Stipe Lukin

A novel approach for deuteration of C–H bonds in a ball mill at ambient temperature using Cys- d ₄ as D-source is developed. In situ Raman, ex situ spectroscopic and DFT data allowed identification of intermediates and insight into the reaction course.

Structural analysis using powder X‐ray diffraction data has overcome many obstacles and nowadays is readily applicable for structural analysis of all types of compounds and materials. Being less straightforward than single crystal diffraction, it requires significant users’ input and consequently, implementation of standardized tools to assess the accuracy of crystal structures. This article discusses potential errors in crystal structure solution and refinement of small‐molecule structures obtained from PXRD data. Moreover, it proposes how accuracy of these structures can be improved by using high‐quality PXRD data, complementary external analytical techniques, knowledge stored in crystal structure databases, as well as an approach to search the parameter space to avoid local minima in testing different sets of geometry restraints.

The past two decades have witnessed a rapid emergence of interest in mechanochemistry-chemical and materials reactivity achieved or sustained by the action of mechanical force-which has led to application of mechanochemistry to almost all areas of modern chemical and materials synthesis: from organic, inorganic, and organometallic chemistry to enzymatic reactions, formation of metal-organic frameworks, hybrid perovskites, and nanoparticle-based materials. The recent success of mechanochemistry by ball milling has also raised questions about the underlying mechanisms and has led to the realization that the rational development and effective harnessing of mechanochemical reactivity for cleaner and more efficient chemical manufacturing will critically depend on establishing a mechanistic understanding of these reactions. Despite their long history, the development of such a knowledge framework for mechanochemical reactions is still incomplete. This is in part due to the, until recently, unsurmountable challenge of directly observing transformations taking place in a rapidly oscillating or rotating milling vessel, with the sample being under the continuous impact of milling media. A transformative change in mechanistic studies of milling reactions was recently introduced through the first two methodologies for real-time in situ monitoring based on synchrotron powder X-ray diffraction and Raman spectroscopy. Introduced in 2013 and 2014, the two new techniques have inspired a period of tremendous method development, resulting also in new techniques for mechanistic mechanochemical studies that are based on temperature and/or pressure monitoring, extended X-ray fine structure (EXAFS), and, latest, nuclear magnetic resonance (NMR) spectroscopy. The new technologies available for real-time monitoring have now inspired the development of experimental strategies and advanced data analysis approaches for the identification and quantification of short-lived reaction intermediates, the development of new mechanistic models, as well as the emergence of more complex monitoring methodologies based on two or three simultaneous monitoring approaches. The use of these new opportunities has, in less than a decade, enabled the first real-time observations of mechanochemical reaction kinetics and the first studies of how the presence of additives, or other means of modifying the mechanochemical reaction, influence reaction rates and pathways. These studies have revealed multistep reaction mechanisms, enabled the identification of autocatalysis, as well as identified molecules and materials that have previously not been known or have even been considered not possible to synthesize through conventional approaches. Mechanistic studies through in situ powder X-ray diffraction (PXRD) and Raman spectroscopy have highlighted the formation of supramolecular complexes (for example, cocrystals) as critical intermediates in organic and metal-organic synthesis and have also been combined with isotope labeling strategies to provide a deeper insight into mechanochemical reaction mechanisms and atomic and molecular dynamics under milling conditions. This Account provides an overview of this exciting, rapidly evolving field by presenting the development and concepts behind the new methodologies for real-time in situ monitoring of mechanochemical reactions, outlining key advances in mechanistic understanding of mechanochemistry, and presenting selected studies important for pushing forward the boundaries of measurement techniques, data analysis, and mapping of reaction mechanisms.

Performing reactions in the solid state offers the largely unexplored possibility of influencing reactivity by manipulating the solid form of the starting reactants. In this work, we explore the use of various solid forms of barbituric acid and its effect on reaction paths and kinetics in a Knoevenagel condensation reaction with vanillin. Modifications of barbituric acid included the use of its desmotrope, a cocrystal, and a salt as the starting reactant. Comparing these reactions with the reaction starting from the commercial keto tautomer of barbituric acid, we find that the reaction kinetics could be accelerated or decelerated, together with a change in the reaction mechanism. Exploring solid forms of reactants can be used as general methodology for manipulating mechanochemical reactivity, further highlighting the benefits of conducting reactions in the solid state, because many of the modifications of solids become unavailable upon dissolution.

Solid-state milling has emerged as an alternative, sustainable approach for preparing virtually all classes of compounds and materials. In situ reaction monitoring is essential to understanding the kinetics and mechanisms of these reactions, but it has proved difficult to use standard analytical techniques to analyze the contents of the closed, rapidly moving reaction chamber (jar). Monitoring by Raman spectroscopy is an attractive choice, because it allows uninterrupted data collection from the outside of a translucent milling jar. It complements the already established in situ monitoring based on powder X-ray diffraction, which has limited accessibility to the wider research community, because it requires a synchrotron X-ray source. The Raman spectroscopy monitoring setup used in this protocol consists of an affordable, small portable spectrometer, a laser source and a Raman probe. Translucent reaction jars, most commonly made from a plastic material, enable interaction of the laser beam with the solid sample residing inside the closed reaction jar and collection of Raman-scattered photons while the ball mill is in operation. Acquired Raman spectra are analyzed using commercial or open-source software for data analysis (e.g., MATLAB, Octave, Python, R). Plotting the Raman spectra versus time enables qualitative analysis of reaction paths. This is demonstrated for an example reaction: the formation in the solid state of a cocrystal between nicotinamide and salicylic acid. A more rigorous data analysis can be achieved using multivariate analysis.

The mechanochemical preparation of silver sulfadiazine and dantrolene, two marketed active pharmaceutical ingredients, was investigated by in situ Raman spectroscopy. For the first time, the mechanochemical transformations involving highly fluorescent compounds could be studied in situ with a high-resolution Raman system combined with a unique suitable Raman probe. Moreover, the kinetic features of the mechanochemical process were examined by a mathematical model allowing to describe the chemical changes under mechanical stress. This approach is promising both to broaden the scope of Raman in situ investigations that would otherwise be impossible and for process optimization at any scale.

Here we describe real-time, in situ monitoring of mechanochemical solid-state metathesis between silver nitrate and the entire series of sodium halides, on the basis of tandem powder X-ray diffraction and Raman spectroscopy monitoring. The mechanistic monitoring reveals that reactions of AgNO₃ with NaX (X = Cl, Br, I) differ in reaction paths, with only the reaction with NaBr providing the NaNO₃ and AgX products directly. The reaction with NaI revealed the presence of a novel, short-lived intermediate phase, while the reaction with NaCl progressed the slowest through the well-defined Ag₂ClNO₃ intermediate double salt. While the corresponding iodide and bromide double salts were not observed as intermediates, all three are readily prepared as pure compounds by milling equimolar mixtures of AgX and AgNO₃. The in situ observation of reactive intermediates in these simple metathesis reactions reveals a surprising resemblance of reactions involving purely ionic components to those of molecular organic solids and cocrystals. This study demonstrates the potential of in situ reaction monitoring for mechanochemical reactions of ionic compounds as well as completes the application of these techniques to all major compound classes.