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Subject Chemistry

Paper No and Title Paper 9 : Organic Chemistry III (Reaction Mechanism-2)

Module No and Title Module 18 : Aldol Condensation

Module Tag CHE_P9_M18

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

MODULE No.18: Aldol Condensation
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TABLE OF CONTENTS

1. Learning Outcomes
2. Introduction
3. Chemistry of carbon-carbon bond formation
3.1 Role of enolate ions
3.2 Carbonyl groups show diverse reactivity
4. Mechanism of aldol reaction
4.1 Aldol reactions in the presence of a base
4.2 Aldol reactions in the presence of acid
4.3 Aldol reactions of unsymmetrical ketones
4.4 Cross- Aldol condensations
4.5 Intramolecular Aldol condensation
5. Summary

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

MODULE No.18: Aldol Condensation
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1. Learning Outcomes
After studying this module, you shall be able to

 Know about enolate chemistry and its importance in synthesis.

 Identify and write aldol reaction.
 Comprehend the mechanism of aldol condensation in base and acid medium.
 Understand the product formation in cross aldol condensation.
 Predict the major product in intramolecular aldol condensation.

2. Introduction
In organic synthesis, by far the most important activating groups are the carbonyl and carboxylic
ester groups. Removal of a proton from the α-carbon atom of a carbonyl compound with base
produces the corresponding α-carbanion, which are resonance stabilized via enolate anion. These
enolate ions are involved in base catalyzed reactions of carbonyl compounds.

Amongst these base catalyzed reactions, the Aldol reaction between an aldehyde and another
aldehyde or a ketone is a good method for making carbon-carbon bonds. In majority of simple
cases, as a result of this reaction, double the number of carbon atoms are present in the final
product as compared to the starting molecule. In general, it’s a challenge to get the desired
product because aldol condensation often gives a mixture of products by the inter-molecular
reaction between two different aldehydes or an aldehyde or ketone as well as a mixture of the syn
and anti-isomers is formed.

Over the last three decades, chemists have evolved methods of controlling the reactions of
enolates with carbon electrophiles. A number of methods have been developed to bring about
directed aldol reaction between two different carbonyl compounds to give a particular aldol
product. The success of these methods, however, depends on the fact that the reactions are carried
out in such a way that the newly formed aldol is trapped as a metal chelate complex. It also
protects it from wasteful side reactions, especially like dissociation into the free carbonyl
components that could undergo non-selective condensation.

3. Chemistry of Carbon-Carbon bond formation

3.1 Role of enolate ions

An enol is exactly what the name implies: an ene-ol. It has a C=C double bond and an OH group
joined directly to one of these double bonded carbon atoms. Recall that this is due to the
phenomenon of tautomerism, where in an α-hydrogen atom (proton) gets shifted to the oxygen
of the keto/aldehydic carbonyl group giving rise to enol and the two are in dynamic equilibrium
with each other. Interestingly there is no change in pH because a proton is lost from carbon and
gained on oxygen. These reactions are known as enolization as it is the conversion of a carbonyl
compound into its enol. These reactions are also named as tautomerisation.
The enolisation can be fastened in acidic and basic medium. This actually forms the basis for
Aldol reaction.
CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)
MODULE No.18: Aldol Condensation
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As an example of enolisation, consider dimedone (I) from which the corresponding enol (II) is
formed by a transfer of a proton (α-hydrogen atom) from the central CH2 group.

Note that the enols are in equilibrium with the keto form in the absence of any base or acid. In
the base-catalysed reactions like Aldol condensation, the enolate ions are the intermediates.
Enolate ion is the conjugate base of the enol and can be formed either directly from the carbonyl
compound by the loss of a C–H proton (α-hydrogen atom) or from the enol by loss of the O–H
proton.

Going by its structure, the enolate ion is simply an alkoxide ion, but it is more stable than the
corresponding simple saturated alkoxides structure because of the conjugation. The negative
charge is mainly on oxygen, the most electronegative atom.

In this module, we shall see how the enolate ions are very important in the Aldol condensation.

