Condensations and Alpha Substitutions of

Carbonyl Compounds
 Alpha Substitution

Alpha substitution is the substitution of one of the

hydrogens attached to the alpha-carbon for an
electrophile.
The reaction occurs through an enolate ion
intermediate.

Chapter 22 2
Condensation with an Aldehyde or
Ketone

The enolate ion attacks the carbonyl group to form an

alkoxide.
Protonation of the alkoxide gives the addition
product: a b-hydroxy carbonyl compound.
Chapter 22 3
 Condensation with Esters

The enolate adds to the ester to form a tetrahedral

intermediate.
Elimination of the leaving group (alkoxide) gives the
substitution product (a b-carbonyl compound).
Chapter 22 4
 KetoEnol Tautomers
O OH
H H
H

keto form enol form

(99.99%) (0.01%)

Tautomerization is an interconversion of
isomers that occur through the migration of a
proton and the movement of a double bond.
Tautomers are not resonance form.
Chapter 22 5
BaseCatalyzed Tautomerism

In the presence of strong bases, ketones and aldehydes act as

weak proton acids.
A proton on the a carbon is abstracted to form a resonance-
stabilized enolate ion with the negative charge spread over a
carbon atom and an oxygen atom.
The equilibrium favors the keto form over the enolate ion.

Chapter 22 6
 Acid-Catalyzed Tautomerism

In acid, a proton is moved from the a-carbon

to oxygen by first protonating oxygen and
then removing a proton from the carbon.

Chapter 22 7
 Racemization

For aldehydes and ketones, the keto form is greatly

favored at equilibrium.
If a chiral carbon has an enolizable hydrogen atom, a
trace of acid or base allows that carbon to invert its
configuration, with the enol serving as the
intermediate. This is called racemization.
Chapter 22 8
 Acidity of a Hydrogens

pKa for a H of aldehyde or ketone ~20.

Much more acidic than alkane or alkene
(pKa > 40) or alkyne (pKa = 25).
Less acidic than water (pKa = 15.7) or
alcohol (pKa = 1619).
Only a small amount of enolate ion is
present at equilibrium.

Chapter 22 9
 Formation and Stability of
Enolate Ions

The equilibrium mixture contains only a small

fraction of the deprotonated, enolate form.
Chapter 22 10
 Energy Diagram of Enolate
Reaction

Even though the ketoenol tautomerism equilibrium

favors the keto form, addition of an electrophile shifts
the equilibrium toward the formation of more enol.
Chapter 22 11
 The a Halogenation of Ketones

When a ketone is treated with a halogen and a base,

an a halogenation reaction occurs.
The reaction is called base-promoted, rather than
base-catalyzed, because a full equivalent of the base
is consumed in the reaction.

Chapter 22 12
 Base-Promoted Halogenation
Mechanism

The base-promoted halogenation takes place by a

nucleophilic attack of an enolate ion on the
electrophilic halogen molecule.
The products are the halogenated ketone and a
halide ion.

Chapter 22 13
 Multiple Halogenations
O O O O
Cl Cl Cl Cl Cl Cl
Cl2 Cl Cl Cl Cl
H _
OH , H2O

The a-haloketone produced is more reactive than

ketone because the enolate ion is stabilized by the
electron-withdrawing halogen.
The second halogenation occurs faster than the first.
Because of the tendency for multiple halogenations
this base-promoted halogenation is not widely used
to prepare monohalogenated ketones.
Chapter 22 14
 Bromoform Reaction

A methyl ketone reacts with a halogen under

strongly basic conditions to give a
carboxylate ion and a molecule of haloform.
The trihalomethyl intermediate is not isolated.
Chapter 22 15
 Mechanism of Haloform
Formation

The trihalomethyl ketone reacts with hydroxide ion to

give a carboxylic acid.
A fast proton exchange gives a carboxylate ion and a
haloform.
When Cl2 is used, chloroform is formed; Br2 forms
bromoform ; and I2 forms iodoform.
Chapter 22 16
 Positive Iodoform Test
for Alcohols

The iodine oxidizes the alcohol to a methyl

ketone and it will give a positive iodoform test.
Iodoform (CHI3) is a yellow solid that will
precipitate out of solution.
Chapter 22 17
 Solved Problem 1
Propose a mechanism for the reaction of 3-pentanone with sodium hydroxide and bromine to give 2-
bromo-3-pentanone.

Solution
In the presence of sodium hydroxide, a small amount of 3-pentanone is present as its enolate.

The enolate reacts with bromine to give the observed product.

Chapter 22 18
 Acid-Catalyzed Halogenation

Ketones also undergo acid-catalyzed a halogenation.

