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Aldol Reactions
Recall that when an aldehyde is treated with hydroxide
(or alkoxide), an equilibrium forms where significant
amounts of both enolate and aldehyde are present.
If the enolate attacks the aldehyde, an aldol reaction
occurs.

Nucleophilic Addition of Enolates

The characteristic reaction of aldehydes and ketones is
nucleophilic addition.
An aldol reaction is a nucleophilic addition in which an
enolate is the nucleophile.

The product features both aldehyde and alcohol groups.

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

Aldol Reactions
The aldol mechanism:

Aldol Reaction with Propanal

A second example of an aldol reaction is shown with propanal
as the starting material.
The two molecules of the aldehyde that participate in the aldol
reaction react in opposite ways.
One molecule becomes an enolatean electron-rich
nucleophile.
One molecule serves as the electrophile because its
carbonyl is electron deficient.

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Joining Carbons to Form Aldol Products

The carbon of one carbonyl component becomes bonded
to the carbonyl carbon of the other component.

Q: Aldol Reactions
A similar reaction for a ketone generally does NOT favor
the -hydroxy ketone product.

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

ANS: Aldol Reactions

Give a reasonable mechanism for the retro-aldol
reaction

Give a reasonable mechanism for the retro-aldol

reaction.

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

ANS: Aldol Reactions

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

Because of the basic conditions, each stereocenter at an alpha

carbon will be racemized

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

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

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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ANS: Aldol Reactions

Give a reasonable mechanism for each

Aldol Reactions
Because the aldol condensation is favored, often it is
impossible to isolate the aldol product without
elimination.

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

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

Condensation is especially favored when extended

conjugation results.

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Q: Aldol Reactions
Predict the major product of the following reaction. Be
careful of stereochemistry.

ANS: Aldol Reactions

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

Because of the basic conditions, each stereocenter at an alpha

carbon will be racemized

Crossed Aldol Reactions

Sometimes it is possible to carry out an aldol reaction
between two different carbonyl compounds.
Such reactions are called crossed or mixed aldol reactions.

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

Example of Crossed Aldol Reactions

In this type of crossed aldol reaction, the initial -hydroxy
compound always loses water to form the highly conjugated
product.

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.

Q: Aldol Reactions
Describe a synthesis necessary to yield the following
compound.

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ANS: Aldol Reactions

Describe a synthesis necessary to yield the following
compound

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?

Dehydration of the Aldol Product

Under the basic reaction conditions, the initial aldol product
is often not isolated.
Instead, it loses the elements of H2O from the and
carbons to form an ,
-unsaturated carbonyl compound.

The Claisen Reactions

In the Claisen reaction, two molecules of an ester react with
each other in the presence of an alkoxide base to form a
-keto ester.
Unlike the aldol reaction which is base-catalyzed, a full
equivalent of base is needed to deprotonate the -keto ester
formed in Step [3] of the Claisen reaction.

Since esters have a leaving group on the carbonyl carbon,

loss of the leaving group occurs to form the product of
substitution, not addition.
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Claisen ReactionExample of
Nucleophilic Substitution
The characteristic reaction of esters is nucleophilic
substitution.
A Claisen reaction is a nucleophilic substitution in which an
enolate is the nucleophile.

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 transesterification is avoided.

Crossed Claisen Reaction

Like the aldol reaction, it is sometimes possible to carry out
a Claisen reaction with two different carbonyl components as
starting materials.
A Claisen reaction between two different carbonyl
compounds is called a crossed Claisen reaction.
A crossed Claisen is synthetically useful in two different
instances:
[1] Between two different esters when only one has
hydrogens, one product is usually formed.

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Q: Claisen Condensations

Crossed Claisen Reaction

[2] Between a ketone and an esterthe enolate is always
formed from the ketone component, and the reaction works
best when the ester has no hydrogens.
The product of this crossed Claisen reaction is a
-dicarbonyl compound, not a -keto ester.

Intramolecular Claisen condensations can also be

achieved.

This DIEKMANN CYCLIZATION proceeds through the

expected 5-membered ring transition state. DRAW it.

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ANS: Claisen Condensations

Claisen Condensations
Give reagents necessary to synthesize the following
molecules.

This Diekmann cyclization proceeds through the

expected 5-membered ring transition state. DRAW it

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Claisen Condensations
Give reagents necessary to synthesize the following
molecules

The Dieckmann Reaction

An intramolecular Claisen reaction is called a Dieckmann
reaction.
Two types of diesters give good yields of cyclic products.

Alkylation of the Alpha Position

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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Alkylation of the Alpha Position

Alkylation of the Alpha Position

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.
What is meant by kinetic and thermodynamic enolate?

Alkylation of the Alpha Position

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

Alkylation of the Alpha Position

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

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Q: Alkylation of the Alpha Position

Give necessary reagents to synthesize the compound
below starting with carbon fragments with five carbons
or less.

The Malonic Ester Synthesis

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.

ANS: Alkylation of the Alpha

Proton
Give necessary reagents to synthesize the compound
below starting with carbon fragments with 5 carbons or
less

The Malonic Ester Synthesis

The enolate is treated with the alkyl halide.

