Yang Chen, Zhou Shuyao, Guo Yilin, Hou Zexi, Li Junhao, Liu Zhirong, Liu Zitong, Zhang Deqing, Li Yanwei, Houk Kendall N, Guo Xuefeng
Beijing National Laboratory for Molecular Sciences, National Biomedical Imaging Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Environment Research Institute, Shandong University, Qingdao 266237, China.
Natl Sci Rev. 2025 Apr 26;12(9):nwaf172. doi: 10.1093/nsr/nwaf172. eCollection 2025 Sep.
Reaction mechanism studies typically involve the characterization of products, and intermediates are often characterized by (sub)millisecond techniques, such as nuclear magnetic resonance, while femto/attosecond spectroscopies are used to elucidate the evolution of transition states and electron dynamics. However, due to the lack of detection techniques in the microsecond to nanosecond range, as well as the emergent complexity with increasing scale, most of the proposed intermediates have not yet been detected, which significantly hinders reaction optimization. Here, we present such a nanosecond-scale real-time single-molecule electrical monitoring technique. Using this technique, a series of hidden intermediates in an example Morita-Baylis-Hillman reaction were directly observed, allowing the visualization of the reaction pathways, clarification of the two proposed proton transfer pathways, and quantitative description of their contributions to the turnover. Moreover, the emergent complexity of the catalysis, including the catalysis oscillation effect and the proton quantum tunneling effect, is further unveiled. Finally, this useful yet low-yield reaction was successfully catalyzed by the application of an electric field, leading to a high turnover frequency (∼5000 s at a 1 V bias voltage). This new paradigm of mechanistic study and reaction optimization shows potential application in scalable synthesis by integrated single-molecule electronic devices on chip.
反应机理研究通常涉及产物的表征，中间体通常采用（亚）毫秒级技术进行表征，如核磁共振，而飞秒/阿秒光谱则用于阐明过渡态的演变和电子动力学。然而，由于缺乏微秒到纳秒范围内的检测技术，以及随着规模增加而出现的复杂性，大多数提出的中间体尚未被检测到，这严重阻碍了反应优化。在此，我们展示了一种纳秒级实时单分子电学监测技术。利用该技术，直接观察到了一个典型的森田-贝利斯-希尔曼反应中的一系列隐藏中间体，从而实现了反应路径的可视化，明确了两种提出的质子转移路径，并对它们对周转的贡献进行了定量描述。此外，还进一步揭示了催化过程中出现的复杂性，包括催化振荡效应和质子量子隧穿效应。最后，通过施加电场成功催化了这个有用但产率低的反应，在1 V偏置电压下实现了高周转频率（约5000 s⁻¹）。这种新的机理研究和反应优化范式显示了在芯片上集成单分子电子器件进行可扩展合成中的潜在应用。
