A kinetic study of mechanically activated atom exchange: the effect of milling frequency and ball mass.

This study investigates the mechanochemical reaction of hydrogen isotope exchange between solid benzoic acid and liquid heavy water. The systematic change of milling conditions revealed that the reaction rate scales with the milling frequency and the mass of the milling balls. The ball size being always the same, faster reactions stem from the use of higher milling frequencies and heavier balls. The kinetic curves are described by a kinetic model that accounts for the statistical, deformational and chemical factors involved in mechanochemical transformations. The results indicate that the reaction is driven by the generation of a new interface area caused by the deformation of the solid reactants.

Mechanochemical reaction kinetics scales linearly with impact energy.

Inelastic collisions of the milling media in ball milling provide energy to the reaction mixture required for chemical transformations. However, movement of the milling media also results in physical mixing of reactants, which may enable a chemical reaction too. Separating the two contributions is challenging and gaining a direct insight into the purely mechanochemically driven reactivity is accordingly hindered. Here, we have applied in situ reaction monitoring by Raman spectroscopy to a suitable, purely mechanically activated, chemical reaction and combined kinetic analysis with numerical simulations to access experimentally unattainable milling parameters. The breadth of milling conditions allows us to establish a linear relationship between the reaction rate and the energy dose received by the sample. Consequently, different kinetic profiles in time scale to the same profile when plotted against the energy dose, which increases with the ball mass, the average ball velocity and the frequency of impacts, but decreases with the hardness of the milling media due to more elastic collisions. The fundamental relationship between kinetics and energy input provides the basis for planning and optimisation of mechanochemical reactions and is essential for transferability of mechanochemical reactions across different milling platforms.

Toward Mechanistic Understanding of Mechanochemical Reactions Using Real-Time In Situ Monitoring.

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.

Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine.

In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin. This work contributes to the elucidation of a reaction mechanism that has been subjected to a number of interpretations over time and paints a clear picture of how mechanosynthesis can be applied and optimized for the preparation of added-value molecules.

Using Desmotropes, Cocrystals, and Salts to Manipulate Reactivity in Mechanochemical Organic Reactions.

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.

Raman spectroscopy for real-time and in situ monitoring of mechanochemical milling reactions.

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.

Mechanochemical Preparation of Active Pharmaceutical Ingredients Monitored by In Situ Raman Spectroscopy.

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.

DNA-specific selectivity in pairing of model nucleobases in the solid state.

Nucleobases methylated at the glycosidic nitrogen atom achieve DNA-specific self-assembly upon heating in the solid state. We report formation and characterisation of the elusive cocrystal of methylated guanine and methylated cytosine, exhibiting Watson-Crick-type hydrogen bonding, and the crystal structure of 9-methylguanine.

Mechanochemical Metathesis between AgNO3 and NaX (X = Cl, Br, I) and Ag2XNO3 Double-Salt Formation.

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.

Direct Visualization of a Mechanochemically Induced Molecular Rearrangement.

Recent progress in the field of mechanochemistry has expanded the discovery of mechanically induced chemical transformations to several areas of science. However, a general fundamental understanding of how mechanochemical reactions by ball milling occur has remained unreached. For this, we have now implemented in situ monitoring of a mechanochemically induced molecular rearrangement by synchrotron X-ray powder diffraction, Raman spectroscopy, and real-time temperature sensing. The results of this study demonstrate that molecular rearrangements can be accomplished in the solid state by ball milling and how in situ monitoring techniques enable the visualization of changes occurring at the exact instant of a molecular migration. The mechanochemical benzil-benzilic acid rearrangement is the focal point of the study.

Direct Mechanocatalysis: Palladium as Milling Media and Catalyst in the Mechanochemical Suzuki Polymerization.

The milling ball is the catalyst. We introduce a palladium-catalyzed reaction inside a ball mill, which makes catalyst powders, ligands, and solvents obsolete. We present a facile and highly sustainable synthesis concept for palladium-catalyzed C-C coupling reactions, exemplarily showcased for the Suzuki polymerization of 4-bromo or 4-iodophenylboronic acid giving poly(para-phenylene). Surprisingly, we observe one of the highest degrees of polymerization (199) reported so far.

Isotope Labeling Reveals Fast Atomic and Molecular Exchange in Mechanochemical Milling Reactions.

Using tandem in situ monitoring and isotope-labeled solids, we reveal that mechanochemical ball-milling overcomes inherently slow solid-state diffusion through continuous comminution and growth of milled particles. This process occurs with or without a net chemical reaction and also occurs between solids and liquid additives that can be practically used for highly efficient deuterium labeling of solids. The presented findings reveal a fundamental aspect of milling reactions and also delineate a methodology that should be considered in the study of mechanochemical reaction mechanisms.

Mechanochemical carbon-carbon bond formation that proceeds via a cocrystal intermediate.

We report the first cocrystal as an intermediate in a solid-state organic reaction wherein molecules of barbituric acid and vanillin assume a favorable orientation for the subsequent Knoevenagel condensation.

Mechanism of Mechanochemical C-H Bond Activation in an Azobenzene Substrate by PdII Catalysts.

