A density functional study of chiral phosphoric acid-catalyzed direct arylation of trifluoromethyl ketone and diarylation of methyl ketone: reaction mechanism and the important role of the CF3 group

The detailed mechanism of the chiral phosphoric acid-catalyzed diarylation reaction between acetophenone and indole has been investigated by DFT methods and compared with that of the reaction between 2,2,2-trifluoroacetophenone and indole. The calculated results confirm our previous hypothesis that the CF3 group in the ketone plays a perfect double role in activating the substrate and stabilizing the single arylation product of tertiary alcohol. It is also demonstrated that the different ratio of the F-substitution in the CH3 group of methyl ketone (CH3-nFn, n = 0, 1, 2, 3) affects the activation energy of the key dehydration step for the proposed diarylation process differently, and determines whether the subsequent rearylation proceeds or is being suppressed. The computational prediction that the prohibitive barriers for CF3 and CHF2 ketones in the rate-determining dehydration step for the diarylation process could be overcome at higher reaction temperature has been validated by our additional experiments at 80 degrees C. Furthermore, the origin of the high enantioselectivity of the chiral phosphoric acid-catalyzed single arylation of trifluoromethyl ketone has been studied with the two-layer ONIOM method. The experimentally observed enantiomeric excess can be successfully rationalized.