Substrate Scope in Organic Reactions: Comparison of Fingerprint-Based and Reactivity-Based Similarity Metrics

Recent advances in reaction development have led to a growing number of literature examples, wherein the number of applicable substrates is often used as an indicator of reaction utility. However, this parameter alone does not adequately reflect the actual reaction utility, with the key factor being the substrate diversity. In this study, reactivity-based molecular descriptors were compared with the structural similarity measure Extended-Connectivity Fingerprints (ECFP), and new evaluation metrics were proposed to quantify the substrate scope in organic reactions. By analyzing six reaction systems for the oxidative coupling of phenols, the potential substrate scope was successfully captured; notably, this was not reflected by the substrate count. Additionally, an evaluation framework exhibiting predictability, chemical validity, and informatic validity was developed. These findings are expected to provide guidelines for the design of substrates for future reaction developments. All source code and data are available on the GitHub repository at https://github.com/poclab-web/substrate-scope-metrics. The web interface is also available at https://github.com/poclab-web/streamlit-substrate-scope-metrics.