The key difference between the enolate and enol forms

The enolate is an intermediate independent ion, which is a resonance stabilized species
(delocalized system), with negative charge on both C and O —we use a double-headed

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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conjugation arrow to connect these two representations.

On the other hand, the enol form is a neutral molecule formed via the shifting of the proton (α-
hydrogen atom) from C to O and requires double bonds to break and form, and this is in real
equilibrium with its keto form, which must be represented by equilibrium arrows.

3.2 Introduction to Aldol Condensation

As you are already aware that carbonyl group is electron deficient at the carbonyl carbon and can
be hence attacked by nucleophiles. Most of these nucleophiles are generated from the reagents
added in appropriate conditions (acidic or basic medium).

The Aldol condensation (in presence of base) involves nucleophilic attack on the carbon of the
carbonyl group but not by any external reagent, rather the nucleophile is generated from the
carbonyl compound which attacks another such molecule. One molecule gets converted to enolate
ion and attacks as nucleophile on aldehyde/ketone molecule.

In an alternate condition (in presence of acids), electrophilic attack of one carbonyl molecule
occurs on the other carbonyl molecule.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Whenever an enolisable aldehyde (or a ketone) i.e., having α-hydrogen atom, is reacted with base
or acid, they condense to give rise to β – hydroxy-aldehydes (or β – hydroxy-ketones) known as
aldols.

The general reaction of Aldol condensation can be represented as follows:

Note that starting from aldehydes, the resulting compounds have both aldehydic as well as
alcoholic group and hence the trivial name “Aldol”. Note that the “ald” and “–OH” are in a
specific position, the –OH is at β – position to the aldehydic group. The product so formed are β–
hydroxyl-aldehydes. The name aldol is given to the whole class of reactions between enolates
(or enols) and carbonyl compounds even if in most cases the product is not a hydroxy-aldehyde at
all. The term “ketols” is also used for similar products obtained from ketones.

This reaction is very important because of the carbon–carbon bond formed in a highly directed
manner.

4. Mechanism of Aldol reaction

The aldol condensation can be achieved by reacting the enolisable aldehydes (or ketones)
i.e, having α-hydrogen atom either with a base or with an acid. Of these, base catalyzed reactions
are more common and give rise to better yields as compared to acid catalyzed one as the later
often lead to dimerization/polymerization as shown below:

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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4.1 Aldol reactions in the presence of a base

4.1.1 Reaction with aldehyde

Let us consider the simplest enolizable aldehyde acetaldehyde (ethanal, CH3CHO). Acetaldehyde
reacts with base (aq. NaOH) to form 3-hydroxy-butanal, which is a β-hydroxy aldehyde.

Mechanism: Let us understand the formation of the product with the help of mechanism.

First step: When a small amount of base e.g., NaOH is added, the α-hydrogen atom of some of
the molecules are abstracted to form the enolate ion via the α-carbanion. The hydroxide ion
abstracts the α-hydrogen atom to form enolate ion which is resonance stabilized with the α-
-
carbanion. The OH ion combines with α-hydrogen atom to form water.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Only a small amount of the nucleophilic enolate ion is formed. This is because, hydroxide ion is
not basic enough to enolize an aldehyde completely. Other non-enolized molecule of aldehyde
then surrounds each molecule of the enolate ion. These aldehyde molecules have the electrophilic
carbonyl group still intact.

Second step: Each enolate ion attacks one of these aldehydes at carbonyl carbon via carbon to
form an alkoxide ion. Hence a new carbon-carbon bond is form.

Third step: The alkoxide ion gets protonated by the water molecule, resulting in the formation of
the aldol product (3-hydroxy-butanal).

4.1.2 Reaction with ketone

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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The aldol reaction is also given by ketones having α-hydrogen

in them. However, these ketones give aldol reaction with lesser
ease as compared to the aldehydes. The reason for this is the steric hindrance and less
electrophilic nature of carbonyl carbon in ketones.

Let us consider acetone as an example. Acetone reacts with base to form 4-hydroxy-4-methyl-
pentan-2-one, which is a β-hydroxy ketone.

