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.