Favorskii rearrangement cyclopropanone intermediate

The currently accepted mechanism for the Favorskii rearrangement of dihalo ketones involves a cyclopropanone intermediate formed by loss of HX. This is followed by attack of alkoxide synchronous with cyclopropanone fragmentation and departure of halide ion to form the unsaturated ester... 

Quantum mechanical/molecular mechanical study on the Favorskii rearrangement in aqueous media has been carried out.39 The results obtained by QM/MM methods show that, of the two accepted mechanisms for Favorskii rearrangement, the semibenzilic acid mechanism (a) is favored over the cyclopropanone mechanism (b) for the a-chlorocyclobutanone system (Scheme 6.2). However, the study of the ring-size effects reveals that the cyclopropanone mechanism is the energetically preferred reactive channel for the a-chlorocyclohexanone ring, probably due to the straining effects on bicycle cyclopropanone, an intermediate that does not appear on the semibenzilic acid pathway. These results provide new information on the key factors responsible for the behavior of reactant systems embedded in aqueous media. 

A common intermediate is required in this Favorskii rearrangement to set the same product. Removal of an aH by OH- is followed by an SN2 displacement of Cl- to give a cyclopropanone ring. Ring opening occurs to give the more stable benzylic carbanion. 

Cyclopropanones deserve special comment, not because of their practical importance (they have no commercial value at this time), but because of their novel behavior and reactivity. No unambiguous synthesis of cyclopropanones was known prior to 1965, and the older textbooks usually contained statements such as cyclopropanones apparently cannot exist. However, they had been postulated as intermediates in various reactions (see, for example, the Favorskii rearrangement, Section 17-2C and Exercise 17-15), but until recently had defied isolation and identification. The problem is that the three-ring ketone is remarkably reactive, especially towards nucleophiles. Because of the associated relief of angle strain, nucleophiles readily add to the carbonyl group without the aid of a catalyst and give good yields of adducts from which the cyclopropanone is not easily recovered ... 

Another useful route to cyclopentanes is the ring contraction of 2-bromo-cyclohexanones by a Favorskii rearrangement to give cyclopentanecarboxylic acids. If a,fi-dibromoketones are used, ring opening of the intermediate cyclopropanone leads selectively to /J,y-unsaturated carboxylic acids (S.A. Achmad, 1963, 1965 J. Wolinsky, 1965). 

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). 

Cyclopropanone is a generally accepted intermediate in the Favorskii rearrangement, as shown in equation 9. BordwelF has suggested that the second step of the Favorskii... 

Other symmetrical intermediates originally identified by radioactive labelling include the cyclopropanone in the Favorskii rearrangement in Chapter 37, p. 000, and a spirocyclic intermediate in electrophilic substitution on an indole in Chapter 43,... 

Favorskii rearrangement Skeletal rearrangement of a-halo ketones via a cyclopropanone intermediate to give carboxylic acids or carboxylic acid derivatives. 164... 

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. 

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. ... 

The stereoisomeric chlorodecalones A and B give different product mixtures on treatment with sodium methoxide in dimethoxyethane. Discuss this result in relationship to the existence of dipolar and cyclopropanone intermediates in Favorskii rearrangements. 

While the RBR does not encompass a true rearrangement of the carbon skeleton, it has been likened, mechanistically, to the Favorskii rearrangement, which does. Indeed, both involve a rate-limiting intramolecular ring-forming step that follows an acid-base equilibrium. The Favorskii intermediate is a cyclopropanone that is formed by a-deprotonation of an a-haloketone, analogous to the episulfone invoked in the RBR mechanism. 

The details of the Favorskii rearrangement continue to attract attention and cyclopropanone intermediates in the peracid epoxidation of allenes have been noted. The fluoride-ion-promoted elimination of chlorotrimethylsilane from (375) leads to the allene oxide (376) which undergoes regiospecific ring-opening with nucleophiles. However, rearrangement of (376) to cyclopropanone (377) only occurs prior to nucleophilic capture when C-1 carries an aryl substituent (Scheme 45). ... 

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. ... 

The existence of a cyclopropanone intermediate was supported by subsequent experimental evidence, although in more polar media the presence of dipolar intermediates has also been inferred. For example, when an aromatic a-bromoketone was treated with base in the presence of furan, the major product was a dipolar cycloaddition adduct which was isolated along with the Favorskii rearrangement product."... 

Finally, a Favorskii rearrangement has been proposed in the biosynthesis of the wailupemycins. " The enzyme-catalyzed conversion of 9 to 11 can be envisioned to proceed through cyclopropanone intermediate 10. A Favorskii rearrangement has also been implicated in the biosynthesis of molecules related to okadaic acid. ... 

Scheme 9.98. One possible pathway for the Favorskii rearrangement (a specific example of the general expression of Equation 9.74) where there are no hydrogens a- to the carbonyl and thus neither a cyclopropanone (Scheme 9.96) nor a carbene (Scheme 9.97) intermediate can obtain in the formation of ethyl 1-phenylcyclohexanecarboxylate.

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