Deciphering complexity in Pd–catalyzed cross-couplings

Abstract

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.

Metadata

Item Type:	Article
Authors/Creators:	Clarke, G.E. Firth, J.D. Ledingham, L.A. Horbaczewskyj, C.S. Bourne, R.A. https://orcid.org/0000-0001-7107-6297 Bray, J.T.W. Martin, P.L. Eastwood, J.B. Campbell, R. Pagett, A. MacQuarrie, D.J. Slattery, J.M. Lynam, J.M. Whitwood, A.C. Milani, J. Hart, S. Wilson, J. Fairlamb, I.J.S.
Copyright, Publisher and Additional Information:	© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
Dates:	Published: 10 May 2024 Published (online): 10 May 2024 Accepted: 12 April 2024
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemical & Process Engineering (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	05 Mar 2025 09:38
Last Modified:	05 Mar 2025 09:38
Published Version:	https://www.nature.com/articles/s41467-024-47939-5
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41467-024-47939-5
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:224028

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Deciphering complexity in Pd–catalyzed cross-couplings

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