Nucleation, the pivotal first step of crystallization, governs the essential characteristics of crystallization products, including size distribution, morphology, and polymorphism. While understanding this process is paramount to the design of chemical, pharmaceutical, and industrial production processes, major knowledge gaps remain, especially with respect to the crystallization of porous solids. Also for nanocrystalline ZIF-8, one of the most widely studied metal-organic frameworks, questions regarding the species involved in the nucleation pathway and their structural and chemical transformations remain unanswered. By combining harmonic light scattering, inherently sensitive to structural changes, with NMR spectroscopy, which reveals molecular exchanges between particles and solution, we were able to capture the crystallization mechanism of ZIF-8 in unprecedented detail. This dual approach provides concurrent structural and chemical insights, revealing key processes not previously observed in ZIF crystallization. Upon mixing, small charged prenucleation clusters (PNCs) are formed, exhibiting an excess of ligands and net positive charge. We show that nucleation is initiated by aggregation of PNCs, through the release of ligands and associated protons to the liquid. This leads to the formation of charge neutral amorphous precursor particles (APPs), which incorporate neutral monomers from the solution and crystallized ZIF-8. Our work highlights chemical dynamics as a vital, yet often overlooked, dimension in the multistage structural evolution of MOFs. By establishing the critical role of PNCs in the nucleation of ZIF-8, new pathways open up for controlling crystallization of metal-organic frameworks through targeted chemical interactions with these species.

In situexperimental studies have been key in uncovering the often elusive pathways of nucleation and crystal growth. In the field of material science and medicine this offers the prospect of controlling crystallization processes to fight disease or tailor materials towards specific applications. To further advance this quest there is a need for flexible techniques mapping the different stages of crystallization with maximal sensitivity. This article reviews the benefits of nonlinear optical techniques to take on this challenge. We provide a perspective on various nucleation and crystal growth studies that were carried out by nonlinear optical probing techniques. A theoretical background is established, different relevant nonlinear optical phenomena are defined, and optical setups that have been used by various authors are summarized. A primary focus is demonstrating the benefits of nonlinear optical techniques for thein situstudy of crystallization. These benefits include low detection limits, complementary information by combining second- and third-order techniques, as well as relatively simple bench-top setups. Through microscopy, high contrast imaging of concomitant formations can moreover be achieved. The discussion outlines several studies involving ionic compounds, noble metal nanoparticles, polymers, metal organic frameworks and pharmaceutical compounds. Finally, we discuss future evolutions in nonlinear optical probing that are expected to further advance the field.