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

Abstract

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.

Rigidifying Ag(I) Complexes for Selective Nitrene Transfer

“…Rather, the nitrene intermediates are electronically similar; both aziridination and C−H insertion occur via hydrogen atom transfer, followed by barrierless radical recombination, suggesting that simple steric effects are responsible for the chemoselectivity. This observation inspired us to search for ways to exploit other types of interactions, in addition to steric repulsion between catalyst and substrate, to improve the tunability of site‐selective C−H bond amidation …”

“…One fluxional behavior in 1 involves rapid association/dissociation of one of the pyridine arms of the tpa ligand on and off the metal, with a predominant tridentate conformation in solution at low temperature. Selectivity for benzylic C−H bond amidation (Scheme ) could be improved slightly when 1 was used at low temperatures in non‐polar solvents, due to increased enhancement of non‐covalent interactions (NCIs) between π‐containing groups in the substrate and the ligand on the catalyst . Replacing one of the pyridine arms of tpa with a phenyl group in 1 a (Scheme ) gave essentially no selectivity between amidation of either the benzylic or tertiary alkyl C−H bonds of 6 .…”

“…However, efforts to identify silver catalysts that exhibit broad scope for the amidation of benzylic and allylic C−H bonds in the presence of other activated bonds were only marginally successful (Scheme C) . To address this challenge, experimental and computational studies of known and new silver catalysts for site‐selective C−H amination were undertaken . The results suggested that competitive NT between benzylic, allylic, and propargylic C−H vs .…”

“…3° alkyl C(sp 3 )−H bonds catalyzed by Ag(tpa)OTf 1 (tpa=tris(2‐pyridylmethyl)amine) are influenced by weak non‐covalent interactions ( π ⋅⋅⋅ π and Ag⋅⋅⋅ π ) between the substrate and the catalyst. Thus, we hypothesized tuning the ligand design to reinforce these directing interactions could lead to more selective catalysts …”

Cooperative assembly of a four-molecule signaling complex formed upon T cell antigen receptor activation

“…S10 with two binary interfaces for each protein not only can enhance specificity but also can offer mechanisms for efficient and regulated assembly and disassembly. Likely, such a mechanism can be further modulated by events such as phosphorylation to cause long-range modulation of flexibility and accessibility (38) as well as allosteric interactions between binding sites, fine-tuning the energetics and oligomeric states of intermediates before full assembly. In fact, due to the membrane anchoring of LAT in vivo, it is conceivable that the interaction is modulated by PLC-γ1 simultaneously interacting with phospholipids of the cell membrane, by multivalent interactions of additional ligands, and through spatial partitioning within the signaling microclusters.…”