Ball milling for mechanochemical reactions

Nature Reviews Methods Primers | (2025) 5:29 1 nature reviews methods primers https://doi.org/10.1038/s43586-025-00401-2 Primer 0123456789();: Check for updates Ball milling for mechanochemical reactions Isaiah R. Speight 1, Karen J. Ardila-Fierro 2, José G. Hernández 2, Franziska Emmerling 3, Adam A. L. Michalchuk 4, Felipe García 5, Evelina Colacino 6 & James Mack 7 Abstract Mechanochemistry is an emerging field with the potential to pave the way for sustainable chemistry. Although the use of mechanical force to initiate chemical reactions has been recognized for millennia, it has often taken a backseat to thermal and photonic methods. Over the past 30 years, mechanochemistry has seen a resurgence of interest, attracting researchers across the globe. Despite its proven ability to address numerous challenges within the chemical community, mechanochemistry remains on the periphery. This Primer serves as a valuable guide for conducting mechanochemical reactions by ball milling, offering an overview of the processes, methods, tools and terminology necessary to embark on research in this field. It also highlights persistent hurdles such as equipment standardization, understanding the impact of new discoveries and the lack of predictability of reaction outcomes. The Primer’s focus is on how mechanochemical ball milling is used in various chemical transformations, distinguishing it from other forms of mechanochemistry discussed in the literature. With a promising future, this Primer serves as a gateway for those aspiring to contribute to the field’s advancement. Sections Introduction Experimentation Results Applications Reproducibility and data deposition Limitations and optimizations Outlook 1Department of Chemistry, William & Mary, Williamsburg, VA, USA. 2Grupo Ciencia de los Materiales, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Antioquia, Colombia. 3Department of Materials Chemistry, BAM Federal Institute for Materials Research and Testing, Berlin, Germany. 4School of Chemistry, University of Birmingham, Birmingham, UK. 5School of Chemistry, Monash University, Clayton, Victoria, Australia. 6ICGM, Univ Montpellier, CNRS, ENSCM, Montpellier, France. 7Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA. e-mail: [email protected].edu Nature Reviews Methods Primers | (2025) 5:29 2 0123456789();: Primer differences of a reaction conducted under mechanochemical conditions as compared with solution. We show how in situ analytical tools are used to track mechanochemical reactions and how these reactions can be applied to real-world industrial problems. We also describe some of the challenges in the field and areas of opportunities to move the field further. Owing to the various review articles that exist on this topic, this Primer covers mechanochemistry conceptually, without the details of specific reactions, which can be found in the literature. It is an exciting time to be in the field of mechanochemistry, and this Primer is designed to lower the barrier of entry. Experimentation Mechanochemical and solvothermal experimental set-ups can target similar reactions but are carried out in different ways. As solvothermal reaction systems have evolved over time from the simple round-bottomed flask to continuous stirred tank reactor, mechanochemistry has made iterative changes to the equipment utilized for synthesis. This section describes common types of ball mills used to carry out mechanochemical reactions and the variations among them. Important terminology, symbols and experimental parameters are discussed in this section. We describe product isolation techniques and comment on the safety considerations required when carrying out ball-milling mechanochemical experiments. Ball-mill types Commercial lab-scale mixer and planetary ball mills are available from various suppliers, providing the ability to conduct reactions from milligrams to hundreds of grams. These versatile machines can be used in single or multiple stations wheremilling jars are mounted. In the most common mixer mills, also called shaker of vibratory mills, the milling jar oscillates horizontally 22 (Fig.1a), but some mixer mills impart vertical23 (Fig.1b) or angular harmonic motions24 to the milling jar (Fig.1c). Such movements promote the collision of one or multiple Introduction A mechanochemical reaction (mechanochemistry), is defined by the International Union of Pure and Applied Chemistry (IUPAC) as a“chemical reaction that is induced by the direct absorption of mechanical energy”. This can be approached in a number of forms, such as ball milling, sonochemistry, tribochemistry, single-molecule force spectroscopy and other more specialized varieties, many of which have been reviewed over the past 10 years1–19. Mechanochemical reactions can be conducted using various experimental techniques to mechanically activate the corresponding chemical system1. Over the years, mechanochemical equipment has evolved drastically to encompass different methods of activation, scales and throughputs. The universal mechanochemical apparatus, which is readily available in most chemical laboratories, is the mortar and pestle20. However, a more systematic and uniform approach to conduct mechanochemical reactions is needed due to the variations in the mechanical energy induced by mortar and pestle, an energy that is dependent upon the individual performing the grinding and grinding duration. In this Primer, we primarily focus on ball-milling techniques, with particular attention paid to mixer and planetary ball mills, which have served as the preferred instruments in the majority of mechanochemical research studies. Aside from the simple removal of solvents, mechanochemical reactions produced by ball milling can give access to products that solution-phase chemistry may prohibit due to the limited solubility of starting reagents or the instability of products in solution17. Slow product formation due to solvent inhibition in solution can be accelerated in mechanochemical conditions. Furthermore, for many mechanochemical reactions, the yield and product purity can be enhanced with respect to the same reaction conducted in solution. These exciting results have led IUPAC to identify this methodology as one of the top ten chemical innovations that will change the world21. In this Primer, we focus on how