Mechanism: The mechanism is similar as in case of aldehydes.

First Step: The first step is the formation of enolate ion, via the removal of α-hydrogen atom. The
enolate ion is resonance stabilized via the α-carbanion.

Second Step: The second step is the attack of enolate ion via the α-carbanion through which it
attacks to another acetone molecule forming an alkoxide ion.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Third Step: The third step is the protonation of alkoxide ion

from water molecule. The product is a β-hydroxy-ketone. The
water molecule is regenerated as hydroxyl ion.

-unsaturated carbonyl compounds

The aldol reaction of acetaldehyde is speedup when one drop of dilute sodium hydroxide is added
to it at room temperature. Also, for acetone the aldol reaction is best done with insoluble barium
hydroxide, Ba(OH)2. The concentration of base should be low in both cases. Without this
precaution, the aldol products are not the compounds isolated from the reaction. With more
amount of base or concentrated base or at higher temperature conditions, further reaction of
dehydration occurs. This is because, the aldol products easily dehydrate under the reaction
conditions to give stable conjugated -unsaturated carbonyl compounds.

These are elimination reactions. Recall that water molecule cannot be easily removed from an
alcohol in basic solution , rather an acid catalysed dehydration is done.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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But, here, the dehydration is easier due to the carbonyl group

that facilitates it. A second enolization reaction initiates the
dehydration and these are E1cB reactions as shown below.

It has been observed that base-catalysed aldol reactions sometimes give the aldol and sometimes
the elimination product. This depends on the condition of the reaction such as the more vigorous
conditions i.e.stronger base, higher temperatures, longer reaction time etc. tend to give the
elimination product. On the other hand partly on the structure of the reagents there are some
combinations that are easy to stop at the aldol stage, while some almost always give the
elimination reaction as well.

4.2 Aldol reactions in the presence of acid

The aldol reaction can be catalyzed with acid also. The acid catalyzed elimination is easier and
give unsaturated products instead of aldols.

To understand the mechanism, let us consider an example of a symmetrical cyclic ketone,

cyclopentanone. The product enone (I ) is formed in good yield.

Mechanism:
First Step: In the acidic medium, protonation of carbonyl oxygen occurs which leads to the
formation of the enol in some molecules. Majority other molecules are in the protonated form due
to acidic medium.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Enols are less nucleophilic than enolates.

Second Step: The second step involves the attack of enol via β- carbon of the enolised molecule on
the electron deficient carbonyl carbon of the protonated molecule. Note that it is due to protonation that the
electrophilic character is enhanced. As a result of this attack, aldol is formed, but not as final
product.

Third Step: The third step comprises of elimination of water to give rise to conjugated
unsaturated ketone

The aldol in this case is a tertiary alcohol and would be likely to eliminate by an E1 mechanism in
acid even without the carbonyl group being present. But the presence of carbonyl group possibly
give the stable conjugated enone . The dehydration is perfectly acid-catalysed because here acid
reappears in the very last step.

Intermediates in this reaction cannot be detected or isolated, as the reaction of ketone and acid
gives a good yield of enone.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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A base-catalysed reaction of cyclopentanone gives the same

product i.e., the enone (I) via the aldol–E1cB elimination
mechanism.

4.3 Aldol reactions of unsymmetrical ketones

If the ketone is blocked on one side, it cannot be enolized , because there is no

that side, hence only one aldol reaction is possible. This type of ketone usually bear a tertiary
alkyl or an aryl substituent.

Let us consider t-Butyl methyl ketone (3,3-dimethylbutan 2-one) as an example. It gives aldol
reaction with various bases in 60–70% yield. Enolization cannot occur towards the t-butyl group

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Another example of blocked carbonyl compound is the lactone or cyclic ester. Usually Open
chain esters do not give aldol reactions but in the case of lactones it is possible because they are
similar to ketones and give unsaturated carbonyl products under basic conditions . Enolization is
unambiguous because the oxygen atom of ester blocks enolization on one side.

The enolate so formed is then react with the carbonyl group of an unenolized lactone, same as in
the case of aldehydes and ketones.