Acidic halogenation may replace one or more alpha
hydrogens depending on how much halogen is used.
Acetic acid serves as both the solvent and the acid
catalyst.
Chapter 22 19
 Mechanism of Acid-Catalyzed
Halogenation

The mechanism of acid-catalyzed halogenation

involves attack of the enol form of the ketone on the
electrophile halogen molecule.
Loss of a proton gives the haloketone and the
hydrogen halide.
Chapter 22 20
 Solved Problem 2
Propose a mechanism for the acid-catalyzed conversion of cyclohexanone to 2-chlorocyclohexanone.

Solution
Under acid catalysis, the ketone is in equilibrium with its enol form.

The enol acts as a weak nucleophile, attacking chlorine to give a resonance-stabilized intermediate.
Loss of a proton gives the product.

Chapter 22 21
 Alkylation of Enolate Ions

Because the enolate has two nucleophilic sites (the

oxygen and the a carbon), it can react at either of
these sites.
The reaction usually takes place primarily at the
acarbon, forming a new CC bond.
Chapter 22 22
 a Alkylation of Enolate Ions

LDA (lithium diisopropylamide) Li+ N[CH(CH3)2]2,

forms the enolate.
The enolate acts as the nucleophile and attacks the
partially positive carbon of the alkyl halide, displacing
the halide and forming a CC bond.
Chapter 22 23
 Enamine Formation

Ketones or aldehydes react with a secondary

amine to form enamines.
The enamine has a nucleophilic a-carbon,
which can be used to attack electrophiles.
Chapter 22 24
Mechanism of Enolate Formation

An enamine results from the reaction of a

ketone or aldehyde with a secondary amine.
Chapter 22 25
 Aldol Condensation

Under basic conditions, the aldol condensation involves the

nucleophilic addition of an enolate ion to another carbonyl
group.
When the reaction is carried out at low temperatures, the b-
hydroxy carbonyl compound can be isolated.
Heating will dehydrate the aldol product to the ab unsaturated
compound.
Chapter 22 26
 Base-Catalyzed Aldol
Condensation: Step 1

During Step 1, the base removes the a-

proton, forming the enolate ion.
The enolate ion has a nucleophilic a-carbon.
Chapter 22 27
 Base-Catalyzed Aldol
Condensation: Step 2

The enolate attacks the carbonyl carbon of a

second molecule of carbonyl compound.

Chapter 22 28
 Base-Catalyzed Aldol
Condensation: Step 3

Protonation of the alkoxide gives the aldol

product.
Chapter 22 29
Dehydration of Aldol Products

Heating a basic or acidic aldol dehydration of the

alcohol functional group.
The product is a a,b-unsaturated conjugated
aldehyde or ketone.
An Aldol condensation, followed by dehydration,
forms a new carboncarbon double bond.
Chapter 22 30
Crossed Aldol Condensations

Chapter 22 31
Successful Crossed Aldol
Condensations

Chapter 22 32
 Solved Problem 3
Propose a mechanism for the base-catalyzed aldol condensation of acetone (Figure 22-2).

Solution
The first step is formation of the enolate to serve as a nucleophile.

The second step is a nucleophilic attack by the enolate on another molecule of acetone. Protonation
gives the aldol product.

Chapter 22 33
 Aldol Cyclization

Intramolecular aldol reactions of diketones are often

used for making five- and six-membered rings.
Rings smaller or larger than five or six members are
not favored due to ring strain or entropy.

Chapter 22 34
Retrosynthesis of Aldol
Condensation

Chapter 22 35
 Claisen Condensation

The Claisen condensation results when an

ester molecule undergoes nucleophilic acyl
substitution by an enolate.

Chapter 22 36
 Crossed Claisen

Two different esters can be used, but

one ester should have no a hydrogens.
Useful esters are benzoates, formates,
carbonates, and oxalates.
Ketones (pKa = 20) may also react with
an ester to form a b-diketone.

Chapter 22 37
 Crossed Claisen Condensation

In a crossed Claisen condensation, an ester

without a hydrogens serves as the
electrophilic component.

Chapter 22 38
 Crossed Claisen Condensation
with Ketones and Esters

Crossed Claisen condensation between ketones and

esters are also possible.
Ketones are more acidic than esters, and the ketone
component is more likely to deprotonate and serve as
the enolate component in the condensation.
Chapter 22 39
 Crossed Claisen Mechanism

The ketone enolate attacks the ester, which

undergoes nucleophilic acyl substitution, and
thereby, acylates the ketone.

Chapter 22 40
 Solved Problem 4
Propose a mechanism for the self-condensation of ethyl acetate to give ethyl acetoacetate.