to conduct a mechanochemical reaction under ball-milling conditions and elucidate the similarities and e Milling materials f Representation of a mechanochemical reaction a Horizontal motion Motion b Vertical motion Reactants and products Ball Motion c Angular harmonic motion Motion Motion d Rotational motion Motion Motion A + B C Milling time Frequency of milling Additives • • • Milling material PTFE Agate Zirconium oxide Hardened steel Tungsten carbide 2.1 2.6 5.9 7.8 14.8 Poor Good to limited Very good Good to limited Very good Approximate density (g cm−3) Wear resistance Fig. 1 | Experimental considerations for mechanochemical reactions by ball milling. a–d, Different types of movement experienced the by milling jars and their content. e, Properties of the most common milling materials used to make the milling jars and milling balls. f, Schematic representation of a mechanochemical reaction showing important experimental parameters and characteristics. The three contacting balls under the reaction arrow are commonly used to represent the reaction initiated by the mechanochemical energy provided by ball milling. PTFE, polytetrafluoroethylene. Adapted from ref. 187, CC BY 4.0. Nature Reviews Methods Primers | (2025) 5:29 3 0123456789();: Primer milling bodies, typically milling balls, against each other and against the inner wall of the milling jar, thus causing impact and frictional forces to be transduced to the sample. In planetary ball mills, one or multiple vertically placed milling jars are connected to a support disk that rotates around a common central axis while the milling jars are spun in the opposite direction around their own axes25 (Fig.1d). This trajectory is analogous to the motion of a planet that revolves around its axis and circulates around a star; it is from this motion that the name planetary mill originates. This motion produces a rotational speed that causes the milling balls to hit the wall inside the jar at high speeds, creating many high-force collisions. Therefore, friction, impact, tension and shear become the main mechanisms that enable mechanochemical transformations to take place. Milling parameters When optimizing a mechanochemical reaction, there are several parameters to control the yield and the selectivity of the transformation. The examples below show that there is not an ideal set of milling conditions for all mechanochemical reactions and that optimization is always required. However, understanding how parameters (such as milling time, milling frequency, milling media and temperature) in milling experiments affect the outcome of reactions will facilitate the development of new mechanochemical transformations and ensure reproducibility26. Milling time. Most mechanochemical reactions by ball milling are carried out under, or close to, solvent-free conditions. Such conditions promote highly concentrated reactions and prevent excess waste 2,27 . As a consequence, mechanochemical reactions often exhibit an enhancement in the rate and yield as compared with the same reactions conducted in solution 28 . Experimentally, milling times (also referred to as reaction times) in mixer mills can be set from seconds or minutes to uninterrupted milling times that can last for several hours (for example, up to 20 h) 29–31 . Additionally, in many cases, milling cycles can be programmed to have periods of mechanical treatment followed by intermittent pauses, in a similar fashion to removing a flask from a stir plate. Here, the direction of the milling sample can also be alternated. Based on solvothermal reactions, it is often observed that longer reaction times are associated with higher conversion rates. However, as it is common for any synthetic protocol, reaching the full conversion of the reactants does not necessarily guarantee a perfect high-yielding reaction. In ball-milling experiments, long reaction times can lead to chemical, mechanical or thermal decomposition of the reactants and/or products, thus negatively impacting the yield32. In practice, milling times can be screened over a range of minutes to hours to determine whether the mechanochemical reaction occurs and to observe any relationship between the duration of the mechanical treatment and the yield or selectivity of the reaction 33 . It is important to consider that long milling times cause higher energy consumption. Depending on the material of construction of the reaction vessel, long milling times could also lead to contamination of the product due to abrasion of the milling media34, making isolation cumbersome. Milling frequency. The kinetic energy transduced to the sample by the milling media during each collision depends on the milling media’s speed. Experimentally, the linear or rotational speed at which the milling jar and its content is shaken or rotated can be controlled by choosing an appropriatemilling frequency, which also influences the number of collisions during a milling process. Therefore, the milling frequency is a key parameter in developing protocols for mechanochemical reactions, especially for those that are energetically challenging and do not merely depend on the proper mixing of the reactants 35,36 . Currently, there are no predictable parameters to determine the appropriate milling frequency for specific mechanochemical reactions. Optimization often requires an iterative process to identify the appropriate frequency. The use of in situ monitoring can reduce the need for ‘trial and error’ experimentation, and it is discussed in detail later in this Primer. In commercial mixer mills, the milling frequency is usually given in Hertz (Hz) and can be set from 3 Hz to 50 Hz, with most reactions carried out at 20 Hz, 25 Hz or 30 Hz. In planetary ball mills, the milling frequency is often expressed in revolutions per minute (rpm), with most commercial instruments being operational from 100 rpm to 1,100 rpm, although numerous mechanochemical reactions are reported to occur at frequencies between 400 rpm and 800 rpm. To better understand the correlation between frequency of milling, energy input and kinetics of mechanochemical reactions, various studies have demonstrated that high milling frequencies increase the reaction rate, likely due to a high energy dose being transferred to the sample37,38. This helps in understanding the fundamental relationship between kinetics and energy