Exploring the Effect of Phosphine Ligand Architecture on a Buchwald–Hartwig Reaction: Ligand Synthesis and Screening of Reaction Conditions

A laboratory project to introduce upper-level undergraduates to Pd-catalyzed C–N σ-bond forming reactions is described. The exercise involves evaluation of monodentate phosphine ligands and solvents for the Buchwald–Hartwig coupling of 4-chloro- or 4-bromo-anisole with morpholine. Students gain experience in the synthesis of a biarylphosphine ligand, performing reactions under anhydrous and anaerobic conditions, with systematic screening and analysis of reaction conditions, and with the use of GC–MS data to gauge the extent of each coupling reaction. Students develop arguments from spectroscopic evidence to support claims regarding the effectiveness of each set of reaction conditions and explore the impact of the ligand within the context of currently accepted mechanistic models. Optimal conditions are determined and used for the scaled-up synthesis of the coupling product, and electronic aspects of the product are explored via computational chemistry.