Solution
The first step is formation of the ester enolate. The equilibrium for this step lies far to the
left; ethoxide deprotonates only a small fraction of the ester.

The enolate ion attacks another molecule of the ester; expulsion of ethoxide ion gives ethyl
acetoacetate.

Chapter 22 41
 Solved Problem 4 (Continued)
Solution (Continued)
In the presence of ethoxide ion, ethyl acetoacetate is deprotonated to give its enolate. This exothermic
deprotonation helps to drive the reaction to completion.

When the reaction is complete, the enolate ion is reprotonated to give ethyl acetoacetate.

Chapter 22 42
 Solved Problem 5
Show what ester would undergo Claisen condensation to give the following b-keto ester.

Solution
First, break the structure apart at the a, b bond (a, b to the ester carbonyl). This is the bond formed in
the Claisen condensation.

Chapter 22 43
 Solved Problem 5 (Continued)
Solution (Continued)
Next, replace the a proton that was lost, and replace the alkoxy group that was lost from the carbonyl.
Two molecules of methyl 3-phenylpropionate result.

Now draw out the reaction. Sodium methoxide is used as the base because the reactants are methyl
esters.

Chapter 22 44
Chapter 22 45
 Malonic Ester Synthesis

The malonic ester synthesis makes substituted

derivatives of acetic acids.
Malonic ester is alkylated or acylated on the carbon
that is alpha to both carbonyl groups, and the
resulting derivative is hydrolyzed and allowed to
decarboxylate.
Chapter 22 46
 Decarboxylation of the
Alkylmalonic Acid

Decarboxylation takes place through a cyclic

transition state, initially giving an enol form
that quickly tautomerizes to the product.

Chapter 22 47
Example of the Malonic
Synthesis

Chapter 22 48
Dialkylation of Malonic Ester

Chapter 22 49
 Solved Problem 6
Show how the malonic ester synthesis is used to prepare 2-benzylbutanoic acid.

Solution
2-Benzylbutanoic acid is a substituted acetic acid having the substituents PhCH2 and CH3CH2.

Adding these substituents to the enolate of malonic ester eventually gives the correct
product.

Chapter 22 50
 Acetoacetic Ester Synthesis

The acetoacetic ester synthesis is similar to

the malonic ester synthesis, but the final
products are ketones.

Chapter 22 51
Alkylation of Acetoacetic Ester

Ethoxide ion completely deprotonates acetoacetic

ester.
The resulting enolate is alkylated by an unhindered
alkyl halide or tosylate to give an alkylacetoacetic
ester.
Chapter 22 52
 Hydrolysis of Alkylacetoacetic
Ester

Acidic hydrolysis of the alkylacetoacetic ester initially

gives an alkylacetoacetic acid, which is a b-keto acid.
The keto group in the b-position promotes
decarboxylation to form a substituted version of
acetone.
Chapter 22 53
 Solved Problem 7
Show how the acetoacetic ester synthesis is used to make 3-propylhex-5-en-2-one.

Solution
The target compound is acetone with an n-propyl group and an allyl group as substituents:

Chapter 22 54
 Solved Problem 7 (Continued)
Solution (Continued)
With an n-propyl halide and an allyl halide as the alkylating agents, the acetoacetic ester synthesis
should produce 3-propyl-5-hexen-2-one. Two alkylation steps give the required substitution:

Hydrolysis proceeds with decarboxylation to give the disubstituted acetone product.

Chapter 22 55
 Conjugate Additions: The
Michael Reaction

a,b-unsaturated carbonyl compounds have unusually

electrophilic double bonds.
The b-carbon is electrophilic because it shares the
partial positive charge of the carbonyl carbon through
resonance.
Chapter 22 56
 1,2-Addition and 1,4-Addition

When attack occurs at the carbonyl group,

protonation of the oxygen leads to a 1,2-addition.
When attack occurs at the -position, the oxygen
atom is the fourth atom counting from the
nucleophile, and the addition is called a 1,4-addition.

Chapter 22 57
Donors and Acceptors

Chapter 22 58
 1,4-Addition of an Enolate to
Methyl Vinyl Ketone (MVK)

An enolate will do a 1,4-attack on the a,b-

unsaturated ketone (MVK).
Chapter 22 59
 Solved Problem 8
Show how the following diketone might be synthesized using a Michael addition.

Solution
A Michael addition would have formed a new bond at the b carbon of the acceptor. Therefore,
we break this molecule apart at the b,g bond.

Chapter 22 60
 Robinson Annulation

With enough base, the product of the Michael

reaction undergoes a spontaneous intramolecular
aldol condensation, usually with dehydration, to give
a six-membered ringa conjugated cyclohexenone.
Chapter 22 61
Robinson Mechanism

Chapter 22 62