Quantum Mechanical/Molecular Mechanical Study on the Favorskii Rearrangement in Aqueous Media

Abstract

In this paper, hybrid quantum mechanical/molecular mechanical (QM/MM) calculations including 500 water molecules mold solvent effects on the molecular mechanisms of the R-chlorocyclobutanone and R-chlorocyclohexanone transpositions to yield cyclopropane and cyclopentane carboxylic acids, respectively, as a model of the Favorskii rearrangement. The two accepted molecular mechanisms, the semibenzilic acid and the cyclopropanone transpositions, as well as the competition between both reaction pathways and the ring size effects are addressed in this investigation. Stationary pointssreactants, products, transition structures, and intermediary species along both reaction pathwaysshave been located and characterized, involving a fully flexible active-site region, by means of GRACE and CHARMM software. The transition structures have been connected with their respective reactants and products by the intrinsic reaction coordinate procedure carried out in the presence of water media, thus obtaining for the first time a realistic reaction pathway for this chemical transposition. The analysis of the results obtained by QM/MM methods shows that the semibenzilic acid mechanism is favored over the cyclopropanone mechanism for the R-chlorocyclobutanone system. However, the study of the ring size effects reveals that the cyclopropanone mechanism is the energetically preferred reactive channel for the R-chlorocyclohexanone ring, probably due to the straining effects on bicycle cyclopropanone, an intermediate that appears on the semibenzilic acid pathway. This later mechanism is described as a two-step one, while the cyclopropanone or Loftfield mechanism is for the first time described as a four-step reaction. These results provide new information on an important chemical reaction and the key factors responsible for the behavior of reactant systems embedded in aqueous media. This methodology allows evaluation of specific solute-solvent interactions as well as weighing up of the different energy contribution terms.

Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond Formations: A Decade Update

“…Quantum mechanical/molecular mechanical (QM/MM) study on the Favorskii rearrangement in aqueous media has been carried out . The results obtained by QM/MM methods show that of the two accepted molecular mechanisms for the Favorskii rearrangement, the semibenzilic acid mechanism is favored over the cyclopropanone mechanism for the α-chlorocyclobutanone system.…”

13 Computational organic chemistry

“…Moliner and co-workers have used a QM/MM method combining AM1 and CHARMM approaches to model the Favorskii reaction in the presence of 400 water molecules. 54 They investigated several reaction mechanisms and used the intrinsic reaction coordinate approach to characterise the potential energy surface. They chose chlorocyclobutanone and chlorocyclohexanone as their model substrates and they found that the preferred mechanism depends on the ring size of the reactant.…”

Theoretical investigation of mono- and bi-function alkylating agents transformed from nitrosodimethylamine derivatives

“…The authors observed that this stepwise pathway is similar to the Favorskii rearrangement reaction [24][25][26]. As shown in Fig.…”

“…As a result of the finding of the di-region theory, the authors propose an alternate pathway of AMMN transformation that leads to a bi-functional alkylating agent which can induce cross-linkage between DNA complementary pair bases. This novel pathway involves an intramolecular rearrangement and is similar to the Favorskii rearrangement reaction [24][25][26]. …”