Question

Many types of carbonyl condensation reactions have acquired specialized names, after the nineteenth-century organic chemists who first studied them. Propose mechanisms for the following named condensations. (a) Perkin condensation: Condensation of an aromatic aldehyde with an acid anhydride (b) Darzens condensation: Condensation of an \(\alpha\)-haloester with a ketone or an aromatic aldehyde

Short answer

Question: Briefly describe the key steps involved in the Perkin and Darzens condensation mechanisms. Answer: In the Perkin condensation mechanism, key steps include: (1) nucleophilic attack of the aromatic aldehyde on the acid anhydride, (2) deprotonation of the tetrahedral intermediate, and (3) protonation of the carbonyl group to form a conjugated unsaturated carboxylic acid. In the Darzens condensation mechanism, key steps include: (1) formation of a carbanion from the α-haloester, (2) nucleophilic attack of the carbanion on the carbonyl group of the ketone or aromatic aldehyde, (3) deprotonation of the tetrahedral intermediate, and (4) intramolecular nucleophilic substitution to form an epoxide as the final product.

Step-by-step solution

Nucleophilic attack of the aromatic aldehyde on the acid anhydride#ac_tag_title#

The aromatic aldehyde protonates the anhydride to turn it into a more electrophilic species. The anion of the aldehyde, which is formed due to the lone pair of the oxygen atom, then attacks the carbonyl carbon of the newly protonated anhydride, forming a tetrahedral intermediate.#ac_tag_content#

Deprotonation of the tetrahedral intermediate#ac_tag_title#

A base (such as a carboxylate ion) deprotonates the tetrahedral intermediate formed in step 1, turning it back into an anion and creating another carboxylate ion as a leaving group.#ac_tag_content#

Protonation of the carbonyl group#ac_tag_title#

The anionic intermediate is protonated by the carboxylate ion to create an aldehyde, and the newly formed carboxylic acid group reforms its carbonyl bond by eliminating the carboxylate ion, leading to the formation of a conjugated unsaturated carboxylic acid.#ac_tag_content# #Darzens condensation mechanism#

Formation of a carbanion#ac_tag_title#

A strong base (such as an alkoxide ion) removes a proton from the \(\alpha\)-carbon of the \(\alpha\)-haloester, creating a carbanion. The carbanion is stabilized by resonance with the adjacent ester group, making it a good nucleophile.#ac_tag_content#

Nucleophilic attack on the carbonyl group#ac_tag_title#

The carbanion from step 1 attacks the carbonyl carbon of the ketone or aromatic aldehyde, forming a new carbon-carbon bond and creating an anionic tetrahedral intermediate.#ac_tag_content#

Deprotonation of the tetrahedral intermediate#ac_tag_title#

A base (such as an alkoxide ion) removes a proton from the newly formed tetrahedral intermediate, turning it back into an anion and creating another alkoxide ion as a leaving group.#ac_tag_content#

Intramolecular nucleophilic substitution#ac_tag_title#

The anion from step 3 undergoes an intramolecular nucleophilic substitution, attacking the α-halogen in the ester and displacing the halogen to form an epoxide - the final product of Darzens condensation.#ac_tag_content#

Key concepts

Perkin Condensation Mechanism

The Perkin condensation is an intriguing organic reaction that leads to the formation of \( \alpha \) , \( \beta \) -unsaturated carboxylic acids. It often involves an aromatic aldehyde reacting with an acid anhydride in the presence of a base, such as a salt of the acid.

During the reaction, the base helps by deprotonating the acidic hydrogen on the aldehyde, generating an anionic form of the aldehyde which is much more nucleophilic. This anion then attacks the electrophilic carbonyl carbon of the acid anhydride in a step known as nucleophilic attack. This creates a tetrahedral intermediate, highlighting the versatility and reactivity of carbonyl compounds.

Following the formation of the tetrahedral structure, a sequence of deprotonations and protonations occurs resulting in the elimination of a carboxylate group. The final outcome is an unsaturated carboxylic acid with a structure that holds immense potential in further chemical transformations.

Darzens Condensation Mechanism

In the Darzens condensation, we witness the formation of glycidic esters (epoxides) from the reaction of \( \alpha \)-haloesters and carbonyl compounds like aldehydes or ketones.

The halogen present on the \( \alpha \)-haloester makes the alpha hydrogen atom more acidic, thus allowing a base to generate a stabilized carbanion. This carbanion is delocalized over the ester group, which enhances its nucleophilic strength. Consequently, it can effectively attack the carbonyl carbon of another molecule, say an aldehyde or ketone. This forms a tetrahedral intermediate which once again undergoes deprotonation.

However, unlike many carbonyl condensations, this intermediate proceeds to an intramolecular nucleophilic substitution, where it attacks the alpha halogen of itself, expelling the halide and forming an epoxide structure. This versatile product is useful in various synthetic applications.

Nucleophilic Attack

Nucleophilic attack lies at the heart of carbonyl condensation reactions, where a nucleophile is an electron-rich species that seeks out electrophilic, or electron-poor, centers.

In both Perkin and Darzens condensations, the initial step is a nucleophilic attack. The anion generated from deprotonation of the aldehyde or the carbanion formed from an \( \alpha \)-haloester serves as the nucleophile. It targets the carbonyl carbon, which is highly electrophilic due to the polarization of the carbon-oxygen double bond. This coalition between the electrophile and nucleophile propels the reaction forward and leads to the construction of new chemical bonds, an underlying principle in synthesis.

Tetrahedral Intermediate

Upon the fusion of a nucleophile and a carbonyl carbon, an intermediate with a tetrahedral geometry forms. This stage is transitory but critical; it's where the reactants are transformed, setting the stage for the final products.

In a normal carbonyl group, the carbon is sp2 hybridized, lying in a plane with 120-degree angles. However, when a nucleophile adds to this carbon, the hybridization shifts to sp3 and a new tetrahedral carbon is created. This intermediate bears four substituents, including a negatively charged oxygen, which can either revert, leading to the starting materials, or be stabilized through various processes like deprotonation, leading towards the desired reaction products.

Carbanion Stability

The stability of the carbanion is a pivotal aspect dictating the course and success of reactions like the Darzens condensation. A carbanion is essentially a carbon atom bearing a negative charge, and its stability is largely dependent on the surrounding environment.

The presence of electron-withdrawing groups such as a carbonyl or halogen near the carbanion helps stabilize the charge through resonance or inductive effects. Moreover, the nature of the substituents attached to the carbanion can dramatically influence its reactivity. For instance, an \( \alpha \)-haloester has a more stable carbanion due to resonance with the ester group. This stability is essential for the carbanion to exist long enough to attack a carbonyl carbon and propagate the condensation mechanism.