input, enables the planning and optimization of mechanochemical reactions, and provides the basis for reproducibility across different milling devices. However, the best result of a mechanochemical reaction is not always achieved at the highest milling speed. In some cases, high milling frequencies can be detrimental to the selectivity of the transformation39,40, or they can promote contamination of the product due to wearing of the milling jar and balls. Milling media. Besides the time and frequency of milling, the milling media (that is, the milling jar and milling balls) can also influence the yield and selectivity of a mechanochemical reaction. This is because the density, hardness and elastic properties of the milling material impact the energy input to the reactants37,38,41, and the composition of the milling media affects the reactivity of the sample during the milling process42–45. The most often used milling materials include steel (stainless and hardened), zirconium dioxide and tungsten carbide (Fig.1e). In addition, reactions using milling jars and balls made of alumina, silicon nitride, corundum, agate and copper are also known3,16,46. To prevent unnecessary abrasion due to a mismatch between the hardness values of the milling media, it is advisable to use milling jars and balls made of the same material. Nevertheless, it is possible to find examples of reactions in which milling jars made of steel, quartz, sapphire or polymers were conducted with milling balls of various materials47–49. In these cases, the use of balls coated with softer materials enables substantial energy transfer to the sample while reducing the mechanical damage of the milling jar. Additionally, the corrosiveness of the reactants or products should also be considered to prevent chemical damage of the milling media 50 . The selection of an appropriate milling jar — for example, one made of a transparent material (such as poly(methyl methacrylate) (PMMA), quartz or sapphire) — allows for in situ monitoring using Raman and fluorescence benchtop spectrometers or synchrotron X-ray diffraction techniques, which are discussed in more detail later51–53. Additional aspects related to the milling media, such as the size and geometry of the jars, the number and size of the balls, and the jar filling degree, influence the outcome of a mechanochemical reaction. For example, in some studies, it has been demonstrated that the activation of the reactants requires individual Nature Reviews Methods Primers | (2025) 5:29 4 0123456789();: Primer collisions of at least a certain strength, thus a small number of large balls performed better than a large number of smaller balls, despite the total mass of balls being kept similar 54 . However, in other systems, the efficiency of the reaction remained unaltered when varying the number or diameter of the milling balls, as long as the total mass of the milling media was kept constant55,56. Therefore, the best number and size of the balls often depends on the specific mechanochemical reaction, and finding the ideal combination requires optimization of the conditions. Regarding the jar filling degree, some ball mill manufacturers recommend filling the milling jar with approximately one-third of sample and one-third of milling balls, thus keeping a proportional space for the free movement of the balls. This ratio is a good approximation for an effective grinding performance in comminution, but it is not necessarily correct when optimizing a mechanochemical reaction 23 . For example, a typical milling experiment set-up includes a few hundred milligrams of sample milled in 10–15 ml milling jars with a single ball of 10 mm in diameter. Additives and temperature. The addition of liquid or solid additives is a common practice during the optimization of mechanochemical reactions by ball milling. For example, the presence of minute (that is, microlitre) amounts of liquid during the milling process, known asliquid-assisted grinding57, can be used to enhance the reaction rate or to alter the selectivity of a reaction compared with neat grinding experiments or reactions in solution58–60. By contrast, solid additives are normally used in larger quantities than the reagents to improve the dispersion of the solid reactants, to vary the rheology of the milling mixture, and to gain processability of liquid or low-melting-point reaction mixtures61. Most commonly used milling auxiliaries such as SiO2, Al2O3, NaCl or sand are chosen due to their supposed chemical inertness, but their presence during a milling process can occasionally affect the outcome of a mechanochemical reaction62–64. Less explored is the impact that atmospheric gases or artificial gaseous atmospheres inside the milling jar can have on the course of a reaction4. Some reports have evidenced that the oxygen in the air can act as an oxidant in ball-milling experiments 65 and that gases such as CO(ref.66), CO 2 (ref. 67), CH 4 (ref. 68) and N2 (ref. 69) can effectively incorporate into mechanochemical reactions. Notably, the relatively small quantities of atmospheric water or oxygen trapped inside the milling jar during set up on the bench do not seem to be detrimental for most mechanochemical reactions, thus avoiding the need for a glove box. However, depending on the sensitivity of the reactants and products, control experiments are recommended to assess the influence of moisture or air on the outcome of the mechanochemical transformation70,71. Another important parameter in mechanochemical reactions by ball milling is the temperature. Normally, ball-milling experiments are carried out without external heating and in the absence of thermal control (without the possibility to sense or set the macroscopic temperature in the milling jar). Depending on the type of milling media, frequency of milling and time, the temperature of the milling jar can rise from just a few degrees to several dozen degrees because of the frictional heat72. However, recent studies have implemented alternatives to measure 49,73 and to heat 35,47,74–78 or cool 39 the milling jar, thus controlling the reaction rates and selectivity of some mechanochemical reactions. In addition to thermally assisted mechanochemical reactions, some ball-milling transformations have also benefited from simultaneous photochemical 79,80 or electrical discharge activation 81 . A detailed discussion