An exchangeable multicomponent ball-milling reactor system

Abstract

A mechanochemical ball mill system includes an outer casing having a cavity formed therein, a cylinder comprising a first material and configured to fit within the cavity, and a pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material. The first and second materials may be different and can be selected to tune aspects of mechanochemical and catalytic reactions in a milling process.

Description

Docket No. 130466.00333AN EXCHANGEABLE MULTICOMPONENT BALL-MILLING REACTOR SYSTEM CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and incorporates by reference, U.S. Provisional Patent Application No. 63 / 749,494, filed on January 25, 2025 and U.S. Provisional Patent Application No. 63 / 964,462, filed on January 21, 2026.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under Award Numbers 2023644 and 2303044 awarded by the National Science Foundation. The government has certain rights in the invention.TECHNICAL FIELD

[0003] This present disclosure relates generally to mechanochemical ball mill reactor vessels and more particularly, but not by way of limitation, to a system whereby differences between different milling regions can be evaluated by means of tuning jar material within traditional milling jars or jars with the capacity to hermetically seal.BACKGROUND

[0004] This section provides background information to facilitate a better understanding of the various aspects of the disclosure. It should be understood that statements in this section of this document are to be read in this light, and not as admissions of prior art.

[0005] There are many ongoing efforts to understand the role fundamental mechanical forces play in mechanochemical reactivity. Shear and impact / compressive interactions in particular have been demonstrated to lead to noticeable changes in reactivity in some chemical systems. Such observations have been achieved by using hand-made mechanical devices like rollers and presses to selectively apply shear or impact / compressive forces in the case of solid reagents or tribometers in the case of solid-liquid reagent systems. Many other studies employ atomic force microscopes, scanning electron microscopy, and other surface chemistry techniques to study changes in chemical reactivity at interfaces when chemicals are pressed and sheared. This work is often coupled with efforts to computationally model chemical surfaces and molecules when subjected to different forces. While such methods are critical to deeper understanding and 14841727 lv 2Docket No. 130466.00333exhibit ideal control over the force applied, these devices fail to replicate the inherently more complex mechanical environments observed in ball milling systems. To bridge these fundamental studies to more complex systems, means to investigate the roles different forces play in macroscale systems and methods to better understand the contributions of shear and impact / compression to reactivity are critically needed. Mills are known to apply both shear and impact / compressive forces in ratios which have not yet been measured. This ratio is suspected to vary depending on mill vessel size and geometry, mill type, vessel loading (with both reagents and grinding media), and mill action. Planetary mills are speculated to involve a greater degree of shear forces predominantly between rolling milling balls and vessel walls, while impact / compressive forces are experienced when milling balls undergo cascade onto the surface of the walls or tops of other balls. The extent of cascading action is known to depend on jar filling and number of balls. Meanwhile, vibratory mills are known to have both shear forces and impact / compressive forces with shear forces predominantly occurring along the vessel wall and impact / compressive forces occurring at the ends of the jars (assuming the typical single milling ball). If the ball is sufficiently small and moves in a characteristic figure eight motion as seen in some shaker mills (predominantly when empty), then impact / compressive forces may also occur at the center of the jar. Studies to quantify and predict the actual in-situ forces at play in mechanochemical reactions thus presents a complex technical challenge that is critical to overcome to realize scale up and better recognize the differences between diverse mechanochemical instrumentation and reaction conditions.SUMMARY

[0006] This summary is provided to introduce a selection of concepts that are further described below in the detailed description. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used as an aid in limiting the scope of claimed subject matter.

