Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

The mild and selective functionalization of carbon-hydrogen (C-H) bonds remains a pivotal challenge in organic synthesis, crucial for developing complex molecular architectures in pharmaceuticals, polymers, and agrochemicals. Despite advancements in directing group (DG) methodologies and computational approaches, predicting accurate regioselectivity in C-H activation poses significant difficulties due to the diversity and complexity of organic compounds. This study introduces a novel quantum mechanics-based computational workflow tailored for the regioselective prediction of C-H activation in the presence of DGs. Utilizing (semi-empirical) quantum calculations hierarchically, the workflow efficiently predicts outcomes by considering concerted metallation deprotonation mechanisms mediated by common catalysts like Pd(OAc)₂. Our methodology not only identifies potential activation sites but also addresses the limitations of existing models by including a broader range of directing groups and reaction conditions while maintaining moderate computational cost. Validation against a comprehensive dataset reveals that the workflow achieves high accuracy, significantly surpassing traditional models in both speed and predictive capability. This development promises substantial advancements in the design of new synthetic routes, offering rapid and reliable regioselectivity predictions that are essential for accelerating innovation in materials science and medicinal chemistry.