In this article, we learn about the Claisen Condensation, an important organic reaction, including its mechanism, its important variants, and its use in biology.
Topics Covered in Other Articles
- Condensation Reactions
- Wittig Reaction
- Williamson Ether Synthesis
- SN1 vs SN2 Reactions
- Diels-Alder Reaction
- Epoxide Functional Group
- Markovnikov’s Rule
- Nucleophilic Substitution Reaction
What is a Claisen Condensation?
In organic chemistry, a Claisen Condensation is a reaction between two ester molecules, producing a dicarbonyl. A base catalyzes the reaction, most often being carboxide salt with the same oxygen-bound R group as the two esters.
The Claisen Condensation is one specific variant of a larger class of organic reactions called Aldol Condensations. If you’d like to learn more about this group of reactions, check out this article.
Importantly, Claisen Condensations involve the formation of a new carbon-carbon bond. Because of this, biological systems often rely on enzyme-catalyzed Claisen Condensations to connect many different organic molecules.
To understand the behavior and importance of Claisen Condensations, let’s first look at the reaction mechanism.
Claisen Condensation Mechanism
To begin a Claisen Condensation, the ɑ-carbon (or carbon immediately adjacent to the carbonyl group) an ester becomes deprotonated by the anion of the carboxide salt. This leaves behind a carbanion.
Next, the lone electron pair on the ɑ-carbon attacks the carbonyl of another ester. This displaces the pi electrons in the carbonyl to the oxygen. Importantly, this step is driven by the electrostatic attraction between the nucleophilic carbanion and the electrophilic carbonyl.
Finally, the carbonyl of the second ester reforms, which ejects the ester’s carboxyl group. This produces our β-dicarbonyl, which means a molecule with two carbonyls two carbons away from each other.
Hydrolysis and Decarboxylation of the β-Dicarbonyl
If the Claisen Condensation takes place under aqueous conditions, the resulting β-dicarbonyl instantly performs a hydrolysis reaction. This involves the attack of a water molecule on the carbonyl of the remaining ester. This once again temporarily disrupts the carbon-oxygen double bond. When the carbonyl reforms, the carboxy group gets ejected. The water group then becomes deprotonated to an alcohol, forming a carboxylic acid group.
This molecule can react further, performing what organic chemists call a “decarboxylation”. Under high temperatures, the relatively unstable carboxylic acid molecule degrades by performing a “benzene-like” circular movement of electrons. This ends up ejecting the entire carboxylic acid group as CO2 and leaving behind an enol. Since they have similar instability, the enol quickly performs keto-enol tautomerization, resulting in a ketone species.
Decarboxylations tend to occur often in biological reaction chains, especially in metabolic cycles. The citric acid cycle, for instance, involves multiple decarboxylations.
Types of Claisen Condensation
The most common type of Claisen Condensation involves two molecularly identical ester molecules. This “Classic Claisen Condensation” has the advantage of being the easiest to control, since the production of side products is minimized.
Claisen Condensations between two different ester molecules are possible as well. However, when two esters occupy the same reaction vessel, any combination of the two esters can and will perform Claisen Condensation, producing many different side products. This tends to be very inefficient for a chemist that only wants to make one β-dicarbonyl product.
Chemists can still perform efficient “Crossed Claisen Condensations” if they choose their ester species carefully. Specifically, the use of ketones and non-enolizeable esters allows for the selective production of one β-dicarbonyl product. In this context, “non-enolizeable” simply means that the ester’s ɑ-carbon cannot become deprotonated. Benzoic ethyl ester provides one example of a non-enolizeable ester, since its ɑ-carbon lacks hydrogens.
Additionally, Claisen Condensations can also occur in intramolecular esters, or esters within the same molecule. Like most intramolecular nucleophile-electrophile reactions, this produces a cyclic structure with the characteristic β-dicarbonyl formation. Organic chemists call these reactions Dieckmann Condensations.
Biological Claisen Condensations
As mentioned before, Clasen Condensations appear frequently in biochemical reactions. Importantly, these reactions involve thioester groups, rather than esters. Thioesters involve sulfur instead of oxygen in the ether group. (O-R → S-R).
Many enzymes have active cysteine residues, which have a thiol (-SH) group that can react with some carbonyl-containing compound to form a thioester. Certain enzyme cofactors, like coenzyme-A, also have thiol groups that allow for the formation of thioesters.
The Claisen Condensation then proceeds in line with the standard Claisen Condensation mechanism. This includes both the Classic and Crossed Claisen Condensations.
These sorts of thioester Claisen Condensations are common in the synthesis of lipids, such as cholesterol, isoprenoids, and fatty acids.