(123g) Electrochemical C(sp3)-H Bond Oxidation of Xenobiotics with Mediators | AIChE

(123g) Electrochemical C(sp3)-H Bond Oxidation of Xenobiotics with Mediators


Tanwar, M. - Presenter, University of Minnesota
Neurock, M., University of Minnesota
Udyavara, S., University of Minnesota
Saito, M., The Scripps Research Institute
Kawamata, Y., The Scripps Research Institute
Sigman, M., University of Utah
Minteer, S., University of Utah
Baran, P., The Scripps Research Institute
The selective oxidation of a C(sp3)-H bond is essential towards synthesizing drug metabolites and motifs for many biologically active compounds. Accessing drug metabolites is critical for designing more effective drugs and determining a specific drug's safety. Direct electrosynthesis techniques employing an anode surface to carry out the oxidation will likely target common substrate functionalities such as carboxylates and aromatic rings and the solvent before activating the C(sp3)-H bonds of the substrate, as the former two require much lower potentials than the latter. In contrast, indirect electrosynthesis routes generate catalytic oxidizing agents known as mediators in-situ to oxidize C(sp3)-H bonds of the substrate, thus promoting hydrogen atom transfer, and suppressing electron transfer from the substrate. Herein, we propose a catalytic cycle for forming the active mediator and its role in the activation of the substrate (Figure 1a). The mediator (M) is first oxidized to generate the oxidized mediator (M•+). The oxidized mediator (M•+) then abstracts a hydrogen atom from the substrate to form the protonated M-H+ species that can then be deprotonated to regenerate the original mediator (M). An efficient mediator requires a low oxidation potential (Eox), a more exergonic H-binding free energy (∆GH-bind), and a low deprotonation free energy (DPFE). However, these thermodynamic descriptors were found to be coupled and cannot be optimized independently, which drives the search to achieve an overall optimum by exploring potential mediators. First-principles density functional theory (DFT) calculations were carried out to screen potential mediators using these descriptors. The computational screening resulted in the discovery of N-ammonium ylides for chemoselective C(sp3)–H oxidation, which experimentally shows either superior or orthogonal site-selectivity and reactivity compared to know oxidation systems. Transition state calculations further elucidate the specific mediator-substrate interactions and examine factors that govern the experimentally obtained selectivity to different oxidation products.