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Organic Chemistry

Second Edition
David Klein

Chapter 22
Alpha Carbon Chemistry: Enols and Enolates

Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
For carbonyl compounds, Greek letters are often used to
describe the proximity of atoms to the carbonyl center.*

This chapter will primarily explore reactions that take place


at the alpha () carbon.
*This method is also used elsewhere, -phenylethanol (PhCH2CH2OH),
omega-3 (-3) fats have a double bond 3 atoms from the chains end,
Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

22-2

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
The reactions we will explore proceed though either an enol
or an enolate intermediate:

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22-3

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
Trace amounts of acid or base catalyst provide
equilibriums in which both the enol and keto forms are
present

How is equilibrium different from resonance?

At equilibrium, >99% of the molecules exist in the keto


form. WHY?
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22-4

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
In rare cases such as the example below, the enol form
is favored in equilibrium

Give two reasons to explain WHY the enol is favored

The solvent can affect the exact percentages


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22-5

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
Phenol is an example where the enol is vastly favored over
the keto at equilibrium. WHY?

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22-6

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
The tautomerization mechanism depends on whether it is
catalyzed by acid or base (very slow without). Acid catalysis:

*Note: the most plentiful base in aqueous acid is water; dont invoke hydroxide under acid catalysis.

For example, in an aqueous solution at pH 2, waters concentration is 55 M, while [OH] is 10-12 M.

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22-7

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
The mechanism for the tautomerization depends on whether
it is acid catalyzed or base catalyzed

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22-8

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
As the tautomerization is practically unavoidable, some
fraction of the molecules will exist in the enol form.
Analyzing the enol form, there is a minor (but significant)
resonance contributor with a nucleophilic carbon atom
single bond

Practice with conceptual checkpoints 22.1


through 22.3
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22-9

double bond

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
In the presence of a strong base, an enolate forms

The enolate is much more nucleophilic than the enol.


WHY?

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22-10

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
The enolate can undergo
C-attack or O-attack.

Enolates generally
undergo C-attack. WHY?

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22-11

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
Alpha protons are the only protons on an aldehyde or
ketone that can be removed to form an enolate
Assign. Shift(ppm)
aldehyde
9.764

2.37

1.64

0.97

HC(=O)-CH2-CH2-CH3

http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?sdbsno=1925

Removing the aldehyde proton or the beta or gamma


proton will NOT yield a resonance stabilized intermediate
Practice with SkillBuilder 22.1
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22-12

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
sp2hybridized carbon, so no overlap between
aldehyde hydrogen and p orbital on the carbonyl C.
H
O
C

C
H
H

Electrostatic charges

H
O
C

of enolate atoms
C
H

Natural charges
of enolate atoms

Better predictor

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
Draw all possible enolates that could form from the following
molecule:

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22-14

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
Why would a chemist want to form an enolate?
To form an enolate, a base must be used to remove an
alpha proton.
The best choice of base depends on the acidity of the
alpha protons.
How do we quantify how acidic something is?

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22-15

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
Lets compare some pKa values for some alpha protons

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22-16

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates

When pKa values are similar, both products and reactants


are present in significant amounts:

Which side will this equilibrium favor?


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22-17

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
In this case, it is an advantage to have both enolate and
aldehyde in solution so they can react with one another

Show how the electrons might move in the reaction


between the enolate and the aldehyde.

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22-18

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
To have the carbonyl react irreversibly, a stronger base
(needing to have low nucleophilicity) such as H- is needed.
*

When is it synthetically desirable to convert all of the


carbonyl into an enolate?
* Note: the authors slides often omit the enolate resonance form
having the negative charge on oxygen (which is the major contributor),
perhaps to emphasize that most reactions take place on the carbon.
Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

22-19

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
LDA is an even stronger base that is frequently used to
promote irreversible enolate formation:

(see box on
Previous slide)

Why is the reaction effectively irreversible?


LDA has two bulky isopropyl groups. Why would such a
bulky base be desirable?
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22-20

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
When a proton is next to two carbonyl groups, its acidity is
increased:

Draw the resonance contributors that allow 2,4pentanedione to be so acidic

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22-21

Klein, Organic Chemistry 2e

22.1 Introduction Alpha Carbon


Chemistry: Enols and Enolates
2,4-Pentanedione is sufficiently acidic that hydroxide or
alkoxides can deprotonate it irreversibly.

