CH 15

9/18/2018
WILLIAM H. BROWN
THOMAS POON
www.wiley.com/college/brown
CHAPTER FIFTEEN
Enolate Anions
Copyright © 2017 John Wiley & Sons, Inc. All rights reserved.
15-1
Acidity of -Hydrogens
• A carbon adjacent to a carbonyl group is

called an -carbon, and a hydrogen bonded
to an -carbon is called an -hydrogen
– -hydrogens of aldehydes, ketones, and esters

are considerably more acidic than alkane or
alkene hydrogens, but less acidic than hydroxyl
hydrogens.
Copyright © 2017 John Wiley & Sons, Inc. All rights reserved. 15-2
1
9/18/2018
Enolate Anions
• We account for the acidity of -hydrogens in two

ways.
– The electron-withdrawing inductive effect of the adjacent
carbonyl group weakens the C–H bond.
– The negative charge on the enolate anion is delocalized
by resonance relative to the anion from an alkane or
alkene.
Acidity of -Hydrogens
2
9/18/2018
Enolate Anions
• Enolate anions can be formed either quantitatively

or under equilibrium conditions.
• Use of a base stronger than the enolate anion
results in quantitative removal of an -hydrogen.
Enolates and New C-C Bonds
• Enolate anions function as nucleophiles in

carbonyl addition reactions.
3
9/18/2018
The Aldol Reaction
• The product of an aldol reaction is

– a β-hydroxyaldehyde or β hydroxyketone.
–.
The Aldol Reaction
• A three-step mechanism
– Step 1: Take away a proton to give an enolate
anion.
– Step 2: Reaction of a nucleophile and an

electrophile to form a new covalent bond.
4
9/18/2018
The Aldol Reaction
– Step 3: Add a proton. Proton transfer from water

gives the aldol product and regenerates
hydroxide ion.
The Aldol Reaction
• Aldol products are very easily dehydrated to an

α, β-unsaturated aldehyde or ketone.
– Aldol reactions are reversible and often little aldol product

is present at equilibrium.
– Equilibrium constants for dehydration are generally large.
– If reaction conditions bring about dehydration, good yields
of an aldol product can be obtained.
5
9/18/2018
Crossed Aldol Reactions
• In a crossed aldol reaction, one kind of

molecule provides the enolate anion and
another kind provides the carbonyl group.
Crossed Aldol Reactions
• Crossed aldol reactions are most successful if:

– One of the reactants has no -hydrogen and,
therefore, cannot form an enolate anion.
– The other reactant has a more reactive carbonyl
group, namely an aldehyde. These aldehydes
have no -hydrogen, and are good enolate anion
acceptors.
6
9/18/2018
Intramolecular Aldols
• Occur when both the enolate anion and the

carbonyl acceptor are in the same molecule.
– This type of aldol reaction is particularly useful for the
formation of 5- and 6-membered rings.
– Because 5- and 6-membered are the most stable rings,
they form in preference to four- or seven- and larger rings.
• Consider the intramolecular aldol reaction of this
diketone, which contains two sets of -carbons.
Intramolecular Aldols
• The five-membered ring is formed in

preference to the seven-membered ring.
7
9/18/2018
Claisen Condensation
• Claisen condensation: A carbonyl condensation

reaction between two esters to give a 　-ketoester.
– Claisen condensations require a nonaqueous

base.
– An aqueous base would bring about hydrolysis of
the ester group.
– The most common nonaqueous bases are
sodium ethoxide in ethanol and sodium
methoxide in methanol.
8
9/18/2018
– Step 1: Take a proton away to form an enolate anion.
– Step 2: Reaction of a nucleophile and an electrophile

to form the new covalent bond. The product is a
tetrahedral carbonyl addition intermediate (TCAI).
– Step 3: Collapse of the TCAI and ejection of a leaving
group.
– Step 4: Take a proton away. Formation of a new enolate

drives the equilibrium for a Claisen condensation to the
right.
9
9/18/2018
– Step 5: Acidification gives the product.
Dieckmann Condensation
• Dieckmann condensation: An
intramolecular Claisen condensation of a
diester to give a five- or six-membered ring.
– The mechanism is identical to that of a Claisen

condensation.
10
9/18/2018
Claisen Condensations
• Crossed Claisen condensation: A Claisen

condensation between two different esters.
– Crossed Claisens are synthetically useful only if
there is an appreciable difference in reactivity
between the two esters.
– Such is the case if one of the esters has no
-hydrogen.
– Crossed Claisen condensations are usually

carried out by using an excess of the ester with
no -hydrogens.
11
9/18/2018
• From previous chapters, we know that

– Base-promoted hydrolysis (saponification) of an
ester followed by acidification converts an ester
to a carboxylic acid (Section 14.3C).
– -ketoacids and -dicarboxylic acids readily
undergo decarboxylation on mild heating (Section
13.8).
-Ketoesters
– The equation here and on the following screen

illustrate the use of a Claisen condensation
followed by saponification, acidification, and
decarboxylation to give a ketone.
12
9/18/2018
-Ketoesters
– The result of a Claisen condensation,

saponification, acidification, and decarboxylation
is a ketone.
– Problem: Show how to bring about this
conversion. Hint: first determine where a –COOH
group might have been and was lost by
decarboxylation.
13
9/18/2018
The Biological World
• Carbonyl condensations are used in the biological

world for making new C–C bonds, such as those in
the biosynthesis of:
– fatty acids.
– steroids, including cholesterol, steroid hormones, and bile
acids.
• The source of carbon atoms for the synthesis of
these biomolecules is the two-carbon acetyl group
of acetyl coenzyme A.