on how mechanochemistry can be combined with other energy sources can be found elsewhere in the literature 77,82 . Although most mechanochemical reactions are currently per - formed with a ball mill, various other mechanochemical devices are growing in popularity. A low-cost method to achieve this goal is often seen through the modified use of common laboratory equipment, such as a tube disperser or rotary evaporator 83 . Resonant acoustic mixing has also proved to be a valuable method for performing various mechanochemical reactions; principles and potential applications can be found in recent reports84–88.Twin screw extruders (TSEs)have been used as one of the alternatives to continuously process reagents rather than performing single-batch reactions, allowing for constant product generation and improving the sustainability of reactions89–93. Options for instrumentation that afford the ability to switch between batch and continuous have been implemented in the form of ball milling92,93. Many of the instruments previously discussed are being used to compensate for the lack of tools designed specifically for mechanochemistry; however, there is a concerted effort towards the development of these custom mechanochemical reactors94. Product isolation and safety considerations Ball-milling experiments do not require any specific safety considerations beyond standard lab procedures as they do not require the use of toxic and volatile solvents 2,27 . Moreover, methodological advantages such as the possibility to utilize safer chemicals or to circumvent the use of glove-box and Schlenk-line techniques make ball-milling protocols less laborious than traditional synthetic alternatives 95 . However, as mechanochemical reactions require intensive mechanical processing of the reactants in closed milling jars, a few additional safety measures are advisable. For example, ball milling of energetic materials or contact-unstable mixtures must be avoided or carried out in small scale following all safety precautions to prevent accidents. This is the situation in which other high-impact methods such as resonant acoustic mixing can be a useful alternative to ball-milling methods 96–98 . Hence, when working with known or potentially energetic materials or contact-unstable mixtures, differential scanning calorimetry analysis of the reagents prior to the milling experiment provides an initial measurement of the overall energetics of the starting materials99. Additionally, experiments involving gaseous reactants or reactions that could overpressure the milling jar must be handled with care. For this, pressure sensors have proven beneficial to monitor mechanochemical reactions in situ and improve safety 100 . Addressing these methodological and safety considerations are expected to facilitate the scaling-up of mechanochemical reactions. In this context, alternative mechanochemical techniques, such as reactive extrusion, have been explored to carry out safe, continuous and solventless mechanochemical reactions 90 . Finally, once the most suitable ball mill has been selected, the best milling parameters have been identified and a safe and successful experiment has been conducted, the experimentalist is faced with the need to isolate the desired product (Fig.1f). Isolation of products made by mechanochemistry does not differ from isolation after any other preparative approach. However, to minimize waste production, purification by precipitation, filtration, recrystallization or sublimation has been proven effective after ball-milling reactions 2,17,27 . If solvent-intensive purification strategies are unavoidable to guarantee the purity of the product, then the use of safer solvents and the development of recyclability plans for waste improve the sustainability of the entire mechanochemical process. Results Mechanochemical transformations can involve rapidly evolving intermediates or can progress (sometimes by different routes) after the Nature Reviews Methods Primers | (2025) 5:29 5 0123456789();: Primer mechanical treatment stops. This makes studying the mechanisms and kinetics of mechanochemical transformations a unique challenge. To this end, researchers have been pushed to further understand what is happening inside the milling vessel rather than only quantify the reaction after milling. Although many analytical techniques are, in principle, available to characterize mechanochemical transformations, not all techniques are suitable for all reactions. When planning a mechanochemical reaction and selecting an analysis protocol, one must first decide whether to monitor the reaction ex situ — usually with the focus to study the final reaction product — or in situ — typically to follow kinetics or reaction mechanisms52. For ex situ analysis of the product, there are essentially no limitations on the available analytical tools. In molecular synthesis, conventional solution-based characterization methods such as nuclear magnetic resonance (NMR) spectroscopy35, mass spectrometry and high-performance liquid chromatography (HPLC)101 are commonly used. By contrast, when investigating solid-state phenomena, such as co-crystallization or polymorphism, common analysis methods include powder X-ray diffraction (PXRD), Raman spectroscopy, X-ray absorption spectroscopy, Mössbauer spectroscopy, photoelectron spectroscopy and solid-state NMR spectroscopy. It is important to note that with ex situ techniques, there is always the risk that the reaction continues even after the mechanochemical reactor has been stopped and samples for analysis have been prepared 102 (Fig.2). Correspondingly, one should be careful when stating that the product analysed ex situ represents the material inside the milling jar during the mechanochemical reaction. Detailed reviews that describe the intricacies and applications of in situ monitoring of mechanochemical reactions are available103–105. Time-resolved in situ monitoring methods Mechanistic and kinetic studies are, in principle, possible to conduct using ex situ analyses106. However, there is growing evidence that manipulating the sample for ex situ analysis can often overlook important intermediate phases49 and in some cases even alter the course of the reaction 107,108 . The development oftime-resolved in situ methods overcomes many challenges associated with studying mechanochemical mechanisms