Precise tuning of chemical reactions with rational design is one of the hot spots in current chemistry research. It can verify mechanism hypotheses and obtain more insight into the mechanism. In addition, precise manipulation of chemical reactions enables multifarious chemical transformation, which can meet demands in potential application scenarios. To a certain degree, how precisely the chemical reactions are tuned demonstrates how deeply we master chemistry.
Tuning chemical reactions at the macroscopic level has been improved tremendously by the chemistry community by modifying the structures of substrates/catalysts, altering reaction conditions, and applying external stimulants such as heat or light. However, tuning chemical reactions at the single-molecule level is still a formidable challenge. While single-molecule redox reactions have been realised and applied in transistors, the fine-tuning of single-molecule catalytic reactions will be a milestone in reaction chemistry.
We are dedicated to extending the functionalities of the carbon-electrode-based single-molecule platform and the investigation of chemical process dynamics on the platform1. The realisation of controllable single-molecule catalysis was one of our goals to gain more insight into catalysis and provide more possibilities for device design. Inspired by the works that have achieved the tuning of catalyst reactivity via altering the electronic factor of ligands2, we conceived the idea to regulate catalysis via controlling the electronic factor of connected ligands. In our former research, the catalysis visualisation and mechanism study have been realised3,4, so determining the tuning strategy was the key.
We need a tuning strategy that is convenient for operation. Ideally, the connected ligand can be utilised without changing or modifying its structure. Furthermore, the electrical tuning strategy is preferred because of the easy operation for us and the outstanding compatibility of different devices. In our previous work, we have employed electrical gate tuning in charge transport5. So, we focus on electrical gate tuning which possesses these features above.
Before the exploration of gate tuning, the mechanism and visualisation of the Mizoroki-Heck reaction are studied. We covalently connected an N-heterocyclic carbene-palladium (NHC–Pd) complex (the bridge molecule) between two graphene point electrodes to form stable Graphene-Molecule-Graphene Single-Molecule Junctions (GMG-SMJs). By adding the fluorescent substrate, the single-molecule connection and the reactivity of the connected bridge molecule are confirmed via several designed experiments. Next, general substrates and reagents are added to the reaction cell (Fig. 1), and regular periodic current changes are monitored. To interpret the current level changes, we conduct a series of control experiments and code programs. Finally, the detail of the Mizoroki-Heck reaction can be visualised by monitoring the current level transformation.
Fig. 1. Diagram of single-molecule Mizoroki-Heck reaction on the device
Based on the visualisation of the Mizoroki-Heck reaction, we explore the electrical gate tuning effects. The gate electrodes are introduced to the devices during the fabrication, and an ionic liquid is employed as the reaction solvent (Fig. 2a–b). We are curious about how the gate voltages influence the reactivity, so the tuning effect of gating on the current through Pd(0) is recorded (Fig. 2c). With further analysis, effective molecular orbital gating energies are deduced quantitatively (Fig. 2d–e), which delights us for the feasibility of electrical gate tuning via controlling the frontier molecular orbitals.
Fig. 2. Structure of the single-molecule device with gate electrodes and gate tuning of the frontier molecular orbitals.
Then, we investigate the electrical gate tuning systemically. When the gate voltages are big enough, the catalytic cycle will be suppressed. Interestingly, under the opposite direction of gate voltages, the suppressing states are different, and the reaction will be trapped in different intermediate(s). Conventional detection methods hardly reveal the details of the suppressed catalytic cycle. Our detection can avoid ignoring the details, and the current level transformations clearly show the elementary reaction within the Mizoroki-Heck catalytic cycle. Unexpectedly, the smooth C–C activation process (the reverse process of olefin insertion) is observed under tense negative gate voltages, which provides a complementary avenue for C–C bond activation under electrostatic fields. Applying and removing gate voltages alternately, we realise the real-time on/off switching of the Mizoroki-Heck reaction
Under mild gating, the catalytic cycle is accessible, companied with the turnover frequency (TOF) increased or decreased. The tuning effect on TOF is complex, showing a nonlinear and non-monotonic trend along gate voltages. We investigate the TOF tuning strenuously, through which we find the origin to explain the tuning regularity. Gate voltages have distinct tuning effects on elementary reaction both in trend and extent deriving from kinetic analysis. Namely, the combined effects of elementary reaction rate tuning result in the overall TOF tuning.
In this work, we realise precise gate tuning of single-molecule catalysis in different dimensions. The tuning platform possesses the capability of single-event tracking, so, to some degree, we have taken a small step toward manipulating a single molecule synthesis as we want. These results extend the tuning scope of chemical reactions from the macroscopic view to the single molecule approach, inspiring new insights into designing different strategies or devices to unveil reaction mechanisms and discover novel phenomena.
 Li, Y., Yang, C. & Guo, X. Single-molecule electrical detection: a promising route toward the fundamental limits of chemistry and life science. Acc. Chem. Res. 53, 159−169 (2020).
 Ugo, R., Pasini, A., Fusi, A. & Cenini, S. Kinetic investigation of some electronic and steric factors in oxidative addition reactions to vaska's compound. J. Am. Chem. Soc. 94, 7364-7370 (1972). (An example)
 Yang, C. et al. Unveiling the full reaction path of the Suzuki–Miyaura cross-coupling in a single-molecule junction. Nat. Nanotechnol. 16, 1214-1223 (2021).
 Yang, C. et al. Single-molecule electrical spectroscopy of organocatalysis. Matter 4, 2874-2885 (2021).
 Xin, N. et al. Tuning charge transport in aromatic-ring single-molecule junctions via ionic-liquid gating. Angew. Chem. Int. Ed. 57, 14026-14031 (2018).
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