[0007] As an example, the kinetics of a Knoevenagel condensation between vanillin and barbituric acid have recently provided insight into the differences between mechanical and traditional solution-based synthetic methods. While the solution-based reaction follows first-order reaction kinetics, it is seen that the mechanochemical reaction kinetics follow a sigmoid with a slow induction period follow by a rapid acceleration in reactivity. Previous studies suggest that the source of this reaction acceleration is related to reactant rheological properties. Examination of the reaction with different milling environments (e.g. in stainless steel, Teflon,24841727 lv 2Docket No. 130466.00333zirconia, and aluminum reaction vessels) as a function of milling frequencies illustrates the role of reagent mechanics. By using reaction vessels with interchangeable mid-sections and end caps of different materials the role of surface energy and localized shear vs. normal loading forces in the milling jars on the reaction kinetics can be examined, and it is seen that these remain sigmoidal regardless of milling jar / ball materials, milling frequency and show that the reaction progress is consistent with a force-activated autocatalytic process. Additionally, milling jars to which the reagent showed high adhesion more readily formed solid volumes of product. For example, using a low force environment (Teflon) resulted in rates ~8x faster than low mixing in high force environments (stainless steel), suggesting that optimizing both interfacial adhesion, impact force, and the relative amount of shear vs normal forces can lead to significant reaction rate improvements.

[0008] In an aspect, a mechanochemical ball mill system includes an outer casing having a cavity fonned therein, a cylinder comprising a first material and configured to fit within the cavity, and a pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material. In some aspects, each end cap of the pair of end caps is configured to thread onto an end of the cylinder. In some aspects, the first and second materials are different.

[0009] In some aspects, the cylinder is comprised of at least two rings, the first ring being comprised of the first material and the second ring being comprised of a material that is different than the first material. In some aspects, the cylinder comprises three rings, the first and third rings being disposed on opposite sides of the second ring and being comprised of the first material. In some aspects, the second ring is comprised of the second material.

[0010] In some aspects, the first material comprises one of stainless steel, zirconia, aluminum, or polytetrafluoroethylene. In some aspects, the second material comprises one of stainless steel, zirconia, aluminum, or polytetrafluoroethylene. In some aspects, the first material has a surface adhesion that is less than a surface adhesion of the second material. In some aspects, the first material has a surface adhesion that is greater than a surface adhesion of the second material.

[0011] In some aspects, at least one of the first material or the second material comprises an optically transparent material comprising a light source to drive photochemical34841727 lv 2Docket No. 130466.00333transformations. In some aspects, at least one of the first material or the second material comprises a piezoelectric material to drive redox transformations.

[0012] In an aspect, an insert for a mechanochemical ball mill system includes a cylinder comprising at least a first material and a pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material. In some aspects, the cylinder is comprised of at least two rings, the first ring being comprised of the first material and the second ring being comprised of a material that is different than the first material. In some aspects, the cylinder comprises three rings, the first and third rings being disposed on opposite sides of the second ring and being comprised of the first material. In some aspects, the second ring is comprised of the second material.

[0013] In some aspects, the first material comprises one of stainless steel, zirconia, aluminum, or polytetrafluoroethylene. In some aspects, the second material comprises one of stainless steel, zirconia, aluminum, or polytetrafluoroethylene.

[0014] In some aspects, the first material has a surface adhesion that is less than a surface adhesion of the second material. In some aspects, the first material has a surface adhesion that is greater than a surface adhesion of the second material.

[0015] In some aspects, at least one of the first material or the second material comprises an optically transparent material comprising a light source to drive photochemical transformations. In some aspects, at least one of the first material or the second material comprises a piezoelectric material to drive redox transformations.

[0016] In an aspect, a method of tuning a location of a reaction in a ball milling reactor jar system includes providing an outer casing having a cavity formed therein, providing a cylinder comprising a first material and configured to fit within the cavity, and providing a pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material. The tuning comprises selecting the first material to be a different material from the second material.

[0017] In some aspects, the tuning comprising selecting regions in the system to place catalytic material to optimize the reaction. In some aspects, the cylinder is comprised of at least two rings, the first ring being comprised of the first material and the second ring being comprised of a material that is different than the first material. In some aspects, the cylinder comprises44841727 lv 2Docket No. 130466.00333three rings, the first and third rings being disposed on opposite sides of the second ring and being comprised of the first material. In some aspects, the second ring is comprised of the second material.

[0018] In some aspects, the first material comprises one of stainless steel, zirconia, aluminum, or polytetrafluoroethylene. In some aspects, the second material comprises one of stainless steel, zirconia, aluminum, or polytetrafluoroethylene.

