A computational study of the mechanism and microkinetic modeling of electrochemical PINOylation

Electrochemical activation of benzylic C–H bonds has recently emerged as a useful mediated electrosynthesis method, in which phthalimide-N-oxyl (PINO) serves as both a hydrogen atom transfer (HAT) mediator and a radical-trapping reagent. Despite its synthetic utility, the factors governing substrate-dependent yield and product selectivity remain poorly understood in PINO-mediated electrosynthesis. In this work, density functional theory was combined to investigate the mechanism of electrochemical PINOylation across the substrate scope reported by Stahl and co-workers. A micro-kinetic modeling approach for mediated electrochemical systems was developed to semi-quantitatively predict selectivity and yield. The model was parameterized using the applied current, the experimental reaction time, and key chemical steps, including HAT between PINO and the substrate, as well as C–O and C–N formation pathways. The simulations show that the reaction outcome is governed not only by the thermodynamics of product-forming steps but also by the approximate PINO concentration, determined by the balance between PINO generation and its consumption by competing radical processes. In particular, the maximum PINO concentration provides a useful mechanistic indicator of experimental yield, while competition at the C–N intermediate controls product ratio. The model has good agreement with the experimental trends in yield and selectivity for about three-quarters of substrates and provides a mechanistic rationale for why certain substrates favor high yield and predominantly C–O product formation. More broadly, this work demonstrates how the microkinetic modeling approach presented here can provide key insights into mediated electrochemical systems to optimize selectivity and yields.