Precise electrical gating of the single-molecule Mizoroki-Heck reaction

The study addresses how to precisely tune and control a catalytic reaction at the single-molecule level using electrical gating, while simultaneously elucidating the detailed reaction mechanism. Precise control of reaction outcomes enables spatial and temporal regulation of chemical processes, with implications for synthesis, materials, biotechnology, devices, and 3D printing. The authors propose applying gate voltages in a single-molecule transistor to modulate the frontier molecular orbitals (FMOs) of a molecular palladium catalyst without modifying the catalyst itself. Gate tuning, fundamental in molecular electronics, allows precise adjustment of molecular energy levels relative to electrode Fermi levels. Leveraging an electrical single-molecule platform with high current and temporal resolution, the work seeks to visualise the Mizoroki-Heck catalytic cycle, uncover intermediates, quantify kinetics, and demonstrate unprecedented gate control of both the overall reaction and its elementary steps. Machine learning is used for efficient analysis of large electrical datasets, and density functional theory (DFT) is employed to rationalise how gate voltage influences kinetics via FMO shifts and oriented external electric fields.

Background in single-molecule electronics shows that gate electrodes in molecular devices can tune FMOs and transport characteristics, enabling single-molecule FETs, often exploiting redox-active bridges. Prior works observed molecular orbital gating and highlighted the potential of oriented external electric fields to modulate reactivity. N-heterocyclic carbene-palladium (NHC-Pd) complexes are established catalysts for cross-coupling, including Heck reactions, and bulky ligands can render oxidative addition reversible. Conventional ensemble methods struggle to isolate and monitor transient intermediates, especially olefin insertion and β-H elimination. Previous single-molecule electrical studies have revealed hidden intermediates and reaction pathways (e.g., Suzuki-Miyaura). This study builds on these advances by integrating gate control to directly regulate a catalytic cycle and by combining machine learning with DFT to map intermediates and energetics.

• Device and catalyst: Synthesised an N-heterocyclic carbene–palladium (NHC-Pd) complex as a molecular catalyst and covalently wired a single molecule between graphene point electrodes to form graphene–molecule–graphene single-molecule junctions (GMG-SMJs). Molecular connection employed amide chemistry to carboxyl-terminated graphene electrodes.
• Device fabrication: CVD-grown monolayer graphene on Cu was transferred to Si/SiO2, patterned into strips, and equipped with Au electrodes (8 nm Cr/60 nm Au). Graphene point contacts were fabricated via dashed-line lithography, plasma etching, and electrical burning to yield carboxyl-terminated gaps. For gated devices, a metal gate (8 nm Cr/60 nm Pt) was patterned by lithography.
• Single-molecule verification: Conductance responsiveness via I–V curves identified connected junctions (~17% yield: 16/92 devices). Single-molecule nature confirmed by STORM super-resolution microscopy during Mizoroki-Heck reaction using styrene and fluorescent 3-bromoperylene substrates; single catalytic-site blinking and synchronised optical/electrical signals indicated one active molecule.
• Reaction monitoring: Reaction solution (DMF) contained 1 mM bromobenzene, 1 mM styrene, and 1 mM DBU. A 0.3 V source–drain bias was applied. Time-resolved current (nA resolution, ~17 µs temporal resolution) recorded the catalytic trajectory as discrete current levels corresponding to intermediates. Machine learning segmented current distributions to identify four levels and analysed dwell times and transition statistics.
• Intermediate assignment: Stepwise additions verified assignments: DBU addition shifted current to Pd(0); PhBr addition generated oxidative addition intermediate; excess styrene induced olefin coordination; a specially designed substrate lacking β-H stalled at olefin insertion. Additional tests with HBr and diphenylethene corroborated the olefin insertion assignment. DFT-based transport simulations (transmission spectra, I–V) and energetics supported the attributions.
• Temperature-dependent kinetics: Measurements at 298, 288, 278, 268, and 258 K enabled extraction of dwell times, rate constants (k ≈ 1/⟨τ⟩ at 1 mM), and activation parameters from Arrhenius analysis. Thermodynamic parameters for steps were computed.
• Gate tuning: Introduced a gate electrode and used an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate) as solvent to form an electric double layer. Recorded I–V curves and Fowler–Nordheim plots across gate voltages (e.g., −2.0 V to +2.0 V). Extracted transition voltages Vtrans and gate efficiency α = ΔVtrans/ΔVG to quantify molecular orbital gating and correlate with reaction modulation.
• Computations: DFT (B3LYP/6-31G(d)-LANL2DZ optimisations; M06L/6-311++G(2d,p)-SDD single points; SMD(DMF)) computed intermediates, transition states, and free energies (298 K, 1 M). Frequency analyses confirmed stationary points. Calculations underpinned step energetics and reversibility trends and rationalised gate effects as FMO shifts and oriented EEF modulation.