and kinetics 52 by allowing experimentalists to follow chemical and structural changes without the need to perturb the material in any way 52 . Unfortunately, the experimental require - ments for time-resolved in situ (TRIS) methods are often restrictive and limit the analytical methods that are available. To date, examples of TRIS monitoring have been made using X-ray diffraction23,109,110, neutron diffraction111, X-ray absorption spectroscopy112,113, solid-state NMR 114 , Raman spectroscopy 51,115,116 , thermometry 49,74 , manometry 117 and acoustic emissions48,118. TRIS analytical methods using X-rays and neutrons require access to specialized research facilities, limiting their accessibility. By contrast, most other methods can be performed in laboratories with only small modifications to the mechanochemical reactor 49,51,74,114,117 . In addition to their accessibility, different TRIS methods provide notably different information about a mechanochemical transformation. Indirect methods such as manometry, thermometry and acoustic emission provide only a general view for the overall reaction profile. By contrast, solid-state structural methods like X-ray diffraction provide information on the nature of the solid crystalline phases, whereas molecular structural methods like Raman and fluorescence spectroscopy provide information on changes in molecular structure. For this reason, there is growing awareness of the benefits of combining multiple TRIS methods simultaneously 49,52,53,112,119 , though such combinations remain rare. Methods for TRIS analysis are still in their infancy23, and much is still to be learned about how best to conduct and interpret these analyses120. Data quality and resolution of TRIS methods are often lower than in ex situ experiments, making quantitative analysis difficult. Temporal resolution needs to be further improved to capture fast reaction kinetics and short-lived intermediates; therefore, not all analytical methods are suitable for mechanochemical monitoring. The simultaneous combination of several complementary techniques remains difficult but is essential for a comprehensive understanding of reactions. Frameworks for analysing complex, multi-phase TRIS data are still evolving, as distinguishing reaction mechanisms from physical mixing effects is difficult. Customized reactors that are compatible with different analytical probes while maintaining realistic milling conditions need further optimization22,23,109,121. Overcoming these limitations will be critical to advancing TRIS analysis as a robust tool for mechanochemical research. ‘Off’ Ex situ Ex situTime-resolved in situ Nascent state Activation Relaxation Milling ‘equilibrium’ ‘Off’Mechanical treatment ‘On’ a b 0.8 1.0 0.6 0.4 0.2 0 030 40 60 Time (min) Wcocrystal 80 100 60% RH; 20 Hz 70% RH; 20 Hz 80% RH; 20 Hz 60% RH; 25 Hz 70% RH; 25 Hz 80% RH; 25 Hz Fig. 2 | Profile of a typical mechanochemical reaction. a, Mechanical treatment drives the solid away from equilibrium, into an energetically ‘activated’ state. Once mechanical treatment is stopped, this excess energy is allowed to relax, although the relaxed state may be still ‘activated’ with respect to the nascent state. b, Conversion fraction (Wcocrystal) of isoniazid–benzoic acid cocrystals as a function of time in premilled mixtures (20 and 25 Hz for 5 min) stored at 40 °C and different relative humidity (RH) values (60%, 70% and 80% RH). Cocrystal formation was monitored by quantitative analysis of sequential powder X-ray diffraction patterns, demonstrating the effect of humidity on the rate of cocrystallization. Part a adapted from ref. 52, CC BY 4.0. Part b adapted with permission from ref. 232, American Chemical Society. Nature Reviews Methods Primers | (2025) 5:29 6 0123456789();: Primer Intensity 2D detector Scattering vector q (nm−1) p z y z 510 15 20 25 30 35 40 45 5 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 10 15 20 25 30 35 40 45 Diode Beamstop Synchrotron set-ups Detector Kapton shield X-ray transparent jar (e.g. PMMA) Scatter guard Pinhole Ionic chamber S3 S2 S1 N N O n O O O O O O n Bb Aa Ba Ab Ac C D Bc PMMA Scattering vector q (nm−1)Scattering vector q (nm−1) Intensity (a.u.) Intensity (a.u.) Equally distributed Caking Snowball Scattering vector q (nm−1) Intensity Scattering vector q (nm−1) Intensity Scattering vector q (nm−1) Intensity Milling area Probing area X-rays Spinning motion 2D Detector b 2θ c 2θ d 2θ Nature Reviews Methods Primers | (2025) 5:29 7 0123456789();: Primer Ongoing method development and critical evaluation of data interpretation approaches will help toestablish best practices for the conduct and application of TRIS investigations. TRIS PXRD. There have been various TRIS PXRD set-ups proposed in the literature, all with minor differences in the experimental considerations (Fig.3A). Despite some technical differences, all TRIS PXRD set-ups have the same basic arrangement and rely on synchrotron X-ray sources (Fig.3Ba). The monochromatic X-ray beam is first passed through a set of optical elements to cut it to the correct size (pinholes) and to measure its intensity for data normalization (ionic chamber). The beam subsequently passes through an X-ray-transparent jar (usually plastics, like PMMA) and interacts with the sample inside. The scattered beam passes through the back side of the jar, before moving through X-raytransparent safety shields, often made of polyimide (Kapton). Although not strictly necessary, these shields are placed to protect the X-ray detector, should experimental failure occur. Finally, the primary beam is stopped by a lead block (the beam stop) while the scattered X-rays (for example, Bragg scattering) strike the detector to produce the signal. This complicated path of the X-ray beam through the experiment leads to a few distortions of the data. First, the final data comprise contributions from the interaction of the X-rays with the PMMA jar (Fig.3Bc) and the Kapton shields (Fig.3Bb). As both components are not (or very poorly) crystalline, they provide broad ‘humps’ to the data, giving rise to a significant background in the XRD pattern. Second, because the sample is located inside a 3D jar, and hence at different distances from the detector, the Bragg scattering becomes artificially broadened or even split (Fig.3C). This effect causes real difficulties for data processing, but