Including Physics-Informed Atomization Constraints in Neural Networks for Reactive Chemistry

Reactive potentials serve as essential tools for investigating chemical reactions with moderate computational costs. However, traditional reactive potentials often depend on fixed, semiempirical parameters, which limits their accuracy and transferability. Overcoming these limitations can significantly expand the applicability of reactive potentials, enabling the simulation of a broader range of reactions under diverse conditions and the prediction of reaction properties, such as barrier heights. This work introduces ANI-1xBB, a novel ANI-based reactive ML potential trained on off-equilibrium molecular conformers generated through an automated bond-breaking workflow. ANI-1xBB significantly enhances the prediction of reaction energetics, barrier heights, and bond dissociation energies, surpassing those of conventional ANI models. Our results show that ANI-1xBB improves transition state modeling and reaction pathway prediction while generalizing effectively to pericyclic reactions and radical-driven processes. Furthermore, the automated data generation strategy supports the efficient construction of large-scale, high-quality reactive data sets, reducing reliance on expensive QM calculations. This work highlights ANI-1xBB as a practical model for accelerating the development of reactive machine learning potentials, offering new opportunities for modeling reaction phenomena.

Reaction mechanism search tools have demonstrated the ability to provide insights into likely products and rate-limiting steps of reacting systems. However, reactions involving several concerted bond changes─as can be found in many key steps of natural product syntheses─can complicate the search process. To mitigate these complications, we present a mechanism search strategy particularly suited to help expedite exploration of an exemplary family of such complex reactions, cyclizations. We provide a cost-effective strategy for identifying relevant elementary reaction steps by combining graph-based enumeration schemes and machine learning techniques for intermediate filtering. Key to this approach is our use of a neural network potential (NNP), AIMNet2-rxn, for computational evaluation of each candidate reaction pathway. In this article, we evaluate the NNP's ability to estimate activation energies, demonstrate the correct anticipation of stereoselectivity, and recapitulate complex enabling steps in natural product synthesis.

Ring strain energy (RSE) is crucial for understanding molecular reactivity, with broad implications in polymerization, click chemistry, drug discovery and beyond. However, quantitatively determining RSE through experiments or quantum mechanics (QM) is resource-intensive, limiting its application on a large scale. We present a machine learning (ML)-based workflow that enables the reliable and efficient prediction of RSE, entirely bypassing traditional QM calculations. Our workflow employs AIMNet2 machine learning interatomic potentials and Auto3D for the identification of low-energy conformers and RSE computation. Remarkably, it achieves an R 2 of 0.997 and a mean absolute error (MAE) of 0.896 kcal/mol when benchmarked against the ωB97M-D4/Def2-TZVPP method, while running orders of magnitude faster than DFT calculations. To demonstrate the utility of our workflow, we successfully differentiated reactive from nonreactive molecules in copper-free click chemistry, [3 + 2] cycloaddition reaction and ring-opening metathesis polymerization, underscoring its transferability to diverse molecular systems. Additionally, we compiled the RSE Atlas, a computational database encompassing 16,905 single-ring molecules, offering a valuable resource for investigating factors influencing RSE. Our approach transforms RSE into a readily computable property, facilitating its integration into reaction designs.