Figure 22.2 summarizes the relevant factors you should


consider when choosing a base.
Practice with conceptual checkpoints 22.6 through 22.8.
Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

22-22

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


H3O+ catalyzes ketoenol tautomerism. HOW?
The enol tautomer can attack a halogen molecule:

The process is autocatalytic the regenerated acid can


catalyze another tautomerization and halogenation.
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22-23

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


When an unsymmetrical ketone is used, bromination
occurs primarily at the more substituted carbon

Because the major product results from the more stable


(more substituted) enol.
A mixture of products is generally unavoidable.
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22-24

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


This provides a two step synthesis for the synthesis of an
,-unsaturated ketone:

Give a mechanism that shows the role of pyridine.


Other bases such as potassium tert-butoxide (why this
one?) may also be used in the second step.
Practice with conceptual checkpoints 22.9 and 22.10.
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22-25

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


The Hell-Volhard-Zelinski(ii,y) reaction brominates the
alpha carbon of a carboxylic acid:

PBr3 forms the acyl bromide, which more readily forms the
enol and attacks the bromine.
Hydrolysis of the acyl bromide is the last step.
Draw a complete mechanism.
Practice checkpoints 22.11 and 22.12
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22-26

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


Alpha halogenation can also be achieved under basic
conditions:

The formation of the enolate is not favored, but the


equilibrium is pushed forward by the second step.
Will the presence of the bromine make the remaining
proton more or less acidic?

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22-27

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


Controlled monosubstitution is not possible. WHY?
Methyl ketones can be converted to carboxylic acids using
excess halogen and hydroxide.

Once all three protons are substituted, the CBr3 group


becomes a decent leaving group.

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22-28

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


Once all three protons are substituted, the CBr3 group
becomes a decent leaving group

The last step


below is
practically
irreversible.
WHY?

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22-29

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


The carboxylate produced on the last slide can be
protonated with H3O+
The reaction works well with Cl2, Br2, and I2, and it is known
as the haloform reaction.
The iodoform reaction may be used to test for methyl
ketones, because iodoform can be observed as a yellow
solid when it forms.
Practice with conceptual checkpoints 22.13 and 22.14.

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22-30

Klein, Organic Chemistry 2e

22.2 Alpha Halogenation of Enols and Enolates


Give the major product for the reaction below. Be careful
with regards to stereochemistry (?!):

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22-31

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Recall that treating an aldehyde with hydroxide or alkoxide
yields an equilibrium in which significant amounts of both
enolate and aldehyde are present.
If the enolate attacks the aldehyde, an aldol reaction
occurs:

The product features both aldehyde and alcohol groups.


Note the location of the OH group on the beta carbon.

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22-32

Klein, Organic Chemistry 2e

22.3 Aldol Reactions

The aldol mechanism

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22-33

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


The aldol reaction is an equilibrium process that generally
favors the products:

How might the temperature affect the equilibrium?

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22-34

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


A similar reaction with ketones generally does NOT favor
the -hydroxyketone product:

Give a reasonable mechanism for the retro-aldol reaction.


Practice with SkillBuilder 22.2
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22-35

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Predict the products for the follow reaction, and give a
reasonable mechanism. Be careful of stereochemistry

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22-36

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


When an aldol product is heated under acidic or basic
conditions, an ,-unsaturated carbonyl forms:

Such a process is called an aldol condensation, because


water is given off.
The elimination reaction above is an equilibrium, which
generally favors the products.
WHY? Consider enthalpy and entropy.
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22-37

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


The elimination of water can be promoted under acidic or
under basic conditions.
Give a reasonable mechanism for each

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22-38

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


When a water is eliminated, two products are possible.
Which will likely be the major product? Use the
mechanism to explain.

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22-39

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Because the aldol condensation is favored, it is often
impossible to isolate the aldol product without elimination:

Condensation is especially favored when extended


conjugation results.

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22-40

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


At low temperatures, condensation is less favored, but the
aldol product is still often difficult to isolate in good yield

Practice with SkillBuilder 22.3.