it can be minimized by carefully aligning the X-ray beam to the tangent of the milling jar to reduce its path length through the sample while any remaining artificial splitting can be corrected analytically (see Lampronti et al. 23 and its associated electronic supplementary information). Treating TRIS PXRD data using these strategies leads to very reliable and detailed data sets, sufficient for extracting with high confidence both phase composition and microstructural detail, even from only milligrams of powder23. An additional complication of TRIS PXRD arises from the calibration of the sample-to-detector distance, which determines how accurately we can convert the scattered intensity from the detector into a useful PXRD profile. Using a well-defined powder standard like Si, CeO2 or LaB6, one could realistically calibrate to the centre of the milling jar or to jar-tangent position at which the measurement is being done, either by measuring the standard powder directly in the milling jar or by attaching an external standard to these positions on the mill. Geometrically, these points should in principle both provide the same sample-to-detector distance. However, we note that if the standard is measured directly in the milling jar, at the position where the TRIS PXRD data will be measured, one obtains also a direct measure of the instrument profile contribution to the data (see details elsewhere 23,122 ). Although in principle the movement of the ball mill during an experiment can slightly affect the alignment, any such changes seem to be below the intrinsic resolution of the method. Attempts have been made to overcome this concern by including alignment standards in the ball mill during the experiment, but care must be taken with this approach. Any material (additive) added to the sample jar can influence and alter a mechanochemical reaction and its outcome. For example, transformation between three polymorphs of the compound 2-nitrophenyl-4-chlorophenyl-disulfide only occurs in the presence of a 1.5 M impurity63, and the presence of seeds of nicotinamide can produce a metastable polymorph of benzamide in pure form64. TRIS Raman spectroscopy. For Raman spectroscopy experiments, the mills are typically set up in darkened rooms or boxes to avoid the influence of other light sources. The Raman set-ups presented in the literature typically comprise a transparent milling jar (typically, PMMA) and a Raman probe that can be adjusted to the inner wall of the milling jar. The data treatment consists of a substation of the jar contribution to the Raman spectra, a base line correction and normalization of the data. Scripts are available for analysis and visualization of TRIS Raman data 51 . The course of a reaction can be qualitatively followed by plotting the intensities of selected Raman bands versus time. For a detailed quantitative analysis of the reaction mixture at a given point in time, a calibration is needed. Alternatively, least-squares procedures can be performed, given that the Raman spectra of the components taking part in the reaction are measured and averaged under the same conditions, leading to a representative spectrum. These least-squares procedures specifically refer to spectral deconvolution techniques in which the Raman spectra are fitted to determine the relative contributions of different components or polymorphs in the sample. Least squares procedures thus require that one knows the system under study and its components. Alternatively, it may also be possible to extract distinct signatures of different polymorphic forms through statistical analyses, such as principal component analysis 123 . It can be difficult to access the formation of intermediates or polymorphs from the Raman data Fig. 3 | Time-resolved in situ powder X-ray diffraction to monitor ball-milling transformations. A, Different experimental set-ups being used for time-resolved in situ powder X-ray diffraction (TRIS PXRD): original set-up in which the X-ray beam passes through horizontally oscillating milling containers, originally designed at ID11 at the European Synchrotron Radiation Facility109,233, with similar installations available at P02.1 PETRA III (refs. 53,234) and μ -spot BESSY-II (refs. 23,115) (part Aa); the set-up developed at the X04SA Materials Science beamline at the Swiss Light Source, Paul Scherrer Institute, where powder moves from the main milling chamber into a thin probing area with polyimide (Kapton) walls and is recycled back into the milling chamber after analysis (part Ab); and optimized set-up for conventional ball milling in which the X-ray beam is carefully aligned to minimize the scattering path and maximize the quality of the diffraction signal (part Ac). b, c and d are X-ray diffraction data collected for an Si standard at different positions in the milling jar.B, Typical set-up for TRIS PXRD at a synchrotron beamline showing the components of the beamline set-up (part Ba), the X-ray scattering associated with Kapton shields (part Bb) and the X-ray scattering associated with a typical poly(methyl methacrylate) (PMMA) milling jar (part Bc). C, The peak profile that results from a typical TRIS PXRD experiment, depending on the location of measurement through the milling jar, alongside a typical PXRD profile. D, Different effects observed in milling vessels as a consequence of different rheologies and implications for the detected XRD pattern. 