Nickel and palladium catalysed cross-coupling reactions: mechanistic insight and new reactivity

<p dir="ltr">Presented herein is an examination of nickel and palladium catalysts in cross-coupling reactions. Particular attention was paid to mechanistic studies, and the use of the insight gained to inform rational reaction design and explain unexpected reactivity.</p><p dir="ltr">Initially, trifluoromethyl iodide, an economical and under-explored CF₃ source, was assessed for its capacity to serve in cross-coupling reactions. While the intended Suzuki-Miyaura coupling reaction was not effective, the combination of CF₃I with certain Pd or Ni catalysts proved exceptionally reactive, and afforded C-H trifluoromethylated products in good to excellent yield. This reaction showed remarkable functional group tolerance, smoothly trifluoromethylating aromatic species featuring aldehyde, nitrile, amine, and even bromide functional groups. Detailed computational and experimental analysis suggested a mechanism involving a key electrophilic aromatic substitution step mediated by a metal-bound difluorocarbene.</p><p dir="ltr">The kinetics of transmetalation at catalytically relevant Ni^(II) species was then examined. Notably, despite the importance of this step to cross-coupling catalytic cycles, very little rate data is available for transmetalation at Ni^(II) species, hindering rational reaction design. In large part, this lack of data is a consequence of the propensity for <i>in situ </i>generated Ni⁽⁰⁾ to comproportionate with, and unduly consume, the Ni^(II) analyte, generating paramagnetic side products that prohibit the use NMR spectroscopy, and generally complicate analysis.</p><p dir="ltr">In the present study, 20 prototypical Ni^(II) catalytic intermediates were synthesized, isolated, and characterized, with a focus on the most commonly employed phosphine ligands and (pseudo)halides. While initial efforts focused on a fluorescence-based analytical technique to circumvent challenges associated with paramagnetism and NMR analysis, an alternative approach eventuated. It was found that by treating the Ni^(II) complexes with unsaturated organo-tin species, transmetalation occurred, followed by rapid reductive elimination, and subsequent sequestration of the Ni⁽⁰⁾ generated by <b>ƞ</b>²-coordination of the organic coupling product. As a result, ³¹P{¹H} NMR spectroscopy could be used to monitor the progress of the transmetalation reactions. In this way, detailed insight was gained into the role of the ligand and (pseudo)halide in influencing the rate of transmetalation at catalytically relevant Ni^(II) species. </p><p dir="ltr">In general, monodentate ligands afforded faster transmetalation than their bidentate counterparts, with rate constants spanning at least 5 orders of magnitude. Comparatively little rate variation was observed between chloro, bromo and iodo based complexes, though the pseudohalides tosylate and triflate both imparted substantial rate enhancements relative to the typical halides. Detailed mechanistic investigations were carried out for two representative complexes, and suggested two different reaction pathways were accessible: a cyclic, and an open bimolecular electrophilic substitution (S_E2) process. </p><p dir="ltr">These results are significant as they mark the first comprehensive kinetic study of transmetalation at a range of catalytically relevant Ni^(II) species. This data will allow for the rational design of nickel catalysed cross-coupling reactions and permit these species to be used most effectively. In addition, it is anticipated that the comprehensive synthetic details provided regarding the preparation of the numerous Ni^(II) complexes will be of value to future researchers seeking precatalysts, as well as analyte species for future kinetic work. In the same regard, it is suggested that the analytical methodology developed within this work may be applied to other classes of transmetalating agents, such as vinyl- or alkynyl magnesium, zinc, or silicon-based reagents. In this way, the methodology developed in this thesis may permit kinetic data relevant to transmetalation in an extensive range of nickel catalysed cross-coupling reactions to be obtained.</p>