[0019] In some aspects, at least one of the first material or second material comprises a catalytically active metal, whereby surface catalytical reactions or the mechanical generation of catalytically active particles derived from the catalytic material occurs.

[0020] In some aspects, the first material has a surface adhesion that is less than a surface adhesion of the second material. In some aspects, the first material has a surface adhesion that is greater than a surface adhesion of the second material.

[0021] In some aspects, at least one of the first material or the second material comprises an optically transparent material comprising a light source to drive photochemical transformations. In some aspects, at least one of the first material or the second material comprises a piezoelectric material to drive redox transformations.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] A more complete understanding of the subject matter of the present disclosure may be obtained by reference to the following Detailed Description when taken in conjunction with the accompanying Drawings wherein:

[0023] FIG. 1 depicts the different types of forces chemical reagents are subject to in a vibratory ball mill, according to aspects of the disclosure.

[0024] FIGS. 2A-2G illustrate aspects of an exchangeable multicomponent ball-milling reactor system (EMBRS), according to aspects of the disclosure.

[0025] FIG. 3 is a cross-sectional view of a milling vessel, according to aspects of the disclosure.

[0026] FIG. 4 illustrates a reaction scheme for Knoevenagel condensation between vanillin and barbituric acid, according to aspects of the disclosure.54841727 lv 2Docket No. 130466.00333

[0027] FIG. 5 A is a graph of % conversion vs. prevalence for an EMBRS, according to aspects of the disclosure.

[0028] FIG. 5B illustrates different configurations of a reaction vessel for use with an EMBRS, according to aspects of the disclosure.

[0029] FIG. 6 is a depiction of two configurations of an EMBRS of Cu and PTFE and the associated Cu surface area within the jars and the wear measured in the sulfonylurea and isocyanate coupling reaction to make Tolbutamide, according to aspects of the disclosure.

[0030] FIG. 7 is a depiction of two configurations of an EMBRS that incorporates piezoelectric material, according to aspects of the disclosure.

[0031] FIG. 8 illustrates steps in a mechanochemically driven condensation of vanillin and barbituric acid (left) and the simplification of the reaction for the autocatalytic model identified for this reaction.DETAILED DESCRIPTION

[0032] It is to be understood that the following disclosure provides many different embodiments or examples, for implementing different features of various embodiments. Specific examples of components and arrangements are described below to simplify the disclosure. These are, of course, merely examples and are not intended to be limiting. The section headings used herein are for organizational purposes and are not to be construed as limiting the subject matter described. Reference will now be made to more specific embodiments of the present disclosure and data that provides support for such embodiments. However, it should be noted that the discourse below is for illustrative purposes only and is not intended to limit the scope of the claimed subject matter in any way.

[0033] Traditional solvothermal methods of chemical synthesis typically rely on the dissolution of reagents in a solvent, heating, and the subsequent purification, and isolation the desired product(s) from the mixture, typically by additional steps of solvent removal. These approaches, however, face challenges related to the need for increased efficiency and sustainability, with 85% of chemicals currently employed for industrial manufacturing are considered hazardous and environmentally damaging. While frequently used solvents can be recycled recovery rates are low, with as much as 20-50% of solvent ending up to the64841727 lv 2Docket No. 130466.00333environment and in some cases this has prompted regulatory action from governmental authorities (e.g. the recent ban on methylene chloride in 2024). Additionally, the process of removing the solvent later results in significant energy waste and inherent inefficiency. The use of solvents can also limit what syntheses can be carried out based on materials solubilities.

[0034] Mechanochemical syntheses on the other hand, removes / limits the need for solvent and instead focuses on carrying out reactions by mixing chemical feedstocks directly in the solid-state. Here, mechanical forces (usually applied by grinding and crushing reagent precursors together) are utilized to alter reaction energy' landscapes to reduce activation barriers, affording more environmentally benign and energetically efficient syntheses. Given the notable benefits of this method, in 2019 mechanochemistry was named by the International Union of Pure and Applied Chemistry’ (IUPAC) as one of top 10 chemical innovations expected to change the world.

