Methyllithium "On-Water" Addition on Ketone: H-Bond Network and Mechanism.

Organolithium compounds play a pivotal role in organic synthesis, yet their high reactivity and extreme moisture sensitivity-due to the polar carbon-lithium bond-typically necessitate strictly anhydrous conditions. Intriguingly, recent studies have demonstrated that the addition of water can facilitate certain organolithium reactions, such as the efficient synthesis of 2,2-disubstituted tetrahydrofurans via the reaction of methyllithium (MeLi) with 4-chloro-1-phenylbutan-1-one under "on-water" conditions. Despite the success of such transformations, the underlying reaction mechanisms and the behavior of MeLi in aqueous environments remain poorly understood. In this work, we study the MeLi-mediated reaction in the presence of water using hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, biased by well-tempered metadynamics within a water-ether droplet solvation model. Both dimeric and tetrameric MeLi clusters were examined. Our findings reveal that a hydrogen-bond network involving partially hydrolysed dimers (MeLi2OH) and diffusing water molecules stabilizes the organolithium species within the ether phase, preventing complete hydrolysis and enabling product formation. Similarly, the partially hydrolysed tetramer cluster MeLi4(OH)3 was also found to support the progression of the addition reaction without full decomposition.