Synthetic reactions that create carbon bonds are very important in organic chemistry. Among those reactions, the aldol reaction is one of the most frequently used synthetic reactions. When learning organic chemistry, the synthetic reaction that is learned by all people is the aldol reaction.
However, the aldol reaction doesn’t end with a single reaction. After a product is formed, the reaction can proceed further by a dehydration reaction. This is called aldol condensation.
Aldol reaction is an important reaction, and it is necessary to understand the reaction mechanism in detail. Otherwise, it is not possible to predict what products can be synthesized.
Many studies have been done on the aldol reaction. Therefore, there are many applications. This section explains the basics of the aldol reaction and aldol condensation.
Table of Contents
- 1 Reaction of Enolates with Ketones or Aldehydes Are Aldol Reactions.
- 2 Crossed Aldol Reactions Are Less Useful
- 3 Aldol Condensation Proceeds in the E1cB Reaction (Elimination Reaction)
- 4 Cyclization in Intramolecular Aldol Reactions
- 5 Aldol Reactions to Create Carbon Bonds
Reaction of Enolates with Ketones or Aldehydes Are Aldol Reactions.
For compounds with carbonyl groups, keto-enol tautomerism is possible. Normally they are in keto form, but they can change their molecular form to enol form.
The ability to be an enol form is related to the α-carbon of the carbonyl group (the carbon atom next to the carbonyl group). The hydrogen atom (α-hydrogen) bonded to the carbon atom next to the carbonyl group is highly acidic and can easily be pulled out by a base. The result is an enol form.
The molecule formed in this process is called an enolate. The protons are pulled out to form enolates as follows.
In enolates, the α-carbon is negatively charged. It is nucleophilic due to its carbanion character. Therefore, it can attack the carbonyl carbons of ketones and aldehydes.
The enolate reacts with the carbonyl compound to yield a new product (β-hydroxycarbonyl compound), as shown below.
This reaction, in which β-hydroxycarbonyl compounds are synthesized, is called the aldol reaction. Since it is an addition reaction, it is also called aldol addition.
-Difference from Claisen Condensation.
Claisen condensation is a chemical reaction similar to the aldol reaction. Claisen condensation is a synthetic reaction of enolates and esters. In addition, unlike the aldol reaction, the ester is leaveed in Claisen condensation. The reaction with enolate is the same, but the reaction mechanism is different.
If the enolate reacts with a ketone or aldehyde, the reaction is an aldol reaction. On the other hand, when enolate reacts with an ester, the reaction is a Claisen condensation. It is important to understand that these differences exist.
Reaction Mechanism of Aldol Addition by Base
So how does the aldol reaction proceed? In general, aldol addition is catalyzed by a base. The formation of enolate by the base causes the aldol reaction to occur.
The reaction mechanism is as follows.
As mentioned above, the alpha carbon is negatively charged. Because of this, it can attack the carbonyl carbons of ketones and aldehydes. As a result, it can create new carbon chains.
-The Reaction Proceeds with an Amount of Catalytic Base
Note that in aldol addition, the synthesis proceeds with a catalytic amount of base. It is not required to add an equivalent amount of base. Therefore, the aldol reaction proceeds even if a weaker base than enolate is used.
What is the reason for this? The entire reaction mechanism of aldol addition can be described as follows.
Initially, the base pulls out a proton to form an enolate. Then, as the aldol addition reaction proceeds, the H+ bound to the base is pulled out and the base is regenerated. Therefore, the base pulls out the alpha hydrogen again to make enolate.
This is the reason why the reaction proceeds if there is a catalytic amount of base in aldol addition. Incidentally, one equivalent amount of base is required for Claisen condensation. The reason for this is that the base does not regenerate as in the aldol reaction.
Crossed Aldol Reactions Are Less Useful
In aldol addition, aldol reactions between the same molecules are frequently used as an example. Is it possible to make an aldol reaction using different molecules? The reaction of two different molecules to produce an aldol reaction is called crossed aldol reaction.
In general, however, crossed aldol reactions are not useful. The reason for this is that many compounds are formed.
For example, is it possible to synthesize the following compounds by adding propionaldehyde after acetaldehyde is enolated with a base?
The answer is that this compound is not the only one that can be synthesized. Many other products can be synthesized as well.
As mentioned earlier, the α-hydrogen of the carbonyl group is highly acidic. Since enolate is also a strong base, enolate pulls out the protons bound to the α-carbon of propionaldehyde. As a result, enolate derived from propionaldehyde is also synthesized.
Thus, two types of enolates are formed in the solution. Therefore, the following four substances each react in solution
- Reaction of acetaldehyde (enolate) with acetaldehyde
- Reaction of acetaldehyde (enolate) with propionaldehyde
- Reaction of propionaldehyde (enolate) with propionaldehyde
- Reaction of propionaldehyde (enolate) with acetaldehyde
Four different compounds are synthesized, as shown in the figure above. The crossed aldol reaction is less useful because many byproducts are synthesized. Because of the complexity of the reaction, there are few cases of aldol reactions of different compounds.
