Quantum mechanical/molecular mechanical study on the Favorskii rearrangement in aqueous media

In this paper, hybrid quantum mechanical/molecular mechanical (QM/MM) calcu lations including 500 water molecules mold solvent effects on the molecular mechanisms of the alpha -chlorocyclobutanone and alpha -chlorocydohexanone transpositions to yield cyclopropane and cyclopentane carboxylic acids, re spectively, as a model of the Favorskii rearrangement. The two accepted mol ecular mechanisms, the semibenzilic acid and the cyclopropanone transpositi ons, as well as the competition between both reaction pathways and the ring size effects are addressed in this investigation. Stationary points-reacta nts, products, transition structures, and intermediary species along both r eaction pathways-have been located and characterized, involving a fully fle xible active-site region, by means of GRACE and CHARMM software. The transi tion structures have been connected with their respective reactants and pro ducts by the intrinsic reaction coordinate procedure carried out in the pre sence of water media, thus obtaining for the first time a realistic reactio n pathway for this chemical transposition. The analysis of the results obta ined by QM/MM methods shows that the semibenzilic acid mechanism is favored over the cyclopropanone mechanism for the a-chlorocyclobutanone system. Ho wever, the study of the ring size effects reveals that the cyclopropanone m echanism is the energetically preferred reactive channel for the alpha -chl orocyclohexanone ring, probably due to the straining effects on bicycle cyc lopropanone, an intermediate that appears on the semibenzilic acid pathway. This later mechanism is described as a two-step one, while the cyclopropan one or Loftfield mechanism is for the first time described as a four-step r eaction. These results provide new information on an important chemical rea ction and the key factors responsible for the behavior of reactant systems embedded in aqueous media. This methodology allows evaluation of specific s olute-solvent interactions as well as weighing up of the different energy c ontribution terms.