Deciphering complexity in Pd–catalyzed cross-couplings

Nature Communications

Understanding complex reaction systems is critical in chemistry. While synthetic methods for selective formation of products are sought after, oftentimes it is the full reaction signature, i.e., complete profile of products/side-products, that informs mechanistic rationale and accelerates discovery chemistry. Here, we report a methodology using high-throughput experimentation and multivariate data analysis to examine the full signature of one of the most complicated chemical reactions catalyzed by palladium known in the chemical literature. A model Pd-catalyzed reaction was selected involving functionalization of 2-bromo-N-phenylbenzamide and multiple bond activation pathways. Principal component analysis, correspondence analysis and heatmaps with hierarchical clustering reveal the factors contributing to the variance in product distributions and show associations between solvents and reaction products. Using robust data from experiments performed with eight solvents, for four different reaction times at five different temperatures, we correlate side-products to a major dominant N-phenyl phenanthridinone product, and many other side products.

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Deciphering complexity in Pd–catalyzed cross-couplings

George E. Clarke 1, James D. Firth 1, Lyndsay A. Ledingham 1, Chris S. Horbaczewskyj 1, Richard A. Bourne 2, Joshua T. W. Bray 1, Poppy L. Martin 1, Jonathan B. Eastwood 1, Rebecca Campbell 1, Alex Pagett 1, Duncan J. MacQuarrie 1, John M. Slattery 1, Jason M. Lynam 1, Adrian C. Whitwood 1, Jessica Milani 1, Sam Hart 1, Julie Wilson 3, Ian J. S. Fairlamb 1

1. Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
2. Institute of Process Research and Development, School of Chemistry & School
   of Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK.
3. Department of Mathematics, University of York, Heslington, York YO10 5DD,
   UK.

DOI: https://doi.org/10.1038/s41467-024-47939-5

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