Molecular chirality is a fundamental feature of living systems and asymmetric chemistry, yet its origin remains unresolved because the earliest symmetry-breaking events are usually obscured in ensemble measurements. In particular, a persistent challenge is to determine how stochastic single-molecule events evolve into population-level enantiomeric excess.

Now, a team at Peking University and collaborating institutions has established a single-molecule platform for real-time, from-the-start monitoring of asymmetric evolution in a Diels–Alder reaction. Using graphene–molecule–graphene single-molecule junctions together with the chirality-induced spin selectivity effect, the researchers directly observed spontaneous mirror-symmetry breaking, identified the molecular origin of reaction chirality, and further demonstrated catalyst-free on-line asymmetric synthesis under electrical control.

Real-time observation of spontaneous mirror-symmetry breaking
In this study, the researchers designed a graphene-based single-molecule junction that enables in situ monitoring of the full reaction trajectory, including intermediate states, pre-reaction charge-transfer complexes, and product states. By introducing ferromagnetic electrodes, they used the chirality-induced spin selectivity effect to distinguish chiral product states in real time. Event-resolved trajectories showed that the corresponding enantiomeric excess did not evolve monotonically, but instead passed through a process of initial symmetry breaking, oscillatory compensation, and eventual stabilization. Mechanistic analysis showed that reaction chirality is not established in the cycloaddition step itself. Instead, it is determined earlier, before formation of the pre-reaction complex, through the initial configuration of the acrylic acid substrate and its coupling to the external electric field.
Based on this, the researchers proposed an excess-compensation mechanism for chiral amplification. In this picture, a small initial enantiomeric excess triggers compensatory formation of the opposite enantiomer, producing oscillations in enantiomeric excess before the system evolves toward a stable enantiomerically enriched state. Temperature-dependent measurements, autocorrelation analysis, and theoretical calculations supported this mechanism.

Electrical control enables on-line asymmetric synthesis
Based on these mechanistic insights, the team developed an on-line asymmetric synthesis strategy. Because the relevant pre-reaction complexes are electrically detectable and have lifetimes on the second timescale, selected reaction pathways can be activated by applying a 1 V pulse at the target charge-transfer state and removing it at the cation state.

Using this approach, the researchers achieved precise control over both stereoselectivity and regioselectivity, with an enantiomeric excess of near 100% and diastereomeric excess above 88%. The work provides a molecular-level framework for understanding the emergence of chirality and suggests a route toward electrically regulated, catalyst-free asymmetric synthesis.

The complete study is accessible via DOI:10.34133/research.1150