One method of making new carbon chains is a synthetic reaction using enolates. One of the organic chemical syntheses with enolates is Claisen condensation.
In Claisen condensation, molecules with esters react with enolates. As a result, new carbonyl compounds can be obtained. When Claisen condensation occurs within a molecule, it is called Dieckmann condensation (intramolecular Claisen condensation).
One of the most important organic chemical reactions is Claisen condensation. However, there are certain things that must be understood beforehand, such as the bases to be used and the reaction mechanism in Claisen condensation.
In order to obtain the desired compound, the correct reagents must be selected and the reaction conditions must be studied. In this section, we will explain the reaction mechanism of Claisen condensation and some important points to keep in mind.
Table of Contents
- 1 The Reaction of Enolate and Ester is Claisen Condensation
- 2 Crossed Claisen Condensation, Which Occurs in Two Types of Molecules
- 3 With the Use of Sodium Hydroxide, It Becomes Carboxylic Acid and Can Decarboxylation
- 4 Use of Enolates and Claisen Condensation
The Reaction of Enolate and Ester is Claisen Condensation
Claisen condensation is a condensation reaction in which two esters react. Claisen condensation is one of the synthetic reactions with enolates.
In compounds with carbonyl groups, including esters, the base tends to pull out the hydrogen atom (alpha hydrogen) of the alpha carbon. The result is a change from a keto form to an enol form compound.
A base converts the molecule to an enol form molecule. The enolate is an enol form compound produced by the base. By adding a basic reagent to the ester, enolate can be synthesized as follows.
The carbon atoms of enolate are negatively charged. Because it is a carbanion, enolate is highly nucleophilic. Therefore, it can attack other carbonyl carbons and create new carbon bonds.
Enolate attacks the ester by nucleophilic attack with the following mechanism of action.
Carbonyl carbons are known to be susceptible to nucleophilic attack. Therefore, the reaction proceeds by nucleophilic attack of the enolate for the ester.
The ester is then released as soon as the electrons of the oxygen atom return. The removal of water or alcohol to form a new molecule is called condensation. This reaction is a type of condensation and was discovered by the German chemist Claisen, hence the name Claisen condensation.
-What Is the Difference Between the Aldol Reaction?
A synthetic reaction similar to Claisen condensation is the aldol reaction. In the same way, the aldol reaction proceeds with the enolate.
In Claisen condensation, enolate reacts with esters. In the aldol reaction, on the other hand, enolate reacts with ketones or aldehydes. Depending on whether the compound reacting with enolate is an ester or a ketone (or aldehyde), the name of the synthetic reaction and the products change.
Note that one equivalent amount of base is required for Claisen condensation. In the aldol reaction, on the other hand, the difference is that the reaction proceeds with a catalytic amount of base.
β-Keto Ester Converts to Enolate by Acid-Base Reaction
Then, are ketones not attacked by enolates after the formation of compounds by Claisen condensation?
The compounds synthesized by Claisen condensation are called β-keto esters. Ketones have a higher electrophilic property than esters. Therefore, it would seem that enolate is a nucleophilic attack on the ketones of the β-keto ester, not the ester.
However, in fact, the product ketone (β-keto ester) does not react with the enolate. This is because the α-carbon of the β-ketoester is highly acidic.
Claisen condensation is a synthetic reaction under basic conditions. The presence of a strong base results in the formation of enolates. Because of the presence of a base in the solution, the hydrogen atom (α-hydrogen) bonded to the α-carbon of the β-keto ester is pulled out by the base. As a result, the following stable enolate ions are formed.
As a result of the change in form from the β-keto ester by the base, it is no longer subject to nucleophilic attack by enolate. Therefore, in Claisen condensation, the β-keto ester and enolate do not react with each other.
When the reaction is stopped, an acidic solution such as hydrochloric acid is added. After the acid-base reaction, the enolate returns to the form of the β-keto ester.
Cyclization by Intramolecular Condensation is called Dieckmann Condensation
When two esters exist in a molecule, they are cyclized by intramolecular Dieckmann condensation. This reaction is called Dieckmann condensation.
The reaction mechanism is exactly the same as that of Claisen condensation. However, the name of the reaction changes depending on whether the two ester molecules condense or whether they condense within a molecule.
Dieckmann condensation occurs when the compound formed by cyclization is a 5-membered or 6-membered ring; at 4 and 7-membered rings, the reaction almost does not proceed because of the large stereochemical strain. In Dieckmann condensation, it is important to understand that the product will be a 5 or 6-membered ring.
If these conditions are met, Dieckmann condensation proceeds by the following reaction mechanism.
If you understand the reaction mechanism of Claisen condensation, Dieckmann condensation is easy to understand. Under base conditions, β-keto esters can be synthesized by cyclization in intramolecular reactions.
