ReactAIvate: A Deep Learning Approach to Predicting Reaction Mechanisms and Unmasking Reactivity Hotspots

Abstract: A chemical reaction mechanism (CRM) is a sequence of molecular-level events involving bond-breaking/forming processes, generating transient intermediates along the reaction pathway as reactants transform into products. Understanding such mechanisms is crucial for designing and discovering new reactions. One of the currently available methods to probe CRMs is quantum mechanical (QM) computations. The resource-intensive nature of QM methods and the scarcity of mechanism-based datasets motivated us to develop reliable ML models for predicting mechanisms. In this study, we created a comprehensive dataset with seven distinct classes, each representing uniquely characterized elementary steps. Subsequently, we developed an interpretable attention-based GNN that achieved near-unity and 96% accuracy, respectively for reaction step classification and the prediction of reactive atoms in each such step, capturing interactions between the broader reaction context and local active regions. The near-perfect classification enables accurate prediction of both individual events and the entire CRM, mitigating potential drawbacks of Seq2Seq approaches, where a wrongly predicted character leads to incoherent CRM identification. In addition to interpretability, our model adeptly identifies key atom(s) even from out-of-distribution classes. This generalizabilty allows for the inclusion of new reaction types in a modular fashion, thus will be of value to experts for understanding the reactivity of new molecules.