The last step is the dehydration which proceeds with E1cB mechanism via the enolate of the aldol
product.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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4.4 Cross-Aldol condensations

So far we have considered only ‘self-condensations’—dimerization reactions of a single carbonyl

compound. These form only a tiny fraction of known aldol reactions.

If two different carbonyl compounds ( both aldehydes or both ketones or combinations ) with one
of them having enolizable hydrogen atoms are reacted in the presence of acid or base resulting in
aldol products, the reaction is referred to as cross- Aldol condensations.
Here, the enolisable carbonyl compound acts as a nucleophile in its enol or enolate form, and the
other carbolyl compound acts as an electrophile.

Let us consider the example of acetophenone (PhCOMe) which reacts with 4-nitro-benzaldehyde
in aqueous alcoholic NaOH , to give almost quantitative yield of the corresponding enone. The
former here has enolizable hydrogen and hence it attacks via its enolate ion to the electron
deficient aldehydic carbon.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Note the electron withdrawing nitro group present in the later

helps to make it more electrophilic and facilitates the attack.

Mechanism

The first step, as earlier, is the formation of an enolate ion using NaOH as a base. Though both
carbonyl compounds are unsymmetrical, there is only one site for enolization as there is only one

In the next steps, the enolate ion attacks the electron deficient aldehydic carbon to give an
alkoxide ion. The alkoxide ion takes proton from the medium (ROH) to form the aldol. The aldol
subsequently dehydrates by the E1cB mechanism.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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Important points to keep in mind while carrying out crossed aldol reaction:

1. Out of two reactant, one must be capable of enolization i.e. should have α-hydrogen.

2. The other must be incapable of enolization and more so important, should be more
electrophilic than the enolizable entity. Electron withdrawing groups present on the
remaining part of the moleule help in increasing the electrophilicity.

4.5 Intramolecular Aldol Condensation

If in place of enolizable monocarbonyl compound, we start with an enolizable dicarbonyl

compound, it leads to intramolecular Aldol reactions. This is because, the molecule shall
have both the electrophilic as well as nucleophilic centre generated during the course of
the reaction. It concludes that both the enolate and the carbonyl components are parts of
a single larger molecule.

But in these cases, there shall always be more than one possibility of the product
formation. In order to find the major product follow the following in sequential manner:
1. If both aldehydic and ketonic groups are present, the enolisation of ketonic group
occurs and its intramolecular attack on aldehydic group occurs to give rise to the major
product of the various possibilities. This is because, in general, aldehydes are more
reactive (electrophilic) than ketones and will usually be the electrophile.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

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2. Stability of the cyclic aldol product controls the

selectivity and promote the formation of 5 or 6-
membered ring as they are more stable. For obtaining best products, on should check for
possible permutations and look for the favourable ring sizes.

For example, in the case of 6-keto-heptanal subjected to reaction with aqueous base, there
are two possibilities for the formation of enolate i.e. at C-5 or C-7 positions because
hydrogen can be abstract from either 5th or 7th position which can attack on aldehydic
carbon and results in the formation of 5membered or 7 membered aldol product
respectively. Of these, the major product contains a 5 membered ring ( 2-acetoxy-
cyclopentan-1-ol) that is formed by the abstraction of hydrogen from 5th carbon atom.
This is the reason of high stability of a 5 membered ring than a 7 membered ring.

5. Summary
 The aldol reaction between an aldehyde and another aldehyde or a ketone is a good
method for making carbon-carbon bonds.
 The enolate ion formed in the aldol reaction is basically the conjugate base of the enol
and can be formed either directly from the carbonyl compound by the loss of a C–H
proton or from the enol by loss of the O–H proton.
 The aldol reaction can be catalyzed with acid also. The acid catalyzed elimination is
easier and give unsaturated products instead of aldols.
 Intramolecular aldol condensation lead to the product having more stable ring.
 Cross aldol condensation can be used for variety of applications.

CHEMISTRY PAPER No. 9 : Organic Chemistry III (Reaction Mechanism-2)

MODULE No.18: Aldol Condensation