-Alkylation with Alkyl Halides is possible
In addition, as mentioned above, the β-keto ester exists as a stable enolate because it is reacted under basic conditions. Therefore, it can be alkylated by reacting it with alkyl halides before adding the acid.
For example, the following.
Even though it is a stable enolate and therefore less reactive, it still has nucleophilic properties because the carbon atoms are negatively charged. Therefore, after proceeding with the reaction by Claisen condensation (or Dieckmann condensation), it is possible to make carbon chains by alkylation.
Crossed Claisen Condensation, Which Occurs in Two Types of Molecules
In Claisen condensation, the chemical reaction is explained by the example of Claisen condensation of the same molecule. Can’t we use two different molecules for Claisen condensation? The synthesis of Claisen condensation with different molecules is called crossed Claisen condensation.
In crossed Claisen condensation, the following reactions are used
- Reaction of ester and ester
- Reaction of an ester with a ketone
As for ketones, they are also known to produce enolates. Therefore, in addition to crossed Claisen condensation between esters, it is also possible to react with an ester and a ketone. For example, the reaction mechanism for an ester and a ketone is as follows.
In ester to Claisen condensation, β-keto esters can be synthesized. On the other hand, crossed Claisen condensation of esters and ketones allows the synthesis of β-diketone compounds.
Crossed Claisen Condensation Is Effective in the Absence of α-Hydrogen
However, there is a point of caution when doing crossed Claisen condensation. That is to use an ester without the α-hydrogen.
To get an enolate, the molecule must have alpha hydrogen; the proton attached to the α-carbon is pulled out to synthesize the enolate. However, if both compounds to be reacted have α-hydrogen, various kinds of enolates are produced and the reaction is complicated.
Therefore, it is necessary to react with esters that have only one α-hydrogen to be pulled out by a base. For example, in the following ester-to-ester reactions, the α-hydrogen is in only one place.
Crossed Claisen condensation is useful when one ester (or ketone) has no alpha-hydrogen in it. If there are several α-hydrogen atoms in the compound to be reacted, the reaction will be complicated. For this reason, crossed Claisen condensation has limited conditions for the reaction.
With the Use of Sodium Hydroxide, It Becomes Carboxylic Acid and Can Decarboxylation
The use of sodium hydroxide (NaOH) as a base used in Claisen condensation is rare.
It is possible to synthesize enolate by using sodium hydroxide. Nevertheless, why is NaOH rarely utilized in Claisen condensation? The reason for this is that OH– attacks the ester, which results in the synthesis of carboxylic acids.
In this way, compounds with a carbonyl group (ketone) in the third position of the carboxylic acid are synthesized.
Incidentally, a carboxylic acid with a ketone at the 3-position is decarboxylated when heated. The compound is decomposed and the carboxylic acid is released as carbon dioxide. The reaction mechanism for decarboxylation is as follows
If you want to get a carboxylic acid or do decarboxylation after Claisen condensation, you can use sodium hydroxide. But otherwise, you don’t use NaOH as a base.
Transesterification with Sodium Methoxide and Sodium Ethoxide
So, is it enough to use any other base? For example, sodium methoxide and sodium ethoxide are known to be bases.
However, there are few opportunities to use alkoxide as a strong base. This is because when sodium methoxide or sodium ethoxide is used, methoxide and ethoxide are formed through transesterification. It is as follows.
It is widely known that adding an alcohol to an ester causes transesterification. Because of the transesterification occurring, we rarely use sodium methoxide or sodium ethoxide in bases.
-The Use of LDA and NaH Is Common
Then, what kind of bases are used in Claisen condensation? Bases such as LDA (lithium diisopropylamide) and NaH (sodium hydroxide) are frequently used in the synthesis of enolates, not only in Claisen condensation but also in other processes.
LDA is a bulky base, as shown below.
Due to its large steric hindrance, LDA has almost no nucleophilic properties and acts only as a base. NaH is also a strong base with no nucleophilic properties. When synthesizing enolates, we should understand the differences in the properties of the bases and think of them as utilizing the most appropriate base.
Use of Enolates and Claisen Condensation
When making new carbon bonds in organic chemistry, chemical reactions that utilize enolates are important. Syntheses using enolates include aldol reactions and Michael addition, one of which is Claisen condensation.
One of the differences from other synthetic reactions is the use of esters. The synthetic reaction using enolates and esters is Claisen condensation. In addition, cyclization by intramolecular Claisen condensation is called Dieckmann condensation.
In Claisen condensation, crossed Claisen condensation, which uses different molecules, is also possible. However, there are only a few situations in which it can be used, such as when a molecule without an alpha hydrogen is used.
In addition, let’s consider the bases to be used. Some bases cause side reactions, so the most appropriate base must be selected in order to obtain the desired compound. By understanding these, you can obtain your target compound by Claisen condensation.