Mechanism of C-H bond activation by various PdII catalysts under milling conditions has been studied by in situ Raman spectroscopy. Common PdII precursors, that is PdCl2 , [Pd(OAc)2 ]3 , PdCl2 (MeCN)2 and [Pd(MeCN)4 ][BF4 ]2 , have been employed for the activation of one or two C-H bonds in an unsymmetrical azobenzene substrate. The C-H activation was achieved by all used PdII precursors and their reactivity increases in the order [Pd(OAc)2 ]3

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole.

Copper-catalyzed mechanochemical click reactions using Cu(II), Cu(I) and Cu(0) catalysts have been successfully implemented to provide novel 6-phenyl-2-(trifluoromethyl)quinolines with a phenyl-1,2,3-triazole moiety at O-4 of the quinoline core. Milling procedures proved to be significantly more efficient than the corresponding solution reactions, with up to a 15-fold gain in yield. Efficiency of both solution and milling procedures depended on the p-substituent in the azide reactant, resulting in H < Cl < Br < I reactivity bias. Solid-state catalysis using Cu(II) and Cu(I) catalysts entailed the direct involvement of the copper species in the reaction and generation of highly luminescent compounds which hindered in situ monitoring by Raman spectroscopy. However, in situ monitoring of the milling processes was enabled by using Cu(0) catalysts in the form of brass milling media which offered a direct insight into the reaction pathway of mechanochemical CuAAC reactions, indicating that the catalysis is most likely conducted on the surface of milling balls. Electron spin resonance spectroscopy was used to determine the oxidation and spin states of the respective copper catalysts in bulk products obtained by milling procedures.

In-Situ and Real-time Monitoring of Mechanochemical Preparation of Li2 Mg(NH2 BH3 )4 and Na2 Mg(NH2 BH3 )4 and Their Thermal Dehydrogenation.

For the first time, in situ monitoring of uninterrupted mechanochemical synthesis of two bimetallic amidoboranes, M2 Mg(NH2 BH3 )4 (M=Li, Na), by means of Raman spectroscopy, has been applied. This approach allowed real-time observation of key intermediate phases, and a straightforward follow-up of the reaction course. Detailed analysis of time-dependent spectra revealed a two-step mechanism through MNH2 BH3 ⋅NH3 BH3 adducts as key intermediate phases which further reacted with MgH2 , giving M2 Mg(NH2 BH3 )4 as final products. The intermediates partially take a competitive pathway toward the oligomeric M(BH3 NH2 BH2 NH2 BH3 ) phases. The crystal structure of the novel bimetallic amidoborane Li2 Mg(NH2 BH3 )4 was solved from high-resolution powder diffraction data and showed an analogous metal coordination to Na2 Mg(NH2 BH3 )4 , but a significantly different crystal packing. Li2 Mg(NH2 BH3 )4 thermally dehydrogenates releasing highly pure H2 in the amount of 7 wt.%, and at a lower temperature then its sodium analogue, making it significantly more viable for practical applications.

Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases.

We report herein quantitative in situ monitoring by simultaneous PXRD and Raman spectroscopy of the mechanochemical reaction between benzoic acid and nicotinamide, affording a rich polymorphic system with four new cocrystal polymorphs, multiple phase transformations, and a variety of reaction pathways. After observing polymorphs by in situ monitoring, we were able to isolate and characterize three of the four polymorphs, most of which are not accessible from solution. Relative stabilities among the isolated polymorphs at ambient conditions were established by slurry experiments. Using two complementary methods for in situ monitoring enabled quantitative assessment and kinetic analysis of each studied mechanochemical reaction, even when involving unknown crystal structures, and short-lived intermediates. In situ Raman monitoring was introduced here also as a standalone laboratory technique for quantitative assessment of mechanochemical reactions and understanding of mechanochemical reactivity. Our results provide an important step toward a complete and high-throughput quantitative approach to mechanochemical reaction kinetics and mechanisms, necessary for the development of the mechanistic framework of milling reactions.

In Situ Monitoring of the Mechanosynthesis of the Archetypal Metal-Organic Framework HKUST-1: Effect of Liquid Additives on the Milling Reactivity.

We have applied in situ monitoring of mechanochemical reactions by high-energy synchrotron powder X-ray diffraction to study the role of liquid additives on the mechanochemical synthesis of the archetypal metal-organic framework (MOF) HKUST-1, which was one of the first and is still among the most widely investigated MOF materials to be synthesized by solvent-free procedures. It is shown here how the kinetics and mechanisms of the mechanochemical synthesis of HKUST-1 can be influenced by milling conditions and additives, yielding on occasion two new and previously undetected intermediate phases containing a mononuclear copper core, and that finally rearrange to form the HKUST-1 architecture. On the basis of in situ data, we were able to tune and direct the milling reactions toward the formation of these intermediates, which were isolated and characterized by spectroscopic and structural means and their magnetic properties compared to those of HKUST-1. The results have shown that despite the relatively large breadth of analysis available for such widely investigated materials as HKUST-1, in situ monitoring of milling reactions can help in the detection and isolation of new materials and to establish efficient reaction conditions for the mechanochemical synthesis of porous MOFs.