(337af) First-Principles Investigation of Mediated Electrochemical Carbon-Hydrogen Activations for Accessing Pharmaceutical Intermediates

C-H activation is one of the most fundamental chemistry due to the abundance of these bonds in drug molecules. This generality, however, makes selective C-H activation one of the biggest challenges in the synthesis field. We first identified the critical thermodynamic activity descriptors that govern the electrocatalytic cycle resembling the enzyme mechanism. Next, I employed density functional theory (DFT) calculations to design new mediators to carry out selective C-H activations based on these descriptors. Our high-throughput calculations have driven recent investigations by predicting novel mediators, which our experimental collaborators are now testing. Through more rigorous analyses, my efforts have also focused on understanding why these mediators target only specific C-H bonds, bringing us closer to unraveling enzymes' behavior. Further, I have built a machine-learning model for predicting selective C-H activation based on the identified descriptors and the current kinetic data from the first-principles simulations. This model will push our efforts toward prediction that will assist in informed decisions for future experiments.

While state-of-the-art, these mediators still demand significant energy input for oxidative C-H activations. Thus, our newer efforts focus on further decreasing the associated energy costs with these mediators. We have identified the underlying cause to be the intrinsic nature of this chemistry, which proceeds by an oxidation-by-oxidation approach. In this approach, we first oxidize the mediator, which then oxidizes the C-H bond. To improve the inherent energy cost of this transformation, we have started working with our experimental collaborators to probe a mediated oxidation-by-reduction pathway. This approach will first involve reducing the mediator, which then oxidizes the C-H bond, leading to a lower net energy requirement. I have employed detailed ab-initio molecular dynamics (AIMD) simulations, DFT calculations, and electron transfer theories to examine this chemistry's critical electron transfer reactions. The current pathway involves a precious metal-based electrocatalyst (Ru, $ 9920/lb). We are further pushing to make this a metal-free pathway with affordable mediators (Nitrobenzene, $ 0.7/lb) in an aqueous medium. Theory guides these efforts with high-throughput calculations to screen a range of candidate mediators. Reactions without precious metals, cheaper mediators, and water as a solvent will tremendously increase the upscaling potential of this process.

In summary, this work utilizes a combination of different first-principles (DFT, AIMD) and data-driven approaches to understand and leverage the fundamentals of C-H activations which are backbones in synthesizing pharmaceutical intermediates, including drugs and metabolites.