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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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) MODULE No.18: Aldol Condensation
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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