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Inverting Steric Effects: Using “Attractive” Noncovalent Interactions To Direct Silver-Catalyzed Nitrene Transfer

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journal contribution
posted on 01.11.2017, 00:00 by Minxue Huang, Tzuhsiung Yang, Jonathan D. Paretsky, John F. Berry, Jennifer M. Schomaker
Nitrene transfer (NT) reactions represent powerful and direct methods to convert C–H bonds into amine groups that are prevalent in many commodity chemicals and pharmaceuticals. The importance of the C–N bond has stimulated the development of numerous transition-metal complexes to effect chemo-, regio-, and diastereoselective NT. An ongoing challenge is to understand how subtle interactions between catalyst and substrate influence the site-selectivity of the C–H amination event. 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 reaction optimization and catalyst design. Experimental results suggest possible roles of noncovalent interactions (NCIs) in directing the NT; computational studies support the involvement of π···π and Ag···π interactions between catalyst and substrate, primarily by lowering the energy of the directed transition state and reaction conformers. 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.