A General Group Testing Strategy for Discovering Chemical Cooperativity

Abstract

ABSTRACT The combinatorial explosion inherent to multi‐component systems limits their experimental exploration and ultimately chemical discovery. Here, we introduce a statistics‐based group‐testing strategy, which we couple with luminescence quenching assays to efficiently identify cooperative molecular interactions. Utilizing the quenching of a photosensitizer as a quick readout for chemical activity, 4,950 substrate pairs were screened in only 504 experiments, enabled through a combinatorial design theory‐based pooling approach and iterative deconvolution. Therefore, two algorithms—a greedy algorithm for group design and an iterative sectioning deconvolution method to resolve active pairs—were implemented. Fifteen cooperative pairs were identified, and the nature of their interactions and the resulting electronic perturbations were investigated. In a systematic follow‐up screen, it was found that the identified active pairs exhibit high reactivity towards a broad group of reaction partners. One such pair led to the discovery of a bench‐stable reagent, enabling efficient and regioselective trifluoromethylthiolation reactions. This work establishes a broadly applicable framework for accelerating the discovery of cooperative reactivity through optimized experimental designs.