Toward Predictive Theory in Single‐Atom Catalysis

ABSTRACT Single‐atom catalysis has become a central framework for experiment‐theory integration, as catalytic performance is highly sensitive to the environment of individual metal atoms, a feature that electronic structure calculations are well‐suited to analyze. Yet much of current theoretical practice relies on simplified single‐site models and narrow reactivity windows, overlooking the intrinsic site diversity and evolution of single‐atom catalysts (SAC). This Perspective discusses how SAC modeling can be reframed through a lifecycle‐oriented view that integrates synthesis, activity, stability, and safety. By adopting ensemble‐based descriptions and modular thermodynamic descriptors, we show how theory can be used systematically in line with the level of structural definition accessible experimentally. Using acetylene hydrochlorination as a prominent SAC application with exceptional data coherence for examining the theory‐experiment interplay, wedemonstrate that site formation and evolution under synthesis and reaction conditions, as well as ensemble‐driven activity trends consistent with experimental yields, can be treated quantitatively. In contrast, stability and safety are more effectively addressed through comparative, pathway‐resolved analyses. More broadly, this perspective points toward a shift in how SAC modeling is framed across reactions, enabling theory to move beyond post‐rationalization toward disciplined prediction.