Computational insights into the effects of reagent structure and bases on nucleophilic monofluoromethylation of aldehydes

ABSTRACT Although fluorobis(phenylsulfonyl)methane (FBSM) and its cyclic analog 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide (FBDT) possess similar physicochemical properties, Shibata et al. found that FBSM failed to undergo nucleophilic monofluoromethylation of aldehydes regardless of the reaction conditions attempted (using various organic and inorganic bases). However, it was later discovered by Hu et al. that the nucleophilic monofluoromethylation could be accomplished by employing lithium hexamethyldisilazide (LiHMDS) as a base. Herein, we present an in-depth computational investigation into the intriguing effects of reagent structure and bases on the nucleophilic monofluoromethylation of aldehydes. The computations reveal the 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed nucleophilic monofluoromethylation of benzaldehyde with acyclic FBSM is a thermodynamically unfavorable process mainly due to the destabilizing O•••O lone pair repulsions in FBSM product, whereas such repulsion could be largely avoided in FBDT product because of its constrained five-membered ring structure. Employing LiHMDS as a base cannot only facilitate the nucleophilic monofluoromethylation via Li–O interactions but also render the monofluoromethylation of benzaldehyde with FBSM thermodynamically favored.