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1. Nanosecond-scale single-molecule reaction dynamics for scalable synthesis on a chip

   https://doi.org/10.1093/nsr/nwaf172  

   Yang, Chen; Zhou, Shuyao; Guo, Yilin; Hou, Zexi; Li, Junhao; Liu, Zhirong; Liu, Zitong; Zhang, Deqing; Li, Yanwei; Houk, Kendall_N; et al (April 2025, National Science Review)

   ABSTRACT 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−1 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. 

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2. Single-Molecule Chemical Reactions Unveiled in Molecular Junctions

   https://doi.org/10.3390/pr10122574  

   Bunker, Ian; Ayinla, Ridwan Tobi; Wang, Kun (December 2022, Processes)

   Understanding chemical processes at the single-molecule scale represents the ultimate limit of analytical chemistry. Single-molecule detection techniques allow one to reveal the detailed dynamics and kinetics of a chemical reaction with unprecedented accuracy. It has also enabled the discoveries of new reaction pathways or intermediates/transition states that are inaccessible in conventional ensemble experiments, which is critical to elucidating their intrinsic mechanisms. Thanks to the rapid development of single-molecule junction (SMJ) techniques, detecting chemical reactions via monitoring the electrical current through single molecules has received an increasing amount of attention and has witnessed tremendous advances in recent years. Research efforts in this direction have opened a new route for probing chemical and physical processes with single-molecule precision. This review presents detailed advancements in probing single-molecule chemical reactions using SMJ techniques. We specifically highlight recent progress in investigating electric-field-driven reactions, reaction dynamics and kinetics, host–guest interactions, and redox reactions of different molecular systems. Finally, we discuss the potential of single-molecule detection using SMJs across various future applications. 

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

   https://doi.org/10.1038/s41467-022-32351-8  

   Zhang, Lei; Yang, Chen; Lu, Chenxi; Li, Xingxing; Guo, Yilin; Zhang, Jianning; Lin, Jinglong; Li, Zhizhou; Jia, Chuancheng; Yang, Jinlong; et al (December 2022, Nature Communications)

   Abstract Precise tuning of chemical reactions with predictable and controllable manners, an ultimate goal chemists desire to achieve, is valuable in the scientific community. This tunability is necessary to understand and regulate chemical transformations at both macroscopic and single-molecule levels to meet demands in potential application scenarios. Herein, we realise accurate tuning of a single-molecule Mizoroki-Heck reaction via applying gate voltages as well as complete deciphering of its detailed intrinsic mechanism by employing an in-situ electrical single-molecule detection, which possesses the capability of single-event tracking. The Mizoroki-Heck reaction can be regulated in different dimensions with a constant catalyst molecule, including the molecular orbital gating of Pd(0) catalyst, the on/off switching of the Mizoroki-Heck reaction, the promotion of its turnover frequency, and the regulation of each elementary reaction within the Mizoroki-Heck catalytic cycle. 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. 

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4. Coherence mapping to identify the intermediates of multi-channel dissociative ionization

   https://doi.org/10.1038/s42004-024-01176-5  

   Stamm, Jacob; Kwon, Sung; Sandhu, Shawn; Sandhu, Jesse; Levine, Benjamin G; Dantus, Marcos (December 2024, Communications Chemistry)

   Abstract Identifying the short-lived intermediates and reaction mechanisms of multi-channel radical cation fragmentation processes remains a current and important challenge to understanding and predicting mass spectra. We find that coherent oscillations in the femtosecond time-dependent yields of several product ions following ultrafast strong-field ionization represent spectroscopic signatures that elucidate their mechanism of formation and identify the intermediate(s) they originate from. Experiments on endo-dicyclopentadiene show that vibrational frequencies from various intermediates are mapped onto their resulting products. Aided by ab initio methods, we identify the vibrational modes of both the cleaved and intact molecular ion intermediates. These results confirm stepwise and concerted fragmentation pathways of the dicyclopentadiene ion. This study highlights the power of tracking the femtosecond dynamics of all product ions simultaneously and sheds further light onto one of the fundamental reaction mechanisms in mass spectrometry, the retro-Diels Alder reaction. 

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5. Divergent stereochemical outcomes in the insertion of donor/donor carbenes into the C–H bonds of stereogenic centers

   https://doi.org/10.1039/d1sc04622e  

   Dishman, Sarah N.; Laconsay, Croix J.; Fettinger, James C.; Tantillo, Dean J.; Shaw, Jared T. (January 2022, Chemical Science)

   Intramolecular C–H insertions with donor/donor dirhodium carbenes provide a concise and highly stereoselective method to set two contiguous stereocenters in a single step. Herein, we report the insertion of donor/donor carbenes into stereogenic carbon centers allowing access to trisubstituted benzodihydrofurans in a single step. This study illuminates, for the first time, the stereochemical impact on the carbene center and delineates the structural factors that enable control over both stereogenic centers. Sterically bulky, highly activated C–H insertion centers exhibit high substrate control yielding a single diastereomer and a single enantiomer of product regardless of the catalyst used. Less bulky, less activated C–H insertion centers exhibit catalyst control over the diastereomeric ratio (dr), where a single enantiomer of each diastereomer is observed with high selectivity. A combination of experimental studies and DFT calculations was used to elucidate the origin of these results. First, hydride transfer from the stereogenic insertion site proceeds with high stereoselectivity to the carbene center, thus determining the absolute configuration of the product. Second, the short lived zwitterionic intermediate can diaster-eoselectively ring-close by a hitherto unreported S E 2 mechanism that is either controlled by the substrate or the catalyst. These results demonstrate that donor/donor carbenes undergo uniquely stereoselective reactions that originate from a stepwise reaction mechanism, in contrast to the analogous concerted reactions of carbenes with one or more electron-withdrawing groups attached. 

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