Toward Precision Measurement and Manipulation of Single‐Molecule Reactions by a Confined Space

Abstract

All chemical reactions can be divided into a series of single molecule reactions (SMRs), the elementary steps that involve only isomerization of, dissociation from, and addition to an individual molecule. Analyzing SMRs is of paramount importance to identify the intrinsic molecular mechanism of a complex chemical reaction, which is otherwise implausible to reveal in an ensemble fashion, owing to the significant static and dynamic heterogeneity of real‐world chemical systems. The single‐molecule measurement and manipulation methods developed recently are playing an increasingly irreplaceable role to detect and recognize short‐lived intermediates, visualize their transient existence, and determinate the kinetics and dynamics of single bond breaking and formation. Notably, none of the above SMRs characterizations can be realized without the aid of a confined space. Therefore, this Review aims to highlight the recent progress in the development of confined space enabled single‐molecule sensing, imaging, and tuning methods to study chemical reactions. Future prospects of SMRs research are also included, including a push toward the physical limit on transduction of information to signals and vice versa, transmission and recording of signals, computational modeling and simulation, and rational design of a confined space for precise SMRs.

Profiling single-molecule reaction kinetics under nanopore confinement

“…Under bias voltages, the single reactant is confined inside a nanopore with controllable movement and direction. The covalent bond formation can be triggered at a specific reactive site, that regulates the ionic current through a nanopore 14,15 . Coupled with high bandwidth current recording system, nanopore could real-time report reactive intermediates [16][17][18] , study the reaction kinetics 19-21, and explore reaction trajectory [22][23][24] at the singlemolecule level.…”

Single-molecule imaging and kinetic analysis of intermolecular polyoxometalate reactions

“…4 Experimentally, if ensemble kinetics methods can be considered 'top-down', then over the last four decades a range of techniques have developed which operate in a 'bottom-up' approach, in which information is measured from individual molecules and built up statistically to provide equivalent information to that which is normally accessible to ensemble kinetics. The key advantage of such single-molecule kinetics approaches lies with their ability to distinguish information that is in principle unobtainable by ensemble-averaging techniques, 5 whether by revealing rare or transient species 6,7 or by providing insight into otherwise unobserved population heterogeneities. 8 The ability to disentangle the constructed statistical distributions by subpopulations in order to probe subsets of the reaction can reveal large uctuations of various underlying properties on an individual molecular basis that collapse to a single averaged ensemble measurement.…”

“…25 The ChemTEM methodology therefore provides both of the requirements common to all elds exploring singlemolecule kinetics: control of molecular positions (connement within the SWNT) and control of energy supplied to the molecules (with the e-beam). 7,22 However with ChemTEM, as with any local-probe method, the key challenge in studying reactions at the single-molecule level is caused by the primary advantage: each measurement provides observations that are specic to a particular molecule in a specic local environment during that measurement. Therefore, ideally, a reaction should be studied at the single-molecule level but for as many examples of single-molecule events as possible at the same time, thus delivering both (i) detailed knowledge of the reaction mechanism and (ii) condence in its generality for that class of molecules.…”

Influence of Electrolyte Concentration on Single-Molecule Sensing of Perfluorocarboxylic Acids

“…By monitoring the through-pore ionic current under a constant potential, nanopore SMSs can link the structures and concentrations of specific targets with the occurrence and frequency of their respective transient current blockade caused by the trapping of single molecules into nanopore ( Qiu et al, 2018 ). Thanks to the ultra-high spatiotemporal resolution, nanopore SMSs enable the accurate identification of rare but crucial species in complex samples ( Qiu et al, 2019 ). The successful commercialization of nanopore based DNA sequencers have also demonstrated the feasibility of developing low-cost, portable nanopore SMSs ( Hayden 2015 ; Quick 2016 ).…”