
The tetrahedral intermediate
expels an alkoxide leaving
group to yield an acyl
substitution product
If the product b-keto ester has
another acidic a proton, 1 full
equivalent of base is used for
deprotonation
Deprotonation of b-keto ester
drives reaction to the product
side giving high yields of
Claisen product
Worked Example 17.7
Predicting the Product of a Claisen
Condensation Reaction
What product would you obtain from Claisen
condensation of ethyl propanoate?
Worked Example 17.7
Predicting the Product of a Claisen
Condensation Reaction
Strategy
• The Claisen condensation of an ester results
in loss of one molecule of alcohol and
formation of a product in which an acyl group
of one reactant bonds to the a carbon of the
second reactant.
Worked Example 17.7
Predicting the Product of a Claisen
Condensation Reaction
Solution
17.9 Intramolecular Claisen
Condensations
Intramolecular Claisen condensations are called Deickman
cyclizations
•
Reaction works best for 1,6 and 1,7 diesters
• 1,6 Diester gives a five-membered cyclic b-keto ester
• 1,7 Diester gives a six-membered cyclic b-keto ester
Intramolecular Claisen Condensations
Mechanism of Dieckmann
cyclization
•
Same as Claisen reaction
mechanism
Intramolecular Claisen Condensations
The cyclic b-keto ester produced in an intramolecular Claisen
cyclization can be further alkylated and decarboxylated
2-cyclohexanones and 2-cyclopentanones are prepared by the
following sequence:
1.
Intramolecular Claisen cyclization
2.
b-Keto ester alkylation
3.
Decarboxylation
17.10 Conjugate Carbonyl Additions:
The Michael Reaction
The conjugate addition of a nucleophilic enolate ion to an a,bunsaturated carbonyl compound is known as the Michael
reaction
• Best reactions are derived from addition of a b-keto ester or
other 1,3-dicarbonyl compound to an unhindered a,bunsaturated ketone
• Ethyl acetoacetate reacts with but-3-en-2-one in the presence of
sodium ethoxide to yield the Michael addition product
Conjugate Carbonyl Additions:
The Michael Reaction
The Michael reaction
Conjugate addition of a
nucleophilic enolate
ion to b carbon of an
a,b-unsaturated
carbonyl compound
• Best Michael
reactions between
stable enolate ions
and unhindered a,bunsaturated ketones
Conjugate Carbonyl Additions:
The Michael Reaction
Michael reaction occurs with a variety of a,b-unsaturated
carbonyl compounds
Worked Example 17.8
Using the Michael Reaction
How might you obtain the following compound using a
Michael reaction?
Worked Example 17.8
Using the Michael Reaction
Strategy
• A Michael reaction involves the conjugate
addition of a stable enolate ion donor to an
a,b-unsaturated carbonyl acceptor, yielding a
1,5-dicarbonyl product
• Usually the stable enolate ion is derived from
a b-diketone, b-keto ester, malonic ester or
similar compound
• The C-C bond made in the conjugate addition
step is the one between the a carbon of the
acidic donor and the b carbon of the
unsaturated acceptor
Worked Example 17.8
Using the Michael Reaction
Solution
17.11 Carbonyl Condensations with
Enamines: The Stork Reaction
Enamine nucleophiles add to a,b-unsaturated acceptors
in Michael-like reactions
• Reactions are particularly important in biological
chemistry
• Enamines are prepared by reaction between a
ketone and a secondary amine
Carbonyl Condensations with
Enamines: The Stork Reaction
Enamines are electronically similar to enolate ions
• Overlap of the nitrogen lone-pair orbital with the
double-bond p orbitals leads to an increase in
electron density on the a carbon atom
Carbonyl Condensations with
Enamines: The Stork Reaction
Stork reaction
Enamine adds to an a,b-unsaturated carbonyl
acceptor in a Michael-like reaction
• Initial product is hydrolyzed by aqueous acid
to yield a 1,5-dicarbonyl compound
• Overall reaction is a three-step sequence:
1.
2.
3.
Enamine formation from a ketone
Michael addition to an a,b-unsaturated
carbonyl compound
Enamine hydrolysis back to ketone
Carbonyl Condensations with
Enamines: The Stork Reaction
The net effect of the Stork reaction is a Michael addition
of a ketone to an a,b-unsaturated carbonyl compound
Carbonyl Condensations with
Enamines: The Stork Reaction
Two advantages to the enamine-Michael
reaction that make the pathway useful in
biological systems
1. Enamine is neutral and easily prepared and
handled
•
Enolate is charged and difficult to prepare
and handle
2. Enamine from a monoketone can be used in
the Michael addition
•
Only enolate ions from b-dicarbonyl
compounds can be used
Worked Example 17.9
Using the Stork Enamine Reaction
How might you use an enamine reaction to prepare the
following compound?
Worked Example 17.9
Using the Stork Enamine Reaction
Strategy
• The overall result of an enamine reaction is
the Michael addition of a ketone as donor to
an a,b-unsaturated carbonyl compound as
acceptor, yielding a 1,5-dicarbonyl product
• The C-C bond made in the Michael addition
step is the one between the a carbon of the
ketone donor and the b carbon of the
unsaturated acceptor
Worked Example 17.9
Using the Stork Enamine Reaction
Solution
17.12 Some Biological Carbonyl
Condensation Reactions
Biological Aldol Reactions
Aldol reactions are particularly important in
carbohydrate metabolism
• Enzymes called aldolases catalyze addition
of a ketone enolate ion to an aldehyde
•
Type I aldolases occur primarily in animals
and higher plants
•
•
Operate through an enolate ion
Type II aldolases occur primarily in fungi and
bacteria
Some Biological Carbonyl
Condensation Reactions
Mechanism of Type I aldolase in glucose biosynthesis
•
•
•
Dihydroxyacetone phosphate is first converted into an enamine
by reaction with the –NH2 group on a lysine amino acid in the
enzyme
Enamine adds to glyceraldehyde 3-phosphate
Resultant iminium ion is hydrolyzed
Some Biological Carbonyl
Condensation Reactions
Mechanism of Type II aldolase in glucose biosynthesis
•
Aldol reaction occurs directly
• Ketone carbonyl group of glyceraldegyde 3-phosphate
complexed to a Zn2+ ion to make it a better acceptor
Some Biological Carbonyl
Condensation Reactions
Biological Claisen Condensations
Claisen condensations occur in a large number of biological
pathways
•
•
In fatty acid biosynthesis an enolate ion generated by
decarboxylation of malonyl ACP adds to the carbonyl group of
another acyl group bonded through a thioester linkage to a
synthase enzyme
The tetrahedral intermediate expels the synthase, giving
acetoacetyl ACP
Some Biological Carbonyl
Condensation Reactions
Mixed Claisen consensations occur frequently in living
organisms
• Butyryl synthase, in the fatty-acid biosynthesis
pathway, reacts with malonyl ACP in a mixed Claisen
condensation to give 3-ketohexanoyl ACP

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