[0035] A challenge in advancing mechanochemical methods for synthesis is developing a clear understanding of the roles of the mechanics of the reaction environment and the interactions between reagents and the reactor materials used involved: i.e. reagent powder in the solid state, reactor and reaction environment (e.g. gas phase composition), the interfacial interactions between the reagents and the reactor surfaces, and type and extent of mechanical forces that are applied to, dissipated into, the reagents. As such the elements of the invention in this disclosure are focused on optimizing these factors.

[0036] To illustrate the utility of the disclosed approaches a Knoevenagel condensation reaction between vanillin and barbituric acid was used as a testbed system to explore the roles of these factors in more detail. The Knoevenagel condensation is an important organic transformation for carbon-carbon bond formation, and it is typically performed by the reaction of aldehydes and ketones to yield a,[3-unsaturated ketones. This classic reaction is important for the synthesis of a host of high-value materials, and serves as an important intermediate step in the synthesis of a range of natural products, pharmaceuticals, polymers, and agrochemicals.

[0037] We chose to illustrate our methodology using the vanillin and barbituric acid system, and this synthesis has served as an important model reaction for mechanochemical studies, including being used as a test case for scalability of mechanochemical processes using twin-screw extrusion.74841727 lv 2Docket No. 130466.00333

[0038] Under traditional solvothermal conditions, the reaction requires approximately 28 days to reach completion, following a simple first-order process, while by milling reagents directly (with sub-stochiometric amounts of water serving as the catalyst) in a mechanochemical mill, it can reach completion within 40 minutes. This speed up is the result in the change of kinetics of the mechanochemical transformation, which exhibits a sigmoidal relationship with an initial slow product formation occurring first (induction period), after which a ‘“positive feedback” process occurs (ca. 3-7 minutes), resulting quickly in near quantitative conversion.

[0039] Previous studies showed that the positive feedback period depends on milling frequency, where at 15 Hz, slow conversion was observed and reached only 20 % after 60 minutes). Increasing frequency to 30 Hz resulting in reaching this 20% conversion in only 13 minutes, achieving 100% shortly thereafter. It w as also found that the positive feedback could begin earlier in the milling process at lower reagent loadings, and it did not change by increasing the amount of initial water or with pre-grinding of the reagent materials.

[0040] To account for these observations, prior work suggested that the reagents cake around a milling ball in a tight “snowball” formation, enabling higher temperatures around the ball and enhanced reactivity suggesting that the induction period is due to the need to first form the reagent layer (adhere around the milling ball), and that this process continues during the positive feedback period, wherein increased reagents experience collisions with sufficient energy to overcome the activation barrier in the condensed state.

[0041] Given that prior work has suggested that the rheology of the reaction system has a significant impact on the reaction kinetics, testing was systematically performed in order to unambiguously relate the kinetics of the reaction to the impact forces experienced by the pow der (modeled by via classical mechanics by using know n frequency, milling ball size, and milling jar / ball mechanical properties), associated surface adhesion, process mixing, and the directionality of the applied forces (impact vs. shear). This was achieved by uniquely controlling the milling material and material location within the vessel, though the system disclosed herein.Need for Selective Force Regimes

[0042] Mechanochemical reactions can be performed in a number of milling systems with different modes of mechanical action. One of the most common laboratory' instruments for mechanochemistry is the vibratory mill, wherein chemical reactants and a grinding ball or balls 84841727 lv 2Docket No. 130466.00333are loaded into a milling reactor vessel (typically built of a single material with internal dimensions of a capped cylinder) and shaken violently in a side-to-side oscillating motion. The frequency of oscillation generally ranges from 10 to 35 Hz depending on the specific mill specifications, but is not limited to this range. During the grinding process, chemical reagents experience shear and impact / compressive forces as shown in FIG. 1. Such mechanical forces can cause reagents to undergo rheological changes, occasionally resulting in changes in phase during the milling process and heat release, material breakdown, and naturally chemical transformation. The complex nature of such chemical reactions and the sensitivity of the transformations to different milling parameters is an active field of research due to the complexity involved in decoupling the contributions of mechanical and chemical phenomenon. It has long since been known that different types of forces applied to chemicals (and materials more generally) lead to different phenomenological behaviors. This can be seen in arguably one of the oldest mechanochemical transformations, rubbing sticks together to make fire. When subjected to impact / compression, wood can be broken, while when subjected to intense shear forces, the yields increased friction resulting in combustion. Thus, knowledge of these forces and the roles they play in any given mechanochemical transformation and controlling them is critical for many systems. Traditionally, analyzing and studying the proportions of different forces and their effects in actual milling systems has been out of reach due to the inherently complex nature of the milling environment and experimental challenges in accessing this information in-situ. Thus, the field relies on ex-situ experiments utilizing devices such as tribometers, atomic force microscopes, and devices designed to apply single types of forces and computational approaches to analyze these systems.Methodology for Studying the Effects of Different Types of Forces in Vibratory Milling

