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Favorskii Rearrangement

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$\alpha$-halogenated ketones undergo skeletal rearrangement in the presence of certain nucleophiles to yield carboxylic acids or derivatives thereof. For example, 2-chlorocyclohexanone is readily converted by alkoxide ion into the ester of a cyclopentanecarboxylic acid. From the considerable amount of data collected from studies of the Favorskii rearrangement it appears that two types of mechanism are operative; the first and more general involves a symmetrical intermediate and the second involves a semi benzilic type sequence. 

When $\alpha$-halo ketones are treated with base, they often rearrange to a carboxylate derivative. This is known as the Favorskii rearrangement. It is reasonably general although the yields are variable. The nature of the carboxylate function depends on the base used; hydroxide leads to a carboxylate salt, alkoxide lead to esters and amines give amides. The reaction has also been carried out with $\alpha$, $\beta$-epoxyketones.

Reactions

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Sodium ethoxide of 1,2-14C-labeled 2-chlorocyclohexanone, ethyl cyclopentanecarboxylate possessing a symmetrical distribution of the label was obtained. Loftfield favored a cyclopropanone as the symmetrical intermediate an idea originating in the early German literature and support for this is found in the recent demonstration that cyclopropanones di, in fact yield Favorskii products under Favorskii reaction conditions. 

Favorskii Rearrangement Reactions

Thus tertramethyl cyclopropanone with sodium methoxide in either methanol or dimethoxy ethane (DME) yields the ester. In cases where a symmetrical intermediate is involved several studies have been carried out in an attempt to distinguish between a cyclopropanone intermediate and a zwitter intermediate.

Solvent effects, conformational effects, and stereochemical properties of the products have all been used in adducing evidence in favor of the cyclopropanone pathway. On the basis of quantum mechanical arguments, however Dewar and Burr contend that the Zwitter pathway is the more probable one.

The carboxylic ring contraction is shown below:

Carboxylic Ring Contraction

Mechanism

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A typical Favorskii rearrangement involves reaction of an $\alpha$-halo ketone with a base to give an ester or carboxylic acid, as in the follwing example. 
Favorskii Rearrangement Mechanism

Two $\alpha$-carbons, in the starting ketone, become equivalent during the course of the reaction. this means that a symmetrical intermediate must be formed. One possible mechanism, which is consistent with the result. 

Favorskii Rearrangement Example

Examples

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Some of the examples of Favorskii rearrangement is given below:

Example 1:

In Favorskii rearrangement an $\alpha$-halo ketone (chloro or bromo) is changed into an ester using an alkoxide ion. 

Alpha Ketone

Example 2:

Cyclic ketones with an axial $\alpha$-halogen generally do not undergo the Favorskii rearrangement, although at least one exception is noted. 

Alpha Halogen

Example 3:
Favorskii rearrangement carried out in deuterium oxide that 2-bromocyclobutanone rearranges to cyclopropane carboxylic acid via a semibenzilic mechanism. 

Deuterium Oxide

Applications

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Rearrangement reactions that are more specialized in their applications, such as the enigmatic Willgerodt synthesis, present interesting mechanistic problems and remain the subject of research. Some of the methods described employ highly toxic or potentially explosive reagents. Worthy of it are diazomethane, sodium azide and hydrazoic acid. Alkyl azides employed in the Schmidt reaction, can also constitute an explosion hazard. Appropriate safety precautions should be taken in the preparation and handling of such compounds.

The Favorskii reaction is a special case of nucleophilic attack on a carbonyl group involving a terminal alkyne with acidic protons. When catalyzed by acid, this reaction is called the Meyer-Schuster rearrangement. A metal acetylide is formed when an alkyne is treated with a strong bases such as a hydroxide or an alkoxide.