Key structural features to favour imines over hydrates in water: pyridoxal phosphate as a muse

Abstract

Imination reactions in water represent a challenge not only because of the high propensity of imines to be hydrolysed but also as a result of the competing hydrate formation through H₂O addition to the aldehyde. In the present work we report a successful approach that allows for favouring imitation reactions while silencing hydrate formation. Such remarkable reactivity and selectivity can be attained by fine-tuning the electronic and steric structural features of the ortho-substituents of the carbonyl groups. It resulted from studying the structure–reactivity relationships in a series of condensation reactions between different amines and aldehydes, comparing the results to the ones obtained in the presence of the biologically-relevant pyridoxal phosphate (PLP). The key role of negatively-charged and sterically-crowding units (i.e., sulfonate groups) in disfavouring hydrate formation was corroborated by DFT and steric-hindrance calculations. Furthermore, the best-performing aldehyde leads to higher imine yields, selectivity and stability than those of PLP itself, allowing for the inhibition of a PLP-dependent enzyme (transaminase) through dynamic aldimine exchange. These results will increase the applicability of imine-based dynamic covalent chemistry (DCvC) under physiological conditions and will pave the way for the design of new carbonyl derivatives that might be used in the dynamic modification of biomolecules.