Reaction mechanisms Favorskii rearrangement

Problem 4.2. Draw a reasonable mechanism for the following reaction. A Favorskii rearrangement is involved. 

Particularly convincing evidence can develop when a number of chemists suggest the same intermediate for a number of different reactions and show that it is possible to trap the intermediate from one reaction, put it into the others, and get the normal products. We are going to describe one set of such related reactions. In Chapter 37 we suggested a mechanism for the Favorskii rearrangement involving a series of remarkable intermediates. Here is an example. 

The generally accepted mechanism for the Favorskii rearrangement involves the formation of reactive cyclopropanone intermediate C. Base abstracts the a-hydrogen from A to give the carbanion B, which undergoes intramolecular Sn2 displacement of the halide ion. The resulting cyclopropanone intermediate C is opened under the reaction conditions to give the more stable carbanion D, which takes proton from solvent to furnish the final product, an ester E (Scheme 2.25). 

Translation of these results into compound I leads to structure X. Unraveling of the strained zwitterion XI derived from this would yield keto aldehyde XII, a structure that plays a central role in the various possible reaction mechanisms that branch off from the starting material I. Furthermore, under photo-lytic conditions, some alkenes react with carbonyl compounds to form four-membered cyclic ethers, namely, oxetanes, by way of a [2-1-2] cycloaddition reaction known as the Patemo-Buchi process. Such a reaction would be all that is necessary to convert XII into the bicyclic cyclopropanone XIII required for the Favorskii-type rearrangement (see Scheme 42.3). Splitting by methanol attack would directly yield compound II. 

Moliner, V., Castillo, R., Safont, V. S., Oliva, M., Bohn, S., Tunon, I., Andres, J. A theoretical study of the Favorskii rearrangement, calculation of gas-phase reaction paths and solvation effects on the molecular mechanism for the transposition of the a-chlorocyclobutanone. J. Am. Chem. Soc. 1997,119,1941-1947. 

When the Favorskii rearrangement is carried out on a substrate which contains an internal nucleophile, this can attack the cyclopropanone intermediate to yield cyclic products. The reaction shown in Scheme 13 provides a route to polysubstituted "y-butyrolactones by this kind of mechanism. 

This reaction is called the Favorskii rearrangement. Again, there are many variations for example, instead of an alkoxide anion, a hydroxide anion or even an amine may be used, in which case the salt of the carboxylic acid or the amide will be formed, respectively. This reaction may also be used so as to result in a ring contraction. Write down the mechanism for the reaction between an alkoxide anion and 2-chlorocyclohexanone. 

In order to distinguish between a mechanism proceeding via a symmetrical cyclopropanone intermediate (Favorskii reaction) and a mechanism closely related to the benzilic acid rearrangement and called semibenzilic (or quasi-Favorskii) rearrangement, the ring contraction of 2-bromocyclobutanone was studied in deuterium oxide using sodium carbonate as base (50 C) or in boiling deuterium oxide only. 

A conceivable mechanism for this reaction considers that malonate anion initially reacts as a base to give an equilibrium mixture of zwitterion 2 and cyclopropanone 3 intermediates, which have been suggested to be involved in the Favorskii rearrangement. ... 

This reaction has a similar mechanism to the Favorskii Rearrangement. 

Treatment of 2-chlorocyclohexanone (69) with aqueous sodium hydroxide leads to the sodium salt of cyclopentanecarboxylic acid (70) in a reaction known as the Favorskii rearrangement (equation 10.91). The ketone 71 has been proposed to be an intermediate in the reaction. Propose a mechanism for the formation of 71. 

The quasi-Favorskii rearrangement has been used often in the synthesis of unnatural, conplex, polycyclic structures. Indeed, this method is uniquely suited for such targets. However, undesired side reactions can occur. An exanple, discussed here within its mechanistic context, is based on a report by Ueda and coworkers. They treated the polycyclic dibrominated diketone 37 with potassium hydroxide in the expectation of obtaining cubane-l,3-dicarboiq lic acid 38. Given what was known about quasi-Favorskii reactions at the time (vide supra), the plan made perfect sense. However, exposure of 37 to 5% KOH for 15 min at 80 °C afforded not 38 but the cyclopropyl lactone 43 fScheme 7.12). A proposed mechanism for the process began with a Haller-Bauer cleavage, always a potential risk in quasi-Favorskii... 

An early study on Favorskii reaction gives a plain explanation how radioactive tracers are used in elucidation of reaction mechanisms (Loftfield 1950). The reaction is the rearrangement of an a-haloketone in alkaline medium. Two mechanisms (1 and 2) had been proposed for the reaction. 

More recent work on the Favorskii rearrangement has focused on testing the ability of increasingly complex substrates to participate in Favorskii and related rearrangements. Efforts have also been directed at determining how reaction conditions affect the precise mechanism of Favorskii rearrangements. Both of these aspects of the Favorskii rearrangement will be discussed in subsequent sections. 

By 1950 five distinct mechanisms had been suggested to account for the formation of the major products of the Favorskii rearrangement. Four involved epoxide, ketene, enol, and carbene intermediates. A fifth mechanism related to the benzylic acid rearrangement was also proposed. Then, in 1951 Loftfield isolated two esters with identical isotope distributions at their a and P carbons from treatment of a radiolabeled, cyclic a-chloroketone with an alkoxide. These two products suggested a symmetrical intermediate, leading Loftfield to postulate the existence of a cyclopropanone along the reaction pathway. ... 

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