Water-Assisted and Catalyst-Free Hetero-Michael Additions: Mechanistic Insights from DFT Investigations

The reaction mechanism of six catalyst-free hetero-Michael addition reactions in water has been investigated using DFT calculations. Our theoretical results revealed the direct involvement of multiple water molecules in the transition states. The water molecules play a catalytic role in lowering the activation barrier for the three thia-Michael reactions. Concerted transition state with two bridging water molecules yields the lowest energy barrier. The formation of a hydrogen bonding network via one or more water molecules in the transition state facilitates proton shuttling from the nucleophile to the electrophile. For the aza-Michael reactions considered, they follow a stepwise mechanism involving the formation of a stable zwitterionic intermediate. In these cases, water influences the reactions via strong (nonspecific) solvent effect and the catalytic role of water is less important for enones that adopt a stable s-cis conformation. The calculated low reaction barriers (44-83 kJ/mol) of the six studied reactions are in excellent accord with the observed facile hetero-Michael reactions in water.

Automated summary

The study investigates the reaction mechanisms of six catalyst-free hetero-Michael addition reactions in water using DFT calculations. Water molecules are directly involved in the transition states, playing a catalytic role in lowering the activation barrier, especially for thia-Michael reactions. The calculated low reaction barriers are in good agreement with the observed facile reactions, indicating the important role of water in these processes.