Favorskii Rearrangement

Professor Dave Explains

26 Jan 202204:46

EducationalLearning

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TLDRThe Favorskii rearrangement is a ring contraction reaction, invented by Alexei Favorskii in 1894, applicable to enolizable alpha-chloro ketones. It involves the formation of an enolate, nucleophilic attack, and cyclopropanone intermediate, leading to a carboxylic acid product. This reaction is not only useful for synthesizing strained ring systems like cubane but also for natural products like epibatidine, demonstrating its versatility in organic synthesis.

Takeaways

🔍 The Favorskii rearrangement is a distinct reaction from the Favorskii reaction and is used for ring contraction in chemistry.
👨‍🔬 It was invented by Russian chemist Alexei Favorskii in 1894 and is applicable to enolizable alpha-chloro ketones.
🔬 The reaction involves the formation of an enolate at the carbon opposite the halogen, followed by a nucleophilic attack on the carbon bearing the chloro group.
💥 A strained cyclopropanone intermediate is formed, which is then attacked by a hydroxide base, leading to the opening of the three-membered ring.
📉 The ring contraction results in the formation of a carboxylic acid with a neighboring carbanion, which undergoes rapid proton transfer.
📚 The regiochemistry of the reaction is such that the less substituted and more stable carbanion is formed, especially in non-symmetrical systems.
🔄 The reaction mechanism is consistent across isomeric alpha-haloketones, yielding the same carboxylate regardless of the starting material's structure.
📉 The reaction can also occur with alpha-bromo ketones, albeit with generally lower yields compared to chloro ketones.
🧪 When anhydrous alkoxides are used as bases, the reaction yields esters instead of carboxylate salts.
🔴 A 14C labeling experiment with alpha-chlorocyclohexanone confirmed the symmetrical intermediate formation of the cyclopropanone.
🛠️ The Favorskii rearrangement is a valuable tool in the synthesis of natural products and other complex structures, as exemplified by its use in the synthesis of cubane and epibatidine.

Q & A

What is the Favorskii rearrangement primarily used for in organic synthesis?
-The Favorskii rearrangement is primarily used for inducing ring contraction in organic synthesis.
Who discovered the Favorskii rearrangement and when?
-The Favorskii rearrangement was discovered by Russian chemist Alexei Favorskii in 1894.
What types of substrates does the Favorskii rearrangement apply to?
-The Favorskii rearrangement applies to enolizable alpha-chloro ketones, including acyclic substrates.
Describe the initial step in the mechanism of the Favorskii rearrangement.
-The initial step involves the formation of an enolate at the carbon opposite the halogen.
What intermediate is formed during the Favorskii rearrangement mechanism?
-A very strained cyclopropanone intermediate is formed during the Favorskii rearrangement mechanism.
What happens to the cyclopropanone intermediate in the Favorskii rearrangement?
-The cyclopropanone intermediate is immediately attacked by the hydroxide base at the carbonyl carbon, leading to the opening of the ring and the formation of a carboxylic acid with a carbanion moiety.
How does the regiochemistry of the Favorskii rearrangement operate in unsymmetrical systems?
-In unsymmetrical systems, the ring usually opens to yield the less substituted and therefore more stable carbanion.
Can the Favorskii rearrangement be performed with alpha-bromo ketones?
-Yes, the Favorskii rearrangement can be performed with alpha-bromo ketones, although generally in lower yield compared to alpha-chloro ketones.
What product is obtained when anhydrous alkoxides are used as bases in the Favorskii rearrangement?
-When anhydrous alkoxides are used as bases, esters are obtained instead of the carboxylate salt.
How was the intermediacy of cyclopropanone confirmed in the Favorskii rearrangement?
-The intermediacy of cyclopropanone was confirmed by labeling the Cl-bearing position with a 14C label and observing the equal distribution of the label in the alpha and beta positions in the product.
What was a notable application of the Favorskii rearrangement in the synthesis of a very strained molecule?
-A notable application of the Favorskii rearrangement was in Eaton’s synthesis of the very strained molecule cubane, where the final cubic structure was established through a Favorskii ring contraction.
How was the Favorskii rearrangement applied in the synthesis of the poisonous alkaloid epibatidine?
-In the synthesis of epibatidine, the Favorskii rearrangement was used to convert the alpha-brominated tropinone to the desired 2.2.1 skeleton from the 3.2.1 precursor, which was then further converted to epibatidine.