An Enzyme-catalyzed Claisen condensation of two acetyl-
CoA.
An aldol reaction with a third molecule of acetyl-CoAis

stereoselective, and gives only the S enantiomer.
14
9/18/2018
– Reduction of the thioester gives (R)-mevalonate.
– Enzyme-catalyzed transfer of phosphate and

pyrophosphate groups from ATP gives a
molecule that then undergoes enzyme-catalyzed
-elimination and decarboxylation. In this last
reaction, CO2 and pyrophosphate are both good
leaving groups.
15
9/18/2018
Cholesterol-Lowering Drugs
– Mevalonate is formed by reduction of the

thioester.
Cholesterol-Lowering Drugs
– The active form of the statin drugs contains a

3,5-dihydroxycarboxylate anion. Notice the
similarity in structure of mevalonate to this
carboxylate anion.
16
9/18/2018
Michael Reaction
• Michael reaction: the addition of an enolate

anion or other nucleophile to an
,-unsaturated carbonyl compound.
Michael Reaction
– Nucleophiles do not ordinarily add to carbon-

carbon double bonds; rather, C=C bonds are
attacked by electrophiles (Section 5.2).
– The presence of an adjacent carbonyl group
activates a carbon-carbon double bond towards a
nucleophile.
17
9/18/2018
Michael Reaction
Michael Reaction
– Step 1: Take a proton away. Treating Nu-H with

base gives the nucleophile.
– Step 2: Reaction of a nucleophile and an

electrophile gives a new covalent bond.
18
9/18/2018
Michael Reaction
– Step 3: Add a proton. Proton transfer from H-B

gives an enol and regenerates the base.
– Step 4: Tautomerism. Keto-enol tautomerism

regenerates the carbonyl group.
Michael Reaction
– Example: Name the type of reaction involved in

each step of this conversion.
19
9/18/2018
Michel Addition of Amines
– Ammonia and amines also function as

nucleophiles in Michael reactions.
– Methylamine, a 1° amine, undergoes a double

Michael addition.
Enolate Anions
• Problem: Show how to synthesize

compounds A, B, and C starting from
methylamine and any other necessary
reagents.
20
9/18/2018
Problem 15.25
• Show reagents and conditions to synthesize

the mild sedative oxamide starting with
butanal.
Problem 15.39
• Show reagents and conditions for this

synthesis of Fentanyl.
Copyright © 2017 John Wiley & Sons, Inc. All rights reserved.
15-42
21
9/18/2018
Enolate Anions
End Chapter 15
22

CH 15

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CH 15

Uploaded by

Copyright:

Available Formats

9/18/2018

• A carbon adjacent to a carbonyl group is

– -hydrogens of aldehydes, ketones, and esters

• We account for the acidity of -hydrogens in two

• Enolate anions can be formed either quantitatively

Enolates and New C-C Bonds

• Enolate anions function as nucleophiles in

The Aldol Reaction

• The product of an aldol reaction is

The Aldol Reaction

– Step 2: Reaction of a nucleophile and an

The Aldol Reaction

– Step 3: Add a proton. Proton transfer from water

The Aldol Reaction

• Aldol products are very easily dehydrated to an

– Aldol reactions are reversible and often little aldol product

Crossed Aldol Reactions

• In a crossed aldol reaction, one kind of

Crossed Aldol Reactions

• Crossed aldol reactions are most successful if:

• Occur when both the enolate anion and the

• The five-membered ring is formed in

• Claisen condensation: A carbonyl condensation

– Claisen condensations require a nonaqueous

– Step 2: Reaction of a nucleophile and an electrophile

– Step 4: Take a proton away. Formation of a new enolate

– The mechanism is identical to that of a Claisen

• Crossed Claisen condensation: A Claisen

– Crossed Claisen condensations are usually

• From previous chapters, we know that

– The equation here and on the following screen

– The result of a Claisen condensation,

The Biological World

• Carbonyl condensations are used in the biological

The Biological World

An aldol reaction with a third molecule of acetyl-CoAis

The Biological World

– Reduction of the thioester gives (R)-mevalonate.

The Biological World

– Enzyme-catalyzed transfer of phosphate and

– Mevalonate is formed by reduction of the

– The active form of the statin drugs contains a

• Michael reaction: the addition of an enolate

– Nucleophiles do not ordinarily add to carbon-

– Step 1: Take a proton away. Treating Nu-H with

– Step 2: Reaction of a nucleophile and an

– Step 3: Add a proton. Proton transfer from H-B

– Step 4: Tautomerism. Keto-enol tautomerism

– Example: Name the type of reaction involved in

Michel Addition of Amines

– Ammonia and amines also function as

– Methylamine, a 1° amine, undergoes a double

• Problem: Show how to synthesize

• Show reagents and conditions to synthesize

• Show reagents and conditions for this

You might also like