Minxue Huang, Tzuhsiung Yang, Jonathan D. Paretsky, John F. Berry, Jennifer M. Schomaker

Nitrene transfer (NT) reactions represent a powerful, direct method to convert C-H bonds into amine groups that are prevalent in numerous commodity chemicals and pharmaceuticals. Indeed, the importance of the C-N bond has stimulated the development of an array of transition-metal complexes to effect regio- and diastereoselective NT. Steric and electronic control is often invoked to explain the observed outcome in these reactions, but the details of the exact interactions that control selectivity are often unclear. We have found that silver-catalyzed NT reactions provide a convenient platform to better understand how the interplay of catalyst and substrate structure impact the site-selectivity of C-H amination. In this work, we explore the underlying reasons why Ag(tpa)OTf (tpa = tris(pyridylmethyl)amine) prefers to activate α-conjugated C-H bonds over 3° alkyl C(sp3)-H bonds and apply these insights to both reaction optimization and catalyst design. Experimental results suggest possible roles of non-covalent interactions (NCIs) in directing the NT; computational studies support the involvement of π···π and Ag···π interactions between the catalyst and substrate, primarily by lowering the energy of the directed transition state and reaction conformers. In addition, a simple Hess's law relationship can be employed to predict selectivities for new substrates containing competing NCIs. The insights presented herein are poised to inspire the design of other catalyst-controlled C-H functionalization reactions.