2θ,the scattering geometry that relates the incident and diffracted X-rays, to fulfil the Bragg condition;a.u., arbitrary units; p, primary beam; q, scattering vector; S1,scattering vector produced by sample located at the jar wall closer to the source; S2, scattering vector produced by the sample distributed randomly within the jar; S3,scattering vector produced by the sample located at jar wall closer to the detector. Part Aa reprinted from ref. 109, Springer Nature Limited. Part Ab adapted with permission from ref. 121, American Chemical Society. Parts Ac, B and C adapted from ref. 23, Springer Nature Limited. Nature Reviews Methods Primers | (2025) 5:29 8 0123456789();: Primer if the species lack distinct Raman bands. In those cases, tandem TRIS experiments115 combining the benefits of XRD and Raman spectroscopy are helpful. The application of Raman spectroscopy can be limited for highly fluorescent samples, resulting in partial or complete shadowing of the Raman bands of the sample. Reducing the power of the incident laser beam can circumvent this issue in some cases. TRIS data analysis Analysis of data from ex situ techniques follows conventional strategies following standard protocols, and it is not discussed here. Instead, we focus our discussion on the unique challenges associated with TRIS data analysis, with a brief overview of available data evaluation strategies and requirements (Table1). When performing any TRIS monitoring experiment, the obtained results are inherently convoluted between signals that come from the reactor and from the sample. In addition, the non-ideal sample environments and restrictions on the data collection time (that is, to achieve time resolution) in TRIS typically leads to data of poorer quality than established ex situ techniques. Specialized data processing is therefore often needed to achieve data that are ready for analysis. The analysis and interpretation of TRIS data is itself a complicated task. In most cases, the probe used for TRIS analysis is stationary and the milling jar (and reacting powder) moves through the probe. Hence, only a small fraction of the powder, at one position in the reactor, is sampled, with the assumption that the reaction is homogeneous across the sample volume. Such assumptions become particularly problematic when the powder rheology leads to ‘clumping’ or ‘snowballing’ 120,124 (Fig.3D). Moreover, TRIS methods generally require specialized milling jars that are transparent to the probing radiation. Unfortunately, it is becoming apparent that changing the jar material can also have a marked influence on the outcome of the reaction, changing kinetics 125 , product41 and product stability126. Details on the analysis of data collected from Raman spectroscopy51 and PXRD23 are given in dedicated reviews, whereas standard protocols for data acquisition/analysis from other in situ methods are not yet available but will appear as the techniques develop further. Mechanochemistry compared with solution There are various reactions that are different under mechanochemical conditions compared with solution. However, many of these differences can be explained by the direct changes in the kinetics or thermodynamics of the reactions under mechanochemical conditions, which are different to what is observed in solution35,124. The development of new techniques to study mechanochemical transformations suggests a need to establish a framework in which the outputs are interpreted. It is common practice to seek connections between phenomena in mechanochemical conditions against existing parameters in solution. For example, how can pH under mechanochemical conditions exist where there are no free-floating ions in a solution to measure? Although comparison with solution certainly provides a solid foundation for trying to interpret mechanochemical reactions, these direct comparisons can often lead to experimental bias, which can diminish many of the exciting and unique features of mechanochemical reactions. Instead, it is imperative to recognize that mechanochemistry is ushering in a new paradigm of the chemical sciences deserving its own foundational principles. It is important not to think that, just because the product distribution is different between a mechanochemical reaction and a solvothermal reaction, the chemistry itself is different. With that said, there are many similarities that are observed between mechanochemical ball-milled reactions and those conducted in solution. Like many solid-state reactions, reactions conducted under ball-milling conditions are faster than the same transformations performed in solution. This is presumably due to limited need for statistical diffusion. Various reactions conducted mechanochemically are associated with higher yields and fewer by-products than solution chemistry. This reflects the lack of the conventional ‘equilibrium’ that occurs in solution and hence the ability to shift apparent equilibria or obtain out-of-equilibrium products127. The kinetic features are also significantly different to those observed in solution. In solution, one typically sees a slow, albeit steady reaction rate (for example, zeroth, first or second order), with the rate proportional to reagent concentration. However, reactions conducted mechanochemically are often accompanied by unconventional kinetics. Many mechanochemical transformations comprise an induction period (that is, a kinetic regime preceding the reaction during which ball milling causes no chemical transformation), which can extend from seconds to hours128,129, depending on the milling conditions and the system at hand. It is not yet known what causes this induction period, although growing evidence suggests it may be due to the need to activate material prior to the onset of the reaction128,130. Other unconventional kinetic features can be due to auto-catalytic processes — or ‘feedback’ effects — in which an otherwise slow mechanochemical reaction self-accelerates due to the release of water59,124,131. Computational methods for prediction Interpreting the results of mechanochemical kinetics is precluded by a lack in understanding of the mechanisms and features that affect Table 1 | Data analysis for common TRIS methods Method Information content Prior knowledge Software XRD Qualitative46 Comparison with databases CCDC, ICDD PDF, ICSD TOPAS, Fullprofa, GSASa Quantitative23 Crystal structure(s), e.g. by Rietveld Raman Spectroscopy Qualitative115,229 Molecular fingerprint Custom open source51 Quantitative123 Reference spectra, e.g. by PCA or LS refinement ssNMR Quantitative114 Phase composition, crystal structure Nmrgluea (ref. 230) XAS Semi-quantitative112 Reference spectra Athenaa, Larcha (ref. 231) CCDC, Cambridge Crystallographic Data Centre; GSAS, General Structure and Analysis System; ICDD PDF, International Centre for Diffraction Data Powder Diffraction File; ICSD, Inorganic Crystal Structure Database; LS, least squares; PCA, principal component analysis; ssNMR, solid-state nuclear magnetic resonance; TOPAS, Total Pattern Analysis Solution; TRIS, time-resolved in situ; XAS, X-ray absorption spectroscopy; XRD, X-ray diffraction. aOpen source. Nature Reviews Methods Primers | (2025) 5:29 9 0123456789();: Primer these reactions. In hopes to overcome this hurdle, there have been marked efforts