A General Group Testing Strategy for Discovering Chemical Cooperativity.

Pflüger PM; Katzenburg F; Sandfort F; Teders M; Gómez-Suárez A; Standley EA; Hopkinson MN; Daniliuc CG; Heuer A; Glorius F

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.