Question

The base-promoted rearrangement of an \(\alpha\)-haloketone to a carboxylic acid, known as the Favorskii rearrangement, is illustrated by the conversion of 2 -chlorocyclohexanone to cyclopentanecarboxylic acid. (a) Propose a mechanism for base-promoted conversion of 2 -chlorocyclohexanone to the proposed intermediate. (b) Propose a mechanism for base-promoted conversion of the proposed intermediate to sodium cyclopentanecarboxylate.

Short answer

Question: Explain the mechanism of Favorskii rearrangement of 2-chlorocyclohexanone to cyclopentanecarboxylic acid, including the formation of the proposed intermediate and the conversion of the intermediate to sodium cyclopentanecarboxylate. Answer: The Favorskii rearrangement involves four main steps: 1. Formation of the proposed intermediate: Deprotonation of the α-halo ketone (2-chlorocyclohexanone) by a strong base (sodium hydroxide) to form an enolate intermediate. 2. Mechanism of the rearrangement of the proposed intermediate: The enolate attacks the carbon with the halogen (chlorine), forming a 5-membered oxycarbanion ring. 3. Formation of sodium cyclopentanecarboxylate: The oxycarbanion is deprotonated by sodium hydroxide, leading to the formation of a double bond and the expulsion of the carbon-oxygen double bond to form sodium cyclopentanecarboxylate. 4. Formation of cyclopentanecarboxylic acid: Sodium cyclopentanecarboxylate reacts with a strong acid (typically hydrochloric acid) to give the final product, cyclopentanecarboxylic acid.

Step-by-step solution

Formation of the Proposed Intermediate

The Favorskii rearrangement begins with the deprotonation of the α-halo ketone by a strong base (such as sodium hydroxide). Deprotonation forms an enolate intermediate. In our case, we start with 2-chlorocyclohexanone and sodium hydroxide (NaOH) as the base. The enolate formation can be illustrated as follows: \[\text{(NaOH)} \longrightarrow [\text{2-chlorocyclohexanone}]^{-} \longrightarrow \text{Proposed Intermediate}\]

Mechanism of the rearrangement of the proposed intermediate

When the enolate is formed, it attacks the carbon atom bearing the halogen (in this case chlorine) to form a 5-membered ring. The halogen is expelled forming a 5-membered ring containing an oxygen and a negative charge, and sodium chloride as a byproduct. The formed intermediate, which is an oxycarbanion, can be represented as follows: \[\text{(Proposed Intermediate)} \longrightarrow \text{5-Membered Ring Intermediate (Oxycarbanion)} \]

Formation of Sodium Cyclopentanecarboxylate

In this step, another equivalent of the strong base (sodium hydroxide) will deprotonate the oxycarbanion at the negatively charged carbon. The negatively charged oxygen will then form a double bond with the carbon adjacent to it, breaking the ring by expelling the carbon-oxygen double bond to form a new carboxylate group. The carboxylate group will then form an ionic bond with the sodium ion present in the reaction medium, forming the sodium salt of the carboxylate product (sodium cyclopentanecarboxylate), as shown: \[\text{(Oxycarbanion)} \longrightarrow \text{Sodium Cyclopentanecarboxylate}\]

Formation of Cyclopentanecarboxylic Acid

The final step is the acidic workup, where the product, sodium cyclopentanecarboxylate, reacts with a strong acid (usually hydrochloric acid) to give the corresponding carboxylic acid, cyclopentanecarboxylic acid. This step can be represented as follows: \[\text{(Sodium Cyclopentanecarboxylate)} + \text{(HCl)} \longrightarrow \text{Cyclopentanecarboxylic Acid} + \text{(NaCl)}\]

Key concepts

Alpha-Haloketone to Carboxylic Acid

The transformation of an alpha-haloketone to a carboxylic acid is an essential organic reaction with practical applications in synthesizing complex molecules. This chemical process involves the modification of a carbon-halogen bond into a carbon-oxygen bond, ultimately yielding a carboxylic acid. A classical example is the Favorskii rearrangement, a base-promoted reaction where an alpha-haloketone, like 2-chlorocyclohexanone, is converted into cyclopentanecarboxylic acid.

During the Favorskii rearrangement, the initial step includes the action of a strong base, usually sodium hydroxide, which deprotonates the alpha-carbon adjacent to the carbonyl group. This step is crucial as it leads to the formation of an enolate intermediate, a negatively charged species that is more nucleophilic and can facilitate further steps in the reaction pathway towards the creation of a carboxylic acid.

Mechanism of Base-Promoted Conversion

The mechanism of base-promoted conversion, particularly in the context of the Favorskii rearrangement, involves several key steps that allow for the transformation of the starting alpha-haloketone. The first step is the deprotonation of the carbon adjacent to the carbonyl group, forming an enolate intermediate. This anionic species is primed for intramolecular nucleophilic attack on the electrophilic carbon bonded to the halogen (chlorine in our case).

Ring Closure

Following the intramolecular attack, a ring-closure occurs leading to the expulsion of the halide ion and the formation of a new bond. This results in a cyclic oxycarbanion intermediate, which is then further deprotonated by the base to produce an incipient carboxylate group. By understanding this base-promoted mechanism, students can appreciate the nuanced steps involved in the Favorskii rearrangement that accomplish the molecular transformation.

Sodium Cyclopentanecarboxylate

Sodium cyclopentanecarboxylate is an important intermediate in the Favorskii rearrangement, and its formation represents the penultimate step before obtaining the final carboxylic acid product. Once the oxycarbanion has been formed, a second equivalent of the strong base deprotonates the carbon atom bearing a negative charge. This activity prompts the highly reactive oxygen to form a carbon-oxygen double bond, which catalyzes the ring-opening process.

The resulting molecule then pairs with a sodium ion to form sodium cyclopentanecarboxylate, a sodium salt of the carboxylic acid, which is easily converted into the free acid upon acidic workup. This compound's formation illustrates the intricate dance of electrons that organic chemists exploit to synthesize desired molecules.

Enolate Intermediate Formation

Enolate intermediate formation is a pivotal moment in base-promoted rearrangements like the Favorskii. The enolate is generated when the base deprotonates the carbon next to a carbonyl group in the alpha-haloketone.

Resonance Stabilization

This intermediate is resonance-stabilized; it can be depicted as having a negative charge either on the oxygen (as in a standard carbonyl anion) or on the carbon (as in an enolate anion), enhancing its stability.

Understanding the nature of enolate intermediates helps explain their nucleophilicity and chemical behavior in subsequent steps of the reaction. It's the enolate's ability to attack electrophilic centers that enables the rearrangement leading to the formation of carboxylic acids, making it a central focus in the study of the Favorskii rearrangement and related organic transformations.