Impact of Model Selection and Conformational Effects on the Descriptors for In Silico Screening Campaigns: A Case...

Data-driven catalyst design is a promising approach for addressing the challenges in identifying suitable catalysts for synthetic transformations. Models with descriptor calculations relying solely on the precatalyst structure are potentially generalizable but may overlook catalyst-substrate interactions. This study explores substrate-specific interactions in the context of Rh-catalyzed asymmetric hydrogenation to elucidate the impact of substrate inclusion on the catalyst structure and on the descriptors derived from it. We compare a catalyst-substrate complex with methyl 2-acetamidoacrylate as a model substrate with the generic precatalyst structure involving a placeholder substrate, norbornadiene, across 11 Rh-based catalysts with bidentate bisphosphine ligands. For these systems, a full conformer ensemble analysis reveals an intriguing finding: the rigid substrate induces conformational freedom in the ligand. This flexibility gives rise to a more diverse conformer landscape, showing a previously overlooked aspect of catalyst-substrate dynamics. Electronic descriptor variations particularly highlight differences between substrate-specific and precatalyst structures. This study suggests that generic precatalyst-like models may lack crucial insights into the conformational freedom of the catalyst. We speculate that such conformational freedom may be a more general phenomenon that can influence the development of generalizable predictive models of computational TM-based catalysis.