towards developing theoretical and computational tools to model and rationalize mechanochemical reactions both at the macroscopic and microscopic scale. Macroscopic analytical kinetic models 132–135 have been developed to help better understand the effects that dominate reaction profiles in terms of features such as mixing, collision frequency and the probability of reaction. However, such models are not predictive in nature. Growing numbers of works have used density functional theory(DFT) simulations to predict the relative stability of product phases in an attempt to rationalize the outcome of mechanochemical reactions 136 . These methods rely on thermodynamic concepts though, which are not always applicable for determining product formation137,138. Instead, others have included in their energy landscape calculations the effects of particle size and surface energy, which seem to be needed to capture more accurately the outcome139. Although such methods have been helpful for rationalizing and predicting the final product phases, they do not allow us to describe the amount of energy required to initiate a mechanochemical reaction or the elementary stages that lead to a mechanochemical reaction. Recent efforts based on vibrationally driven excitation have proved to be promising in this regard to predict single-component mechanochemical reactions140,141, whereas simulations of shear processes at surfaces seem promising for the simulation of the elementary stages in multi-component reactions142. Applications With applications to various sub-fields and industries, mechanochemistry has become a robust and impactful technique. Mechanochemical conditions can be used for a variety of chemical transformations, ranging from fundamental bond formations to complex materials and catalytic methods, with the most common applications discussed below. Synthesis of molecular inorganic materials The demand for sustainable chemical processes is driving the development of greener methods2,27, with mechanochemistry emerging as a key solvent-free approach that complements traditional solution-based synthesis for both molecular solids and advanced materials. Although solvents are still essential for extraction and purification, the advantages of reducing their use are becoming increasingly recognized, even by sceptics within the synthetic chemistry community143. With solvent reduction in mind, mechanochemistry has been successfully utilized for the synthesis of a wide range of main-group compounds144,145, as well as metal and organometallic complexes146–150, and in catalysis43,151, along with other technologically relevant inorganic materials such as metal–organic frameworks (MOFs) 152,153 , perovskites 154 and battery materials 155 . One particularly exciting aspect of mechanochemistry is its ability to facilitate multicomponent, multistep reactions, as well as enabling the synthesis of compounds that are easily accessible in solution3. Among multicomponent, multistep reactions for metal complex synthesis, notable examples include a three-component synthesis of salen complexes156, a one-step, five-component route to rhenium(I) complexes from a metal carbonyl via orthogonal oxidative addition and ligand exchange 157 (Fig.4a), and the direct synthesis of indium(III) complexes from ligand precursors and indium trichloride 158 . Remarkably, such reactions can also use gaseous reactants, as shown by the synthesis of copper(II) N-heterocyclic carbene complexes directly from copper metal, an imidazolium salt and oxygen gas65. Other multicomponent mechanochemical reactions involving molecular inorganic materials 159 include the direct one-step synthesis of air-stable and moisture-stable cyclophosphazanes frameworks160 as well as their use in the assembly of high-order cocrystalline materials161. The appeal of mechanochemistry lies in its ability to achieve products Si Sn Re2(CO)10 Re F CO CO CO CO CO NN Re I CO CO CO CO CO AgF TMEDA one-pot: NaI, oxone, AgF, TMEDA TMEDA = AgF, TMEDA NaI, oxone P N a b c d Re F CO NCO NCO Fig. 4 | Inorganic compounds synthesized with mechanochemistry. a, A one‐step, five‐component route or a three‐step sequential route for the mechanochemical synthesis of a target Re(I) complex from a simple carbonyl157. b, Adamantoid tert‐butylphosphazane P4(NtBu)6 (ref. 160). c, Trimethylsilylated tetraallyltin(IV)162. d, Representative luminescence photographs of MAPbX3 (MA= CH3NH3+, X= Cl, Br, I)perovskite solutions under a 365 nm ultraviolet lamp irradiation. TMEDA, tetramethylethylenediamine.Part d reprinted with permission from ref. 173, American Chemical Society. Nature Reviews Methods Primers | (2025) 5:29 16 0123456789();: Primer 117. Brekalo, I. et al. 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Our actions help connect research initiatives across Europe and enable scientists to grow their ideas by sharing them with their peers. This boosts their research, career and innovation (www.cost.eu). E.C. is grateful to Région Occitanie (France) for the Pre-Maturation 2020 − MECH-API grant (ESR_PRE-MAT − 00262) and to Campus France and French–Estonian cooperation Programme Hubert Curien France-Estonia (PHC PARROT 2021–2023). I.R.S. and J.M. are grateful to the NSF Center for Mechanical Control of Chemistry and the National Science Foundation (CHE-2303044). K.J.A.-F. and J.G.H. acknowledge financial support from the International Centre for Genetic Engineering and Biotechnology (ICGEB) research grant (CRP/COL23-04_EC) and the Universidad de Antioquia (CODI 2024-67930). Author contributions Introduction (J.M. and I.R.S.); Experimentation (J.M., J.G.H. and K.J.A-F.); Results (J.M., F.E. and A.A.L.M.); Applications (J.M. and F.G.); Reproducibility and data deposition (J.M. and E.C.); Limitations and optimizations (J.M., I.R.S. and E.C.); Outlook (J.M. and I.R.S.). Competing interests The authors declare no competing interests. Additional information Peer review information Nature Reviews Methods Primers thanks the anonymous reviewers for their contribution to the peer review of this work. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Related links Active pharmaceutical ingredients: https://clincalc.com/DrugStats/Top200Drugs.aspx Mechanochemical reaction: https://goldbook.iupac.org/terms/view/MT07141 Planetary ballmills: https://www.youtube.com/watch?v=5ShOAS3EGGU © Springer Nature Limited 2025