Carbonyl Condensation

Reactions
John McMurry

Why this chapter?

Carbonyl condensation reactions also

occur often in metabolic pathways.

Also one of the general methods used to

form C-C bonds.

Condensation Reactions

Carbonyl compounds are both the electrophile and

nucleophile in carbonyl condensation reactions

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

General Mechanism of Condensations

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

Mechanism of Aldol Reactions:

Predicting Aldol Products

The product will have an alcohol and a carbonyl

in a 1,3 relationship (a beta-hydroxy carbonyl)

Problem 1:

10

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

11

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

12

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

13

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

14

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

15

Example:

What is the structure of the enone obtained from

aldol condensation of acetaldehyde?

16

Problem 2:

Predict the enone product from aldols of:

17

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

18

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

19

Problem 3:

20

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

21

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

22

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

23

Problem 4:

24

6. Intramolecular Aldol Reactions

Treatment of certain dicarbonyl compounds with

base produces cyclic products by intramolecular
reaction

25

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

26

Problem 5:

Which product would you expect to obtain from

base treatment of the following:

27

7. The Claisen Condensation Reaction

Reaction of an ester having an hydrogen with 1 equivalent

of a base to yield a b-keto ester

28

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

29

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

30

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

31

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

32

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 bketoester)

33

Mechanism of the Dieckmann

Cyclization

34

Alkylation of Dieckmann Product

The cyclic b-keto ester can be further alkylated

and decarboxylated as in the acetoacetic ester
synthesis

35

Learning Check:

Predict the product:

10. Conjugate Carbonyl Additions:

The Michael Reaction

Enolates can add as nucleophiles to ,bunsaturated 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

38

Mechanism of the Michael

Nucleophilic
addition of a
enolate ion
donor to the b
carbon of an
,bunsaturated
carbonyl
acceptor

39

Generality of the Michael Reaction

Occurs with a variety of ,b-unsaturated carbonyl compounds

(aldehydes, esters, nitriles, amides, and nitro compounds)

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

40

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

42

Enamines Are Nucleophilic

43

Enamine Addition and Hydrolysis

Enamine adds to an ,b-unsaturated carbonyl acceptor

The product is hydrolyzed to a 1,5-dicarbonyl
compound

44

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

47

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

50

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

1.
2.
3.
4.
5.

The benzene ring makes the carbonyl group unreactive

towards aldol reactions.
A carbonyl group must be connected to two alkyl groups
in order to undergo an aldol reaction.
The molecule does not possess any hydrogens to the
carbonyl group.
Electrophilic aromatic substitution competes favorably
with the aldol reaction.
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.
O

3.
O

OH

OH
HO

4.

5.
O

OH

O
OH

Learning Check:
Which starting material(s) will produce the following aldol
reaction product?

1.

2.

4.

3.

5.

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

2.

1.
3.

4.

5.

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

1. O

2.
H

3. O

O
H

5. O

4. O
H

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

1.

2.
3.

4.

5.

Learning Check:
Which
of the
following
willyield
yieldthethe
compound
Which
of the
followingreactions
reactions will
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.
O

3.
O

5.

4.

O
O

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

NaOH
Ethanol
A

1.
2.

3.
4.
5.

A
B
Both A and C
Both B and D
A, B, and C

Learning Check:
Which starting material(s) will produce the following aldol
reaction product?

1.

2.

4.

3.

5.

Select the correct aldol reaction product for the following

reaction.

2.

1.
3.

4.

5.

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.
O

3.
O

5.

4.

O
O

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

NaOH
Ethanol
A

1.
2.

3.
4.
5.

A
B
Both A and C
Both B and D
A, B, and C

Learning Check:
Which of the following is the best candidate for a crossed Claisen
reaction with ethyl acetate?

2.

1.

3.
O

OCH3

OCH3

CO2CH3

5.

4.

O
CH3O

Ph

CH3O

Learning Check:
What type of reaction occurs in a Claisen condensation?
1.
2.

3.
4.

5.

electrophilic aromatic
substitution
nucleophilic addition
hydrolysis
nucleophilic acyl
substitution
decarboxylation

Learning Check:
Select the correct Claisen condensation product for the following
reaction.

1.

2.

4.

3.

5.

Learning Check:
Predict the outcome of the following reaction.

1.

2.

4.

3.

5.

Learning Check:
What is the expected major product of the following reaction?
O

NaOH, EtOH

1.

2.
3.

4.

HO

5.
O

Learning Check:
Predict the outcome of the following reaction.

1.

3.

2.

4.

5.

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

1.
2.
3.

4.
5.

Claisen condensation
aldol reaction
nucleophilic acyl substitution
-elimination
both Claisen condensation and
nucleophilic acyl substitution