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22-41

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Predict the major product of the following reaction. Be
careful of stereochemistry

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22-42

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Substrates can react in a crossed aldol or mixed aldol
reaction. Predict 4 possible products in the reaction below

Such a complicated mixture of products is not very practical


synthetically. WHY?
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22-43

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Practical crossed aldol reactions can be achieved through one
of two methods:
1. One of the substrates is relatively unhindered and without alpha
protons:

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22-44

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


1. One of the substrates is relatively unhindered and without
alpha protons

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22-45

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Practical crossed aldol reactions can be achieved through one
of two methods:
2. One substrate is added dropwise to LDA forming the enolate
first. Subsequent addition of the second substrate produces the
desired product:

Practice with
SkillBuilder 22.4
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22-46

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Describe an aldol route to yield the following compound:

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22-47

Klein, Organic Chemistry 2e

22.3 Aldol Reactions


Cyclic compounds can be formed through intramolecular
aldol reactions.

One group forms an enolate that attacks


the other group.
Recall that 5 and 6-membered rings are
most likely to form. WHY?
Practice conceptual checkpoints 22.25
through 22.27.
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22-48

Klein, Organic Chemistry 2e

22.4 Claisen Condensations


Esters also undergo reversible condensations reactions

Unlike a ketone or aldehyde, an ester has a leaving group...


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22-49

Klein, Organic Chemistry 2e

22.4 Claisen Condensations


Esters also undergo reversible condensations reactions

The resulting doubly-stabilized enolate must be treated


with an acid in a last step. WHY?
A beta-keto ester is produced
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22-50

Klein, Organic Chemistry 2e

22.4 Claisen Condensations


There are some limitations to the Claisen condensation:
1. The starting ester must have two alpha protons, because
removal of the second proton by the alkoxide ion is what drives
the equilibrium forward.
2. Hydroxide cannot be used as the base to promote Claisen
condensations, because a hydrolysis reaction occurs between
hydroxide and the ester.
3. An alkoxide equivalent to the OR group of the ester is a good
base, because nontrivial transesterification is avoided.

Practice conceptual checkpoints 22.28 and 22.29.

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22-51

Klein, Organic Chemistry 2e

22.4 Claisen Condensations


Crossed Claisen reactions can also be achieved using the
same strategies employed in crossed aldol reactions

Practice with conceptual checkpoint 22.30


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22-52

Klein, Organic Chemistry 2e

22.4 Claisen Condensations


Intramolecular Claisen condensations can also be achieved

This Diekmann cyclization proceeds through the expected


5-membered ring transition state. DRAW it.
Practice with conceptual checkpoints 22.31 and 22.32.

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22-53

Klein, Organic Chemistry 2e

22.4 Claisen Condensations


Draw reactants needed to synthesize the following molecules:

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22-54

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


The alpha position can be alkylated when an enolate is
treated with an alkyl halide:

The enolate attacks the alkyl halide via an SN2 reaction:

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22-55

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


When 2 or 3 alkyl halides are used, the enolate can act as
a base in an E2 reaction. SHOW a mechanism.
The aldol reaction also competes with the desired
alkylation, so a strong base, such as LDA, must be used.
Regioselectivity is often an issue when forming enolates.
If the compound below is treated with a strong base, two
enolates can form see next few slides:

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22-56

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton

What is meant by kinetic and thermodynamic enolate?


See next few slides for details
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22-57

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


For clarity, the kinetic and thermodynamic pathways are
exaggerated below
Explain the energy
differences below
using steric and stability
arguments

Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

22-58

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


LDA is a strong base, and at low temperatures, it will react
effectively irreversibly.
NaH is not quite as strong, and if heat is available, the
system will be reversible:

Practice with conceptual


checkpoints 22.33 and
22.24.
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22-59

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


Give reagents necessary to synthesize the compound below
starting with carbon fragments having five or fewer carbons:

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22-60

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


The malonic ester synthesis allows a halide to be converted
into a carboxylic acid with two additional carbons:

Diethyl malonate is first treated with a base to form a


doubly-stabilized enolate:

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22-61

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


The enolate is treated with the alkyl halide

The resulting diester can be hydrolyzed with acid or base


using heat

And then
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22-62

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


One of the resulting carboxylic acid groups can be
decarboxylated with heat through a pericyclic reaction:

Why isnt the second carboxylic acid group removed?

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22-63

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


Here is an example of the overall synthesis

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22-64

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


Double alkylation can also be achieved:

Practice with SkillBuilder 22.5.


