Single-Molecule Electrical Detection: A Promising Route toward the Fundamental Limits of Chemistry and Life Science.

The ultimate limit of analytical chemistry is single-molecule detection, which allows one to visualize the dynamic processes of chemical/biological interactions with single-molecule or single-event sensitivity and hence enables the study of stochastic fluctuations under equilibrium conditions and the observation of time trajectories and reaction pathways of individual species in nonequilibrated systems. In addition, such studies may also allow the direct observation of novel microscopic quantum effects and fundamental discoveries of underlying molecular mechanisms in organic reactions and biological processes that are not accessible in ensemble experiments, thus providing unique opportunities to solve the key problems of physical, chemical, and life sciences. Consequently, the field of single-molecule detection has received considerable attention and has witnessed tremendous advances in different directions in combination with other disciplines. This Account describes our ongoing work on the development of groundbreaking methods (termed "single-molecule electrical approaches") of translating the detailed processes of chemical reactions or biological functions into detectable electrical signals at the single-event level on the platform of single-molecule electronic devices, with a particular focus on graphene-molecule-graphene single-molecule junctions (GMG-SMJs) and silicon-nanowire-based single-molecule electrical nanocircuits. These nanocircuit-based architectures are complementary to conventional optical or mechanical techniques but exhibit obvious advantages such as the absence of problems associated with bleaching and fluorescent labeling. Dash-line lithography (DLL) is an efficient lithographic method of cutting graphene and forming carboxylic-acid-functionalized nanogapped graphene point contact arrays developed to address the formidable challenges of molecular device fabrication difficulty and poor stability. Molecules of interest terminated by amines on both ends can be covalently sandwiched between graphene point contacts to create high-throughput robust GMG-SMJs containing only one molecule as the conductive element. In conjunction with the ease of device fabrication and device stability, this feature distinguishes GMG-SMJs as a new testbed platform for single-molecule analysis characterized by high temporal resolution and superior signal-to-noise ratios. By exploiting the DLL method, we have fabricated molecular devices that are sensitive to external stimuli and are capable of transducing chemical/biochemical events into electrical signals at the single-molecule level, with notable examples including host-guest interaction, hydrogen bond dynamics, DNA intercalation, photoinduced conformational transition, carbocation formation, nucleophilic addition, and stereoelectronic effect. In addition to GMG-SMJs and considering compatibility with the silicon-based industry, we have also developed a reliable method of point-functionalizing silicon-nanowire-based nanotransistors to afford single-molecule electrical nanocircuits. This approach proved to be a robust platform for single-molecule electrical analysis capable of probing fast dynamic processes such as single-protein detection, DNA hybridization/polymorphism, and motor rotation dynamics. The above systematic investigations emphasize the importance and unique advantages of universal single-molecule electrical approaches for realizing direct, label-free, real-time electrical measurements of reaction dynamics with single-event sensitivity. These approaches promise a fascinating mainstream platform to explore the dynamics of stochastic processes in chemical/biological systems as well as gain information in fields ranging from reaction chemistry for elucidating the intrinsic mechanisms to genomics or proteomics for accurate molecular and even point-of-care clinical diagnoses.