Abstract: Junctions comprising individual molecules “wired” between nanoscale electrodes approach the limit of miniaturization for electronic circuits used in computation and data storage. While model studies of these atomically precise systems expose molecular structure-charge transport property relationships critical for the development of useful electronic components (e.g., wires, switches, or diodes), the wider application, stability, and capabilities of such junctions, for example, to follow chemical bond forming and breaking processes, remain understudied. Accordingly, we are applying ambient atmosphere and glovebox-based scanning tunnelling microscope-based break-junction (STM-BJ) methods to probe metal-single molecule-metal junctions formed from reactive molecules and functional electrode metals. In this presentation, I will review our recent discovery that junctions generated in situ with Ag-C(sp3) interfacial linkages appear to rapidly react with surface-adsorbed oxygen to provide an unusual Ag-O-C(sp3) (alkoxide) contact chemistry. In addition, I will highlight the ability of gold surfaces, often considered to be “chemically inert,” to function as Lewis acids that can promote interfacial reactions involving carbocation intermediates. This research focus, in combination with our broader program, aims to develop a deeper understanding of molecular assembly and heterogeneous catalysis, as well as charge transport processes through molecular materials from the nanoscale to bulk. Our findings are relevant for the design of new molecular-scale devices and extended ordered polymers with improved properties, towards applications in nanoelectronics, energy storage, and sensing.