• Real-time single-molecule electrical readout of the Mizoroki-Heck catalytic cycle revealed four discrete current levels corresponding to stable intermediates: I = Pd(0) (NHC–Pd(0)), II = olefin insertion intermediate, III = oxidative addition intermediate, IV = olefin coordination intermediate. Assignments validated by stepwise substrate/additive experiments and DFT/transport simulations.
• Transition statistics showed: I ⇄ III (Pd(0) ⇄ oxidative addition) reversible; III ⇄ IV (oxidative addition ⇄ olefin coordination) reversible; IV → II (olefin coordination → olefin insertion) forward; II → I (olefin insertion → Pd(0) via β-H elimination and product release) effectively irreversible under basic conditions due to low forward barriers and HBr scavenging by DBU.
• Dwell times at 298 K (mean ± s.d.): Pd(0) 6.1 ± 0.2 ms; oxidative addition 4.8 ± 0.6 ms; olefin coordination 3.0 ± 0.6 ms; olefin insertion 32 ± 4 ms. From τ, single-step rates were obtained (k ≈ 1/⟨τ⟩ at 1 mM). Temperature dependence yielded activation energies and activation/thermodynamic parameters (not accessible previously in situ for this reaction).
• Molecular orbital gating: Negative gate voltages increased tunnelling current; positive gate voltages decreased it. Fowler–Nordheim analysis and Vtrans vs VG gave gate efficiency α = (1.1 ± 0.0) × 10^−1, indicating HOMO-mediated transport. Gate voltage shifted HOMO closer/farther from the graphene Fermi level (quantified by effective gating energy eVG,eff ≈ α e VG).
• Gate-enabled on/off switching: At VG = −2.0 V, Pd(0) was not observed and the catalytic cycle was blocked (hidden interconversions among higher intermediates persisted). At VG = +2.0 V, only Pd(0) was detected and catalysis ceased. Without gating, the reaction proceeded normally. Thus, reaction could be switched on/off by gate voltage.
• Step-specific modulation: Gate tuning altered kinetics of oxidative addition, olefin coordination/insertion, β-H elimination, and reductive elimination. Depending on VG polarity/magnitude, oxidative addition was promoted or suppressed, and Pd(0) regeneration rates were modulated, resulting in overall rate tuning and turnover frequency control without changing the catalyst structure.
• Integration of machine learning with single-molecule electronics enabled robust identification of current levels and high-throughput analysis across devices, confirming reproducibility of gating effects.

The study demonstrates that an external gate voltage can precisely regulate a catalytic reaction at the single-molecule level by shifting the FMOs of a molecular Pd catalyst relative to electrode Fermi levels, thereby modulating elementary steps such as oxidative addition and reductive elimination. The electrical single-molecule platform provides single-event resolution to map intermediates, reversibility, and kinetics, including previously elusive steps like olefin insertion and β-H elimination. The observed HOMO-mediated transport and quantitative gate efficiency connect transport physics with catalytic reactivity control. Gate voltages function as oriented external electric fields, altering barrier heights and stabilising intermediates, which accounts for the observed on/off switching and rate modulation. These findings validate the hypothesis that gate tuning offers a non-invasive, temporal, and reversible means to control catalysis with a constant catalyst molecule, expanding the toolbox for mechanistic interrogation and enabling programmable catalysis with potential applications in devices and spatially/temporally controlled chemical processes.

High-resolution single-molecule electrical detection elucidated the full Mizoroki-Heck catalytic cycle, identified four intermediates, quantified dwell times and activation parameters, and revealed reversibility patterns. Introducing a gate electrode enabled molecular orbital gating and precise control over both the entire catalytic cycle (on/off switching) and individual elementary steps, without modifying the catalyst. This establishes a general strategy for FET-based single-molecule catalysis and demonstrates the practical impact of oriented external electric fields on reaction mechanisms. Future work could extend this approach to other catalytic transformations, investigate different catalyst frameworks and ligands to tailor gate responsiveness, integrate multi-gate architectures for more complex control, and explore device-level applications where spatial and temporal reaction control is required.

• Some intermediates were difficult to capture directly: the β-H elimination intermediate could not be dwelled due to low barrier and HBr scavenging by DBU; the olefin coordination intermediate was not detected via stepwise-addition controls (inferred from trajectories and statistics).
• Spectroscopic ambiguity remained regarding a slight blue shift in fluorescence at shorter wavelength, potentially due to photobleaching or other mechanisms.
• Results were obtained under specific single-molecule junction conditions (graphene electrodes, ionic liquid gating for gate studies, defined substrates and base), which may limit generalisability without further validation across different environments and catalysts.