# A General Group Testing Strategy for Discovering Chemical Cooperativity

## TL;DR

A new method using group testing and luminescence screening efficiently identifies cooperative chemical interactions, leading to the discovery of a useful reagent for trifluoromethylthiolation reactions.

## Contribution

A statistics-based group-testing strategy combined with luminescence quenching assays to identify cooperative molecular interactions efficiently.

## Key findings

- 15 cooperative molecular pairs were identified using a combinatorial design and iterative deconvolution.
- An active pair led to the discovery of a bench-stable reagent for efficient trifluoromethylthiolation reactions.
- The method enables screening of 4,950 substrate pairs in only 504 experiments.

## 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.

A combinatorial design theory‐based group testing strategy coupled with luminescence screening to uncover cooperative interactions in a large combinatorial space. Iterative deconvolution identifies reactive molecular pairs and enables the discovery of trifluoromethylthiolation (SCF3) reagents.