"Click" formation of the imine bond in water.

The imine bond is a cornerstone of supramolecular chemistry because it combines stability and reversibility with ease of formation and the availability of a large number of precursors. Yet, the low hydrolytic stability of imines poses an important limitation as it prevents their application in water. Here, we show imine bond formation in water with the characteristics of a 'click' reaction: fast, quantitative and selective using reactants in a stoichiometric ratio at sub millimolar concentrations. Our strategy relies on the presence of a Zn(ii)-metal complex in one of the precursors that binds and preorganizes the other reactant, activates the carbonyl for nucleophilic attack and stabilizes the imine through coordination. The reaction proceeds with fast kinetics (k ∼5 M-1 s-1) and yields a highly stable imine (K > 105 M-1) at neutral pH. Imine formation remains effective in a complex chemical matrix such as E. coli cell lysate. It is further shown that structural tuning of the building blocks enables efficient imine bond formation using either aromatic or aliphatic amines without requiring any other functional groups. The imines obtained following this strategy enable dynamic combinatorial chemistry at submillimolar concentrations in water.