In this paper we examine a highly complex Pd-catalyzed reaction system that can form many products – the reaction of two molecules of 2-bromo-N-phenylbenzamide, which affords N-phenyl phenanthridinone as the primary product. The reaction is accompanied by a plethora of side-products, formed through activation of multiple sites, including C-Br, C-C, C-N, C-H and N-H bonds. The reaction is a valuable benchmark for understanding complex reaction systems and networks, from either mechanistic, discovery or safety perspectives. Automated high-throughput experimentation methods, using both batch and flow screening technologies, have enabled a relatively broad reaction space to be explored, particularly in terms of reaction temperatures and different solvents over time, despite the reaction being of a heterogeneous nature. Data analysis of the reaction outcomes (Principal Component Analysis, Correspondence analysis and Heat Map analysis using hierarchical clustering) has allowed us to examine the factors contributing to the variance in product distributions, showing associations between solvents and reaction products. Furthermore, the heat maps have enabled the interactions between products to be assessed and ordered using hierarchical clustering. From these data we connect certain side-products to the major dominant N-phenyl phenanthridinone product, and the post-chemical modification of other side products. Complementary stoichiometric organopalladium studies (primarily using NMR and MS techniques) allowed us to examine the Pd precatalyst activation pathway and gain insights into likely Pd intermediates of the reaction, particularly an oxidative addition intermediate and advanced downstream PdII intermediate following activation of two molecules of 2-bromo-benzamide. Generally, automated reaction screening and advanced data analysis tools are transforming the way we examine catalytic processes. Our research offers a unique and highly complementary approach to revealing important mechanistic data on what is arguably one of the most complex Pd catalyzed transformations known in the chemical literature.
For details:
Deciphering Complexity in Pd–Catalyzed Cross-Couplings: Side-Product Profiling and Rich Data Analysis of Many Reaction Outcomes Reveals an Intricate Network of Catalytic Cycles
George E. Clarke a, James D. Firth a, Lyndsay A. Ledingham a, Chris S. Horbaczewskyj a, Richard Bourne b, Joshua W. T. Bray a, Poppy L. Martin a, Rebecca Campbell a, Alex Pagett a, Duncan J. MacQuar-rie a, John M. Slattery a, Jason M. Lynam a, Adrian C. Whitwood a, Jessica Milani a, Sam Hart a, Julie Wil-son c and Ian J. S. Fairlamb a
a Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
b School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, UK
c Department of Mathematics, University of York, Heslington, York, YO10 5DD, UK
For more information about Chemspeed solutions:
FLEX CATSCREEN
ISYNTH CATSCREEN
