Visualizing small molecules via transmission electron microscopy

Transmission electron microscopy (TEM) is a cutting-edge characterization technique renowned for its ability to achieve atomic resolution. Owing to its exceptional capacity for microscopic characterization, TEM has emerged as an essential and powerful tool in the realms of structural characterization and chemical analysis. Its applications span a diverse array of fields, including materials science, chemistry, and biology, offering unprecedented insights into the fundamental structure understanding of various substances. The capability of TEM to facilitate direct observation of small molecules holds significant promise for advancing our understanding of molecular structures, host-guest interactions, and their dynamic behaviors. However, a couple of challenges hide this potential. Notably, issues such as electron beam irradiation can damage small molecules, while low contrast of small molecules compared to the background presents considerable obstacles during imaging. These factors necessitate the continued development of innovative techniques that enhance the efficacy of TEM. In this review, we offer a brief introduction to advanced TEM techniques aimed at directly imaging small molecules, including cryo-electron microscopy, low electron dose imaging, and in situ TEM techniques. We review recent advancements in atomic-resolution TEM studies involving small molecules, highlighting significant findings and methodological improvements that have emerged in the field. In addition, we provide an outlook on the future trajectory of TEM studies on small molecules, emphasizing the potential progress that could stimulate further scientific exploration in this realm.