Outlines

00:00

🔬 Introduction to Favorskii Rearrangement

The Favorskii rearrangement is distinct from the Favorskii reaction and is primarily used for ring contraction in synthesis. Invented by Alexei Favorskii in 1894, it applies to enolizable alpha-chloro ketones and is notable for its role in producing smaller ring systems.

🔄 Mechanism of Favorskii Rearrangement

The mechanism begins with enolate formation at the carbon opposite the halogen. The enolate's nucleophilic carbon attacks the carbon bearing the chloro group, creating a strained cyclopropanone intermediate. Hydroxide base then attacks this intermediate, leading to ring opening and formation of a carboxylic acid with a carbanion moiety. Proton transfer finalizes the product, favoring the formation of the less substituted, more stable carbanion.

🧪 Regiochemistry and Isomer Considerations

The rearrangement's regiochemistry favors the less substituted carbanion, leading to consistent products regardless of starting isomer differences. This is illustrated with alpha-haloketones, where enolate attack on the halogen forms the same cyclopropanone intermediate, too unstable to be isolated.

🔍 Alternative Reactants and Base Effects

Alpha-bromo ketones can also undergo the Favorskii rearrangement, though with lower yields. When anhydrous alkoxides are used as bases, esters are obtained instead of carboxylate salts, showcasing the versatility of the reaction depending on reactants and conditions.

🧪 Experimental Confirmation

Labeling experiments with 14C confirm the symmetrical nature of the cyclopropanone intermediate. In labeled alpha-chlorocyclohexanone, the rearrangement to cyclopentanecarboxylate shows equal distribution of the label, proving the intermediate can open both ways equally.

🔬 Applications in Synthesis

The Favorskii rearrangement is valuable in synthesizing strained systems and complex structures. It was crucial in Eaton’s synthesis of cubane and the synthesis of the alkaloid epibatidine. These examples highlight the rearrangement's utility in constructing intricate ring systems from larger precursors.

🔍 Epibatidine Synthesis

Starting from protected tropinone, alpha-bromination produces a mixture of exo and endo alpha-bromides. Ring contraction using methoxide forms the desired 2.2.1 skeleton from the 3.2.1 precursor, which is then converted to racemic epibatidine, demonstrating the rearrangement’s role in synthesizing natural products.

🔬 Conclusion and Utility

The Favorskii rearrangement remains a powerful tool in synthetic chemistry, facilitating the formation of complex and strained structures. Its versatility and applicability to various substrates make it indispensable in the synthesis of natural products and other significant compounds.

Mindmap

Keywords

💡Favorskii rearrangement

The Favorskii rearrangement is a chemical reaction that involves the ring contraction of cyclic compounds. It is named after the Russian chemist Alexei Favorskii who discovered it in 1894. In the context of the video, this reaction is crucial for synthesizing complex organic compounds, especially when starting from larger ring structures that can be contracted to form more strained systems, as seen in the synthesis of cubane and epibatidine.

💡Ring contraction

Ring contraction refers to a chemical process where a ring in a molecule becomes smaller, typically by the removal of one or more atoms from the ring structure. In the video, ring contraction is the primary outcome of the Favorskii rearrangement, which is used to transform larger ring systems into smaller, often more biologically active, compounds.

💡Enolizable

Enolizable compounds are those that can form an enol, which is a type of tautomeric isomer of a carbonyl compound. In the script, the Favorskii rearrangement applies to enolizable alpha-chloro ketones, indicating that these compounds can undergo a specific type of isomerization crucial for the reaction to proceed.

