Transcript Chapter 20: Carboxylic Acids and Nitriles

Chapter 23. Carbonyl
Condensation Reactions
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
2
23.1 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
3
General Condensations
4
Aldehydes & Ketones and Aldol Equilibrium

The aldol
reaction is
reversible,
favoring the
condensation
product only
for aldehydes
with no 
substituent

Steric factors
are increased
in the aldol
product
5
Mechanism of Aldol Reactions


Aldol reactions, like all
carbonyl
condensations, occur
by nucleophilic
addition of the enolate
ion of the donor
molecule to the
carbonyl group of the
acceptor molecule
The addition
intermediate is
protonated to give an
alcohol product
6
Predicting Aldol Products
The product will have an alcohol and a carbonyl in a
1,3 relationship (a beta-hydroxy carbonyl)
Learning Check: Know how to……
Predict the aldol reaction products of:
23.2 Carbonyl Condensation versus AlphaSubstitution



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
9
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
10
23.3 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
11
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
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

13
Learning Check:
What is the structure of the enone obtained from aldol
condensation of acetaldehyde?
Solution:
What is the structure of the enone obtained from aldol
condensation of acetaldehyde?
Learning Check: Know how to…
Predict the enone product from aldols of:
23.4 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
17
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
18
Learning Check: Know how to…
Prepare the following from an aldol condensation:
23.5 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

20
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
21
Mixed Aldols With Acidic Carbonyl
Compounds


Ethyl acetoacetate is completely converted into its enolate
ion under less basic conditions than monocarbonyl
partners
Aldol condensations with ethyl acetoacetate occur
preferentially to give the mixed product
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23.6 Intramolecular Aldol Reactions

Treatment of certain dicarbonyl compounds with base
produces cyclic products by intramolecular reaction
23
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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Learning Check:
Which product would you expect to obtain from base treatment of
the following?
Solution:
Which product would you expect to obtain from base treatment of
the following?
O
23.7 The Claisen Condensation Reaction

Reaction of an ester having an  hydrogen with 1
equivalent of a base to yield a b-keto ester
27
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
See the simulation at
www.thomsonedu.com

If the starting ester has more than
one acidic a hydrogen, the product
b-keto ester has a doubly activated
proton that can be abstracted by
base

Requires a full equivalent of base
rather than a catalytic amount

The deprotonation drives the
reaction to the product
28
Learning Check:
Predict the product of Claisen condensation of ethyl propanoate
29
Solution:
Predict the product of Claisen condensation of ethyl propanoate
30
23.8 Mixed Claisen Condensations

Successful when one of the two esters 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 bdiketones
Best when the ester component has no  hydrogens and
can't act as the nucleophilic donor
32
Learning Check: Know how to…
Predict the product of the following reaction:
23.9 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)
34
Mechanism of the Dieckmann
Cyclization
35
Alkylation of Dieckmann Product

The cyclic b-keto ester can be further alkylated and
decarboxylated as in the acetoacetic ester synthesis
36
Learning Check: Know how to…

Predict the product:
23.10 Conjugate Carbonyl Additions: The
Michael Reaction

Enolates can add as nucleophiles to ,b-unsaturated
aldehydes and ketones to give the conjugate addition
product
38
Best Conditions for the Michael Reaction
When a particularly stable enolate ion
 Example: Enolate from a b-keto ester or other 1,3dicarbonyl compound adding to an unhindered ,bunsaturated ketone

39
Mechanism of the Michael

Nucleophilic
addition of a
enolate ion
donor to the b
carbon of an
,b-unsaturated
carbonyl
acceptor
40
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
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Learning Check:

Make the following using a Michael Reaction:
Solution:

Make the following using a Michael Reaction:
23.11 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
44
Enamines Are Nucleophilic

Overlap of the nitrogen lone-pair orbital with the doublebond π orbitals increases electron density on the  carbon
atom
45
Enamine Addition and Hydrolysis
Enamine adds to an ,b-unsaturated carbonyl acceptor
 The product is hydrolyzed to a 1,5-dicarbonyl compound

46
Learning Check:

Prepare Using a Stork Enamine Reaction
Solution:

Prepare Using a Stork Enamine Reaction
Learning Check: Know how to…

Prepare Using a Stork Enamine Reaction
23.12 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:
23.13 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

53
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.
The molecule does not possess any hydrogens α to the carbonyl group.
3.
4.
Electrophilic aromatic substitution competes favorably with the aldol
reaction.
5.
Nucleophilic acyl substitution competes favorably with the aldol
reaction.
Solution:
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.
The molecule does not possess any hydrogens α to the carbonyl group.
3.
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.
O
3.
O
OH
O
OH
HO
4.
5.
O
OH
O
OH
Solution:
Predict the aldol reaction product of the following ketone.
O
NaOH
Ethanol
1.
2.
O
3.
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.
4.
3.
5.
Solution:
Which starting material(s) will produce the following aldol
reaction product?
1.
2.
4.
3.
5.
Solution:
Select the correct aldol reaction product for the following
reaction.
2.
1.
3.
4.
5.
Solution:
Which pair of compounds would be required to prepare
the following aldol product?
O
1.
2.
O
H
3.
O
H
+
O
+
H
+
O
+
5.
O
H
O
H
4.
O
O
O
+
O
O
Learning Check:
Which of the following reactions will yield the compound
shown below?
1.
2.
3.
4.
5.
Solution:
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
O
5.
4.
O
O
Solution:
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
O
5.
4.
O
O
Learning Check:
Predict the aldol reaction product(s) of the following ketone.
O
O
O
O
NaOH
Ethanol
A
1.
2.
3.
4.
5.
A
B
Both A and C
Both B and D
A, B, and C
B
O
O
C
D
Solution:
Predict the aldol reaction product(s) of the following ketone.
O
O
O
O
NaOH
Ethanol
A
1.
2.
3.
4.
5.
A
B
Both A and C
Both B and D
A, B, and C
B
O
O
C
D
Learning Check:
Which of the following is the best candidate for a crossed
Claisen reaction with ethyl acetate?
2.
1.
3.
O
O
OCH3
OCH3
CO2CH3
5.
4.
O
O
CH3O
Ph
CH3O
Solution:
Which of the following is the best candidate for a crossed
Claisen reaction with ethyl acetate?
2.
1.
3.
O
O
OCH3
OCH3
CO2CH3
5.
4.
O
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
Solution:
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.
Solution:
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.
Solution:
Predict the outcome of the following reaction.
1.
2.
4.
3.
5.
Learning Check:
What is the expected major product of the following
O
reaction?
O
NaOH, EtOH
1.
2.
3.
O
O
4.
HO
O
O
5.
O
Solution:
What is the expected major product of the following
O
reaction?
O
NaOH, EtOH
1.
2.
3.
O
O
4.
HO
O
O
5.
O
Learning Check:
Predict the outcome of the following reaction.
1.
3.
2.
4.
5.
Solution:
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
β-elimination
both Claisen condensation and nucleophilic acyl
substitution
Solution:
What type of reaction has occurred in the given biological
process?
1.
2.
3.
4.
5.
Claisen condensation
aldol reaction
nucleophilic acyl substitution
β-elimination
both Claisen condensation and nucleophilic acyl
substitution