This study investigates the chemistry of the Au–S interface at the nanoscale using single-molecule break junction techniques and flicker noise measurements. The researchers probe the conductance and analyze flicker noise for various aliphatic and aromatic thiol derivatives and thioethers. They demonstrate that flicker noise can unambiguously differentiate between stronger chemisorption (Au–SR) and weaker physisorption (Au–SRR) interactions. The Au rearrangement in chemisorbed Au–SR junctions is similar to that in pure Au–Au metal contact breaking, while thioethers show the formation of a weaker Au–SRR bond, indicating changes in the Au/anchoring group interface. Additionally, the study explores the interfacial electric field-catalyzed ring-opening reaction of cyclic thioethers under mild conditions, which is typically required harsher conditions for breaking the C–S bond. The results highlight the potential of single-molecule conductance and flicker noise analysis in tuning and monitoring chemical reactions at the single-molecule level.This study investigates the chemistry of the Au–S interface at the nanoscale using single-molecule break junction techniques and flicker noise measurements. The researchers probe the conductance and analyze flicker noise for various aliphatic and aromatic thiol derivatives and thioethers. They demonstrate that flicker noise can unambiguously differentiate between stronger chemisorption (Au–SR) and weaker physisorption (Au–SRR) interactions. The Au rearrangement in chemisorbed Au–SR junctions is similar to that in pure Au–Au metal contact breaking, while thioethers show the formation of a weaker Au–SRR bond, indicating changes in the Au/anchoring group interface. Additionally, the study explores the interfacial electric field-catalyzed ring-opening reaction of cyclic thioethers under mild conditions, which is typically required harsher conditions for breaking the C–S bond. The results highlight the potential of single-molecule conductance and flicker noise analysis in tuning and monitoring chemical reactions at the single-molecule level.