Crossed Aldol Reaction Should Be Performed with a Compound Without α-Hydrogen
So does the crossed aldol reaction make no sense? No. Under certain conditions, the crossed aldol reaction makes sense. That is, when an aldol addition is made using a compound that does not have α-hydrogen atom.
In some compounds, there are no hydrogen atoms in the alpha carbon. In that case, no acid-base reaction occurs when reacting with enolate. The synthetic reaction can proceed without the formation of other enolates in the solution.
For example, the following compounds react with each other.
The compound shown in the above figure, which reacts with enolate, has no α-hydrogen. Therefore, no acid-base reaction occurs, only one reaction. To make the crossed aldol reaction successful, you should understand that the compounds to be reacted are limited.
As for what form of enolate can be synthesized, the regioselectivity can be controlled by the type of base; if the steric hindrance is small, such as NaH, an enolate with many substituents is synthesized. On the other hand, in the case of a base with high bulk, such as LDA, an enolate with few substituents is synthesized due to steric hindrance.
Subsequently, by adding a carbonyl compound without α-hydrogen, the desired compound can be obtained by the crossed aldol reaction.
Aldol Condensation Proceeds in the E1cB Reaction (Elimination Reaction)
In addition, to obtain an aldol compound (β-hydroxycarbonyl compound), a small amount of a base is added to the aldol addition. By adding a catalytic amount of base, the target compound can be obtained while generating enolate.
On the other hand, if the amount of base is high, different compounds can be synthesized. Specifically, alkene compounds can be obtained through elimination reactions.
Normally, the alcohol does not leave. However, if -OH (hydroxy group) is present at the β-position of the ketone (carbonyl group), the hydroxy group is released after the compound is enolated. The reaction mechanism is as follows.
This is called the E1cB reaction. If a ketone is present, the compound becomes an enolate because the alpha hydrogen is highly acidic. Then when the electrons return, if there are leaving groups, the elimination reaction occurs, making a double bond.
The removal of water or alcohol to form a new molecule is called condensation. Starting from the aldol reaction, the E1cB reaction leads to the elimination of -OH, and this reaction is called aldol condensation as mentioned above. In addition to aldol addition, the condensation reaction proceeds in aldol condensation.
Incidentally, in general, aldol condensation tends to progress under extreme conditions, such as the use of strong bases, high reaction temperatures and long reaction times.
-Crossed Aldol Condensation Is Available
As for aldol condensation, crossed aldol condensation is also available. When performing crossed aldol reactions, if the base is in excess, the E1cB reaction proceeds and crossed aldol condensation occurs.
Whether you want to get an aldol compound or an alkene by crossed aldol condensation, be sure to adjust the amount of base.
Dehydration by E1 or E2 Elimination Occurs in Acid Catalyst (Acidic Conditions)
As for aldol condensation, it proceeds under acidic conditions as well as basic conditions. The fact that alkenes (double bonds) are formed by the elimination reaction is the same. However, the reaction mechanism is different from that of basic conditions. With the use of an acid catalyst, dehydration occurs by E1 or E2 elimination.
Under acidic conditions, a proton binds to an oxygen atom, which gives it a positive charge. Water is then released and a double bond is formed.
The reaction mechanism for dehydration by E2 desorption, for example, under acid-catalyzed conditions, is as follows.
Since the reaction takes place under acidic conditions, the number of bases present in the solution is extremely small. However, since α-hydrogen is highly acidic, the E2 reaction proceeds even with a small amount of bases. In addition, the reaction may proceed in the E1 reaction.
Cyclization in Intramolecular Aldol Reactions
If the molecule has a ketone (carbonyl group) or aldehyde (formyl group) functional group in the same molecule, it will be cyclized. This is called intramolecular aldol reaction.
The reaction mechanism is the same as the aldol addition described above. Let’s understand that an aldol reaction occurs within the same molecule. In this case, compounds with five or six membered rings are mainly synthesized. For example, in the following compounds, the addition of a base causes the aldol reaction (aldol condensation) to proceed.
What is important is the formation of the six-membered ring compound.
In the carbonyl compound shown above, there are two α-carbon locations. However, the enolate can only attack at one location. For example, in the following reaction mechanism, an eight-membered ring compound is formed.
However, it is not possible to synthesize 8-membered ring compounds due to their high strain. Only compounds with 6-membered rings, which have less strain, can be obtained by intramolecular aldol condensation.
In aldol addition and aldol condensation, it is also important to consider regioselectivity. For intramolecular aldol condensation, compounds with 5 or 6-membered rings can be obtained.
Aldol Reactions to Create Carbon Bonds
When studying organic chemistry, the one thing we all study is the aldol reaction. The reaction of enolates with ketones (or aldehydes) is an aldol reaction.
The first thing to understand is the aldol addition. The enolate attacks the carbonyl carbons to give a β-hydroxycarbonyl compound. 1 equivalent amount of base is not needed; aldol addition proceeds with a catalytic amount of base.
However, if the amount of base is high, elimination reactions will occur. Dehydration results in the formation of compounds with alkenes (double bonds). Aldol condensation can also occur with acid catalysts to produce alkenes.
Although the aldol reaction is an important reaction to create carbon bonds, the product varies depending on the reaction conditions and the base used. So let’s understand how the reaction can be made to obtain the desired compound.