A DFT-based mechanistic study on the formation of oximes

Oxime chemistry has been proven to be a reliable bioconjugation method for biomedical applications. Because of its stable and bio-orthogonal nature, a number of materials have been devised for in vitro and in vivo applications such as drug delivery, imaging, and biochemical assays. Polymers, synthetic molecules, nanoparticles, and biomolecules carrying alkoxyamine and aldehyde/ketone functional groups could be linked to each other through oxime bond, and a variety of modular platforms could be produced. Formation of oximes is catalyzed in acidic medium, and the proposed reaction mechanism follows classical imine formation pathways. Aniline has been found to accelerate the rate of oxime formation several orders of magnitude. In this computational study, we analyzed the proposed mechanism on model systems using DFT calculations including a solvation model. The energetics of the reaction steps in neutral and acidic conditions as well as in the presence of aniline was performed. Explicit water molecules were included in the calculations to study the energetics of solvent assisted proton transfer steps.