The acetoacetic ester synthesis is a very similar process:

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22-65

Klein, Organic Chemistry 2e

22.5 Alkylation of the Alpha Proton


Give a complete mechanism for the process below

Practice with SkillBuilder 22.6

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22-66

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Recall that ,-unsaturated carbonyls can be made easily
through aldol condensations

,-unsaturated carbonyls have three resonance


contributors:

Which contributors are electrophilic?


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22-67

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Grignard reagents generally attack the carbonyl position
of ,-unsaturated carbonyls yielding a 1,2 addition

In contrast, Gilman reagents generally attacks the beta


position giving 1,4 addition or conjugate addition

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22-68

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Conjugate addition of ,-unsaturated carbonyls starts
with attack at the beta position:

WHY is the
nucleophile
generally favored
to attack the beta
position?
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22-69

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


More reactive nucleophiles (e.g., Grignard) are more likely
to attack the carbonyl directly. WHY?
Enolates are generally less reactive than Grignards, but
more reactive than Gilman reagents, so enolates often give
a mixture of 1,2- and 1,4- addition products
Doubly-stabilized enolates are stable enough to react
primarily at the beta position

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22-70

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


When an enolate attacks a beta carbon, the process is called
a Michael addition:

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22-71

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Give a mechanism showing the reaction between the two
compounds shown below:

Practice with conceptual checkpoints 22.44 through 22.46.

Copyright 2015 John Wiley & Sons, Inc. All rights reserved.

22-72

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Because singly-stabilized enolates do not give high yielding
Michael additions, Gilbert Stork developed a synthesis
using an enamine intermediate.
Recall the enamine synthesis from chapter 20:

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22-73

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Enolates and enamines have reactivity in common:

The enamine is less nucleophilic and more likely to act


as a Michael donor
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22-74

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions

Water hydrolyzes the imine and tautomerizes and


protonates the enol
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22-75

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


Give reagents necessary to synthesize the molecule
below using the Stork enamine synthesis

Practice with SkillBuilder 22.7


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22-76

Klein, Organic Chemistry 2e

22.6 Conjugate Addition Reactions


The Robinson Annulation utilizes the a Michael addition
followed by an aldol condensation

Practice checkpoints 22.49 and 22.50


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22-77

Klein, Organic Chemistry 2e

22.7 Synthetic Strategies


Most of the reactions in this chapter are C-C bond
forming
Three of the reactions yield a product with two
functional groups
The positions of the functional groups in the product
can be used to design necessary reagents in the
synthesis see next few slides
Practice with SkillBuilder 22.8

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22-78

Klein, Organic Chemistry 2e

22.7 Synthetic Strategies


Stork enamine synthesis 1,5-dicarbonyl compounds

Aldol and Claisen 1,3-difunctional compounds

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22-79

Klein, Organic Chemistry 2e

22.7 Synthetic Strategies


We have learned two methods of alkylation
1. The alpha position of an enolate attacks an alkyl halide
2. A Michael donor attacks the beta position of a Michael
acceptor

These two reactions can also be combined

Give a reasonable mechanism


Practice with SkillBuilder 22.9
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22-80

Klein, Organic Chemistry 2e

22.7 Synthetic Strategies


Give reagents necessary for the following synthesis

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22-81

Klein, Organic Chemistry 2e

Additional Practice Problems


Explain why an enolate is more likely to produce products
resulting from attack by the alpha carbon than by direct
attack by the oxygen. Is the argument kinetic, thermodynamic
or both?

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22-82

Klein, Organic Chemistry 2e

Additional Practice Problems


Give the major products for the reaction below

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22-83

Klein, Organic Chemistry 2e

Additional Practice Problems


Using both kinetic and thermodynamic arguments,
explain why aldol reactions involving a ketone are less
product favored than those involving aldehydes

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22-84

Klein, Organic Chemistry 2e

Additional Practice Problems


Give reagents necessary to produce the product below
using aldol chemistry:

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22-85

Klein, Organic Chemistry 2e

Additional Practice Problems


Give reagents necessary for the synthesis below

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22-86

Klein, Organic Chemistry 2e

Additional Practice Problems


Give reagents necessary for the synthesis below

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22-87

Klein, Organic Chemistry 2e