Carbonyl Condensation

Reactions
John McMurry

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Why this chapter?

Carbonyl condensation reactions also

occur often in metabolic pathways.

Also one of the general methods used to

form C-C bonds.

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Condensation Reactions
Carbonyl compounds are both the electrophile and
nucleophile in carbonyl condensation reactions

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1. Carbonyl Condensation: The Aldol Reaction

Acetaldehyde reacts in basic solution (NaOEt, NaOH) with

another molecule of acetaldhyde
The b-hydroxy aldehyde product is aldol (aldehyde +
alcohol)
This is a general reaction of aldehydes and ketones

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General Mechanism of Condensations

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The Equilibrium of the Aldol
The aldol reaction is reversible, favoring the
condensation product only for aldehydes with no
substituent (RCH2CHO) BUT favoring reactant for
disubstituted aldehydes (R2CHCHO) and for most
ketones

Steric factors are probably responsible, since increased

substitution near the reaction site increases steric
congestion in the aldol product

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Mechanism of Aldol Reactions:

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Predicting Aldol Products
The product will have an alcohol and a carbonyl
in a 1,3 relationship (a beta-hydroxy carbonyl)

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Problem 1:

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2. Carbonyl Condensation vs Alpha-Substitution
Carbonyl condensations and substitutions both involve
formation of enolate ion intermediates
Alpha-substitution reactions are accomplished by
converting all of the carbonyl compound to enolate form
so it is not an electrophile
Immediate addition of an alkyl halide to completes the
alkylation reaction

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Conditions for Condensations
A small amount of base is used to generate a small amount
of enolate in the presence of unreacted carbonyl compound
After the condensation, the basic catalyst is regenerated

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3. Dehydration of Aldol Products: Synthesis of Enones

The b-hydroxy carbonyl products dehydrate to

yield conjugated enones
The term condensation refers to the net loss of
water and combination of 2 molecules

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Dehydration of b-Hydroxy Ketones and Aldehydes
The hydrogen is removed by a base, yielding an
enolate ion that expels the -OH leaving group
Under acidic conditions the -OH group is
protonated and water is expelled

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Driving the Equilibrium
Removal of water from the aldol reaction mixture
can be used to drive the reaction toward products
Even if the initial aldol favors reactants, the
subsequent dehydration step pushes the reaction
to completion

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Example:

What is the structure of the enone obtained from

aldol condensation of acetaldehyde?

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Problem 2:

Predict the enone product from aldols of:

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4. Using Aldol Reactions in Synthesis
If a desired molecule contains either a b-hydroxy
carbonyl or a conjugated enone, it might come
from an aldol reaction

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Extending the Synthesis
Subsequent transformations can be carried out on
the aldol products
A saturated ketone might be prepared by catalytic
hydrogenation of the enone product

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Problem 3:

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5. Mixed Aldol Reactions
A mixed aldol reaction between two similar
aldehyde or ketone partners leads to a mixture of
four possible products
This is not useful

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Practical Mixed Aldols
If one of the carbonyl partners contains no hydrogens and
the carbonyl is unhindered (such as benzaldehyde and
formaldehyde) it is a good electrophile and can react with
enolates, then a mixed aldol reaction is likely to be
successful
2-methylcyclohexanone gives the mixed aldol product on
reaction with benzaldehyde

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Mixed Aldols with Acidic Carbonyl Compounds

Ethyl acetoacetate is completely converted into its

enolate ion than monocarbonyl partners
Aldol condensations with ethyl acetoacetate occur
preferentially to give the mixed product

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Problem 4:

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6. Intramolecular Aldol Reactions
Treatment of certain dicarbonyl compounds with
base produces cyclic products by intramolecular
reaction

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Mechanism of Intramolecular Aldol Reactions
Both the nucleophilic carbonyl anion donor and the electrophilic
carbonyl acceptor are now in the same molecule.
The least strained product is formed because the reaction is
reversible

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Problem 5:
Which product would you expect to obtain from
base treatment of the following:

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7. The Claisen Condensation Reaction
Reaction of an ester having an hydrogen with 1 equivalent
of a base to yield a b-keto ester

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Mechanism of the Claisen Condensation

Similar to aldol
condensation:
nucleophilic acyl
substitution of an
ester enolate ion
on the carbonyl
group of a
second ester
molecule

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Problem 6:
Show the products you would expect to obtain by
Claisen condensation of the following esters:
(a) (CH3)2CHCH2CO2Et
(b) Ethyl phenylacetate
(c) Ethyl cyclohexylacetate

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8. Mixed Claisen Condensation
Successful when one of the two esters components has no
hydrogen and thus cant form an enolate ion.acts as the
electrophilic acceptor in reactions with other ester anions to
give mixed b-keto esters

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Esters and Ketones
Reactions between esters and ketones, resulting
in b-diketones
Best when the ester component has no
hydrogens and can't act as the nucleophilic donor

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9. Intramolecular Claisen Condensations:
The Dieckmann Cyclization
Intramolecular Claisen condensation
Best with 1,6-diesters (product: 5-membered
b-ketoester) and 1,7-diesters (product: 6-membered b-
ketoester)

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Mechanism of the Dieckmann
Cyclization

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Alkylation of Dieckmann Product
The cyclic b-keto ester can be further alkylated
and decarboxylated as in the acetoacetic ester
synthesis

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Learning Check:
Predict the product:
10. Conjugate Carbonyl Additions:
The Michael Reaction
Enolates can add as nucleophiles to ,b-
unsaturated aldehydes and ketones to give the
conjugate addition product