💡Enolate

An enolate is a type of anion that is formed by the deprotonation of an enol or an enolizable compound. In the video, the formation of an enolate at the carbon opposite the halogen is a key step in the Favorskii rearrangement, as it sets the stage for the nucleophilic attack that leads to ring contraction.

💡Nucleophilic

Nucleophilicity is the ability of a chemical species to donate an electron pair to an electrophile, forming a covalent bond. In the context of the Favorskii rearrangement, the nucleophilic carbon from the enolate attacks the carbon bearing the chloro group, which is a critical step in the formation of the cyclopropanone intermediate.

💡Cyclopropanone

Cyclopropanone is a strained three-membered ring compound with a ketone functional group. In the script, a cyclopropanone intermediate is formed during the Favorskii rearrangement, which is highly reactive and leads to the opening of the ring to form a carboxylic acid.

💡Carboxylic acid

A carboxylic acid is an organic compound containing the carboxyl group (-COOH). In the video, the Favorskii rearrangement results in the formation of a carboxylic acid with a carbanion moiety adjacent to it, which is a key product of the reaction.

💡Regiochemistry

Regiochemistry is the branch of chemistry that deals with the orientation of atoms in space and the control of the position of functional groups in organic molecules. In the script, regiochemistry is important for understanding how the Favorskii rearrangement leads to the formation of a less substituted and more stable carbanion, which is crucial for the synthesis of the desired compounds.

💡Isomeric

Isomeric refers to compounds that have the same molecular formula but different structural arrangements of atoms. The script mentions that isomeric alpha-haloketones yield the same carboxylate in the Favorskii rearrangement, highlighting the reaction's ability to produce consistent products from structurally different starting materials.

💡Anhydrous alkoxides

Anhydrous alkoxides are bases that do not contain water. In the video, when anhydrous alkoxides are used as bases in the Favorskii rearrangement, esters are obtained instead of carboxylate salts, indicating a variation in the reaction's outcome based on the choice of base.

💡14C label

14C label refers to the use of carbon-14 as a radioactive isotope in a compound to track its presence and movement during chemical reactions. In the script, alpha-chlorocyclohexanone labeled with 14C is used to demonstrate the symmetrical intermediate formation in the Favorskii rearrangement, with the label being equally distributed in the alpha and beta positions of the product.

💡Epibatidine

Epibatidine is a naturally occurring alkaloid found in certain frog species and is known for its potent painkilling properties. In the video, the synthesis of epibatidine is mentioned as an application of the Favorskii rearrangement, where the reaction is used to contract a ring and form the 2.2.1 skeleton necessary for the final product.

Highlights

The Favorskii rearrangement is a classical reaction inducing ring contraction.

The reaction was invented by Russian chemist Alexei Favorskii in 1894.

The Favorskii rearrangement applies to enolizable alpha-chloro ketones and acyclic substrates, mainly used as a ring contraction tool.

Formation of an enolate at the carbon opposite the halogen initiates the reaction.

The nucleophilic carbon from the enolate attacks the carbon bearing the chloro group, producing a strained cyclopropanone intermediate.

The cyclopropanone intermediate is attacked by the hydroxide base at the carbonyl carbon.

This leads to a carboxylic acid with a carbanion moiety next door, and rapid proton transfer gives the final product.

Opening of the ring usually occurs to yield the less substituted and more stable carbanion in unsymmetrical systems.

Isomeric alpha-haloketones yield the same carboxylate due to enolate attack on the bromide.

The reaction works for alpha-bromo ketones as well as chloro ketones, though generally in lower yield.

Anhydrous alkoxides as bases yield esters instead of carboxylate salts.

The formation of a symmetrical intermediate is confirmed through equal distribution of a 14C label in the product.

Applications in synthesis include ring-contraction leading to strained systems, such as in Eaton’s synthesis of cubane.

The Favorskii rearrangement was used in the synthesis of the poisonous alkaloid epibatidine.

The rearrangement continues to be a useful tool in synthesizing natural products and other structures of interest.

Transcripts

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