The resulting diester can be hydrolyzed with acid or

base, and using heat.

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The Malonic Ester Synthesis

One of the resulting carboxylic acid groups can be
DECARBOXYLATED with heat through a pericyclic
reaction.

Alkylation of the Alpha Position

Here is an example of the overall synthesis.

Why isnt the second carboxylic acid group removed?

The Malonic Ester Synthesis

Malonic Ester Synthesis

Double alkylation can also be achieved:

The malonic ester synthesis results in the preparation of

carboxylic acids having two general structures:

The acetoacetic ester synthesis is a very similar process.

The malonic ester synthesis is a stepwise method for converting

diethyl malonate into a carboxylic acid having one or two alkyl
groups on the carbon.

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Decarboxylation of Malonic Esters

Heating diethyl malonate with acid and water hydrolyzes both
esters to carboxy groups, forming a -diacid (1,3-diacid).

-Diacids are unstable to heat and decarboxylate resulting in

cleavage of a CC bond and formation of a carboxylic acid.

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Path of Malonic Ester Synthesis

Thus, the malonic ester synthesis converts diethyl malonate to a
carboxylic acid in three steps.

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Decarboxylation Result
The net result of decarboxylation is cleavage of a CC bond on
the carbon, with loss of CO2.
Decarboxylation occurs readily whenever a carboxy group
(COOH) is bonded to the carbon of another carbonyl group.

This can also occur with -keto acids, forming a ketone.

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Example of Malonic Ester Synthesis

The synthesis of 2-butanoic acid (CH3CH2CH2COOH) from diethyl
malonate illustrates the basic process:

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Repeated Malonic Ester Synthesis

If the first two steps of the reaction sequence are repeated prior to
hydrolysis and decarboxylation, then a carboxylic acid having two
new alkyl groups on the carbon can be synthesized.
This is illustrated in the synthesis of 2-benzylbutanoic acid
[CH3CH2CH(CH2C6H5)COOH] from diethyl malonate.

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Retrosynthetic Analysis of Malonic Esters

To use the malonic ester synthesis, you must be able to determine
what starting materials are needed to prepare a given
compoundthat is, you must work backwards in the
retrosynthetic direction.
This involves a two-step process:

Intramolecular Malonic Ester Synthesis

An intramolecular malonic ester synthesis can be used to form
rings having three to six atoms, provided the appropriate dihalide
is used as starting material.
For example, cyclopentanecarboxylic acid can be prepared from
diethyl malonate and 1,4-dibromobutane (BrCH2CH2CH2CH2Br)
by the following sequence of reactions.

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Q: The Malonic Ester Synthesis

Give a complete mechanism for the process below.

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ANS: The Malonic Ester Synthesis

Give a complete mechanism for the process below

Haloform Reaction
The addition of one Br atom stabilizes the second enolate due to
the electron-withdrawing inductive effect of Br.
As a result, the H of -bromopropiophenone is more acidic than
the H atoms of propiophenone, making it easier to remove with
base.
Halogenation of a methyl ketone with excess halogen, called the
haloform reaction, results in the cleavage of a CC
bond and formation of two products, a carboxylate anion and
CHX3 (commonly called haloform).
The final cleavage step is actually a nucleophilic substitution,
made possible by the fact that the tri-substituted CX3 is now a
good leaving group.

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Haloform Reaction
In the haloform reaction, the three H atoms of the CH3 group are
successively replaced by X to form an intermediate that is oxidatively
cleaved with base.
Methyl ketones form iodoform (CHI3), a pale yellow solid that
precipitates from the reaction mixture.
This reaction is the basis of the iodoform test to detect methyl
ketones.
Methyl ketones give a positive iodoform test (appearance of a yellow
solid) whereas other ketones give a negative iodoform test (no
change in the reaction mixture).

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Forming -Dicarbonyl Compounds

-Dicarbonyl compounds are also prepared by reacting an
enolate with ethyl chloroformate or diethyl carbonate.

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The Michael Reaction

The Michael reaction involves two carbonyl components
the enolate of one carbonyl compound and an
,
-unsaturated carbonyl compound.

Preparing -Keto Esters

Reaction [2] is noteworthy because it provides easy access
to -keto esters, which are useful starting materials in the
acetoacetic ester synthesis.
In this reaction, Cl is eliminated rather than OEt in Step [3]
because Cl is a better leaving group, as shown in the
following steps.

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Michael Acceptors

The ,
-unsaturated carbonyl component is often called a
Michael acceptor.

Recall that ,
-unsaturated carbonyl compounds are
resonance stabilized and have two electrophilic sitesthe
carbonyl carbon and the carbon.

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Conjugate Addition Reactions

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

Michael Reaction Products

Using the Michael Reaction

When the product of a Michael reaction is also a -keto ester,

it can be hydrolyzed and decarboxylated by heating in
aqueous acid.
This forms a 1,5-dicarbonyl compound.
1,5-dicarbonyl compounds are starting materials for
intramolecular aldol reactions.

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

Michael Reactions
Conjugate addition of ,-unsaturated carbonyls starts
with attack at the beta position.

In contrast, Gilman reagents generally attacks the beta

position giving 1,4 addition, or CONJUGATE ADDITION.

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