37
Best Conditions for the Michael Reaction
When a particularly stable enolate ion
Example: Enolate from a b-keto ester or other
1,3-dicarbonyl compound adding to an
unhindered ,b-unsaturated ketone

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Mechanism of the Michael
Nucleophilic
addition of a
enolate ion
donor to the b
carbon of an
,b-
unsaturated
carbonyl
acceptor

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 Generality of the Michael Reaction
Occurs with a variety of ,b-unsaturated carbonyl compounds
(aldehydes, esters, nitriles, amides, and nitro compounds)

Donors
include b-
diketones,
b-keto
esters,
malonic
esters, b-
keto
nitriles, and
nitro
compounds

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Learning Check:
Make the following using a Michael
Reaction:

Solution:
11. Carbonyl Condensations with Enamines:
The Stork Reaction
Enamines are equivalent to enolates in their
reactions and can be used to accomplish the
transformations under milder conditions
Enamines are prepared from a ketone and a
secondary amine

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Enamines Are Nucleophilic

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Enamine Addition and Hydrolysis
Enamine adds to an ,b-unsaturated carbonyl acceptor
The product is hydrolyzed to a 1,5-dicarbonyl
compound

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Learning Check:
Prepare Using a Stork Enamine Reaction

Solution:
Learning Check: Know how to
Prepare Using a Stork Enamine Reaction
12. The Robinson Annulation Reaction
A two-step process: combines a
Michael reaction with an
intramolecular aldol reaction
The product is a substituted 2-cyclohexenone

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Robinson Annulation Example
Synthesis of estrone
Learning Check: Know how to..
Prepare via a Robinson Annulation:
13. Some Biological Carbonyl Condensation
Reactions
Malonyl ACP is decarboxylated and enolate is formed
Enolate is added to the carbonyl group of another acyl group
through a thioester linkage to a synthase
Tetrahedral intermediate gives acetoacetyl ACP

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Learning Check:
Which of the following statements explains why the following
aldehyde will not undergo an aldol reaction with itself?

1. The benzene ring makes the carbonyl group unreactive

towards aldol reactions.
2. A carbonyl group must be connected to two alkyl groups
in order to undergo an aldol reaction.
3. The molecule does not possess any hydrogens to the
carbonyl group.
4. Electrophilic aromatic substitution competes favorably
with the aldol reaction.
5. Nucleophilic acyl substitution competes favorably with the
aldol reaction.
Learning Check:
Predict the aldol reaction product of the following ketone.
O NaOH

Ethanol

1. 2. 3.
O
O OH O OH

HO

4. 5.
O OH
O
OH
Learning Check:
Which starting material(s) will produce the following aldol
reaction product?

1. 2. 3.

4. 5.
Learning Check:
Select the correct aldol reaction product for the following
reaction.

1. 2.

3.

5.
4.
 Learning Check:
Which pair of compounds would be required to prepare the
following aldol product?

O
1. O 2.
O O O
H +
+
3. O
H
O

O
H +

5. O
4. O H +
O
H +
O
Learning Check:
Which of the following reactions will yield the compound
shown below?

1. 2.

3.

4. 5.
Learning Check:
Which of the
Which following
of the followingreactions willyield
reactions will yieldthethe compound
compound shown
shown below?
below?

1. 2.

3.

4. 5.
 Learning Check:
Which of the following would not be produced in the aldol
reaction between 2-butanone and acetophenone?
O
O NaOH
+
Ethanol

1. 2. 3.
O O O

5.
4. O

O
 Learning Check:
Predict the aldol reaction product(s) of the following ketone.
O O
O O NaOH

Ethanol

A B

O O
1. A
2. B
C D
3. Both A and C
4. Both B and D
5. A, B, and C
 Learning Check:
Which starting material(s) will produce the following aldol
reaction product?

1. 2. 3.

4. 5.
Select the correct aldol reaction product for the following
reaction.

1. 2.

3.

5.
4.
 Learning Check:
Which of the following reactions will yield the compound shown
below?

1. 2.

3.

4. 5.
Learning Check:
Which of the following would not be produced in the aldol reaction between
2-butanone and acetophenone?
O
O NaOH
+
Ethanol

1. 2. 3.
O O O

5.
4. O

O
Learning Check:
Predict the aldol reaction product(s) of the following ketone.
O O
O O NaOH

Ethanol

A B

O O

1. A
2. B C D

3. Both A and C
4. Both B and D
5. A, B, and C
 Learning Check:
Which of the following is the best candidate for a crossed Claisen
reaction with ethyl acetate?

1. 2. 3.
O O
OCH3
CO2CH3 OCH3

5.
4. O
O
Ph CH3O
CH3O
 Learning Check:
What type of reaction occurs in a Claisen condensation?
1. electrophilic aromatic
substitution
2. nucleophilic addition
3. hydrolysis
4. nucleophilic acyl
substitution
5. decarboxylation
 Learning Check:
Select the correct Claisen condensation product for the following
reaction.

1. 2. 3.

5.
4.
 Learning Check:
Predict the outcome of the following reaction.

1. 2. 3.

4. 5.
 Learning Check:
What is the expected major product of the following reaction?

O NaOH, EtOH

1. 2.

3. O
O

4. HO 5.
O

O
O
 Learning Check:
Predict the outcome of the following reaction.

1. 2. 3.

4. 5.
 Learning Check:
What type of reaction has occurred in the given biological process?

1. Claisen condensation
2. aldol reaction
3. nucleophilic acyl substitution
4. -elimination
5. both Claisen condensation and
nucleophilic acyl substitution