[0043] Traditional milling methods typically rely on single material systems where the vessel body and milling ball are identical. Materials that are often used include: stainless steel, hardened stainless steel, agate, zirconia, silicon nitride, tungsten carbide, or other ceramics. Less frequently polymers like polytetrafluoroethylene (PTFE), polycarbonate, polymethyl methacrylate (PMMA), or polylactic acid (PLA) are used. When materials are mixed, the mixing is performed out of convenience or to obtain higher impact / compressive forces by milling with tougher balls. Compared to these traditional approaches, the unique EMBRS discussed herein exploits the separation of the milling vessel into regions of different materials94841727 lv 2Docket No. 130466.00333to enable analysis of the ensuing changes in material mechanics and interfacial properties on reaction performance.

[0044] Differences in reaction performance are achieved by the differing physical and chemical interactions between the milled chemicals and the vessel materials located in the different milling regions and the milling parameters. Reaction performance is tuned using a multi-part device comprising, for example, a cylindrical body and two interchangeable end caps, which are interchangeable with any desired material (e.g., see FIGS. 2F, 2G, 6, 7). The device is configured to be placed within standard milling vessels (e.g., see FIGS. 2A-2C, 3). In various aspects, the cylinder may be comprised of a singular ring or may be comprised of two or more rings. In various aspects, each ring and end cap may be made of a desired material in order to tune the location of the reaction. FIGS. 2A-2C and 3 illustrate milling vessels into which the device may be inserted. The ability to reliably maintain the reaction atmospheric environment achieved in the outer layer enables the device to be applied to reaction systems where inert or reactive gas mixtures are required or when EMBERS component materials could have different chemistry under different conditions. When this capacity is not required, EMBERS can nest inside standard milling jars. The device illustrated here w as made to match the internal dimensions of 10 mL Retsch MM 400 milling vessels enabling results to be correlated directly to many known mechanochemical transformations and reaction conditions available in literature. In principle, the same methodology can be utilized to match the internal dimensions of other mills, and reactor vessel shapes and sizes, and manufactured to fit within other milling systems.

[0045] FIGS. 2A-2H illustrate aspects of a milling vessel 100 and an EMBRS 120 according to aspects of the disclosure. Vessel 100 includes a pair of housings 102, 104 that can be joined together by a clamp 106 (e.g., a toggle clamp). Housings 102, 104 define a chamber into which EMBRS 120 fits. In some aspects, an O-ring 108 can be fitted to an O-ring holder 110 and inserted between the housings 102, 104 to provide a fluid-tight seal therebetween. Clamp 106 interacts with lips of housings 102, 104 to impart a compressive force onto O-ring 108 to effect the seal. As shown in FIG. 2F, EMBRS 120 includes three portions: a middle portion 122(1) and two end caps 124(2). Middle portion 122(1) is made of a first material, and end caps 124(2) are made of a second material. FIG. 2G illustrates a reverse configuration with a middle portion 122(2) being made of the second material and end caps 124(1) being made of the first material.104841727 lv 2Docket No. 130466.00333The first and second materials can be any of, for example, stainless steel, Teflon, zirconia, copper, and aluminum.

[0046] FIG. 3 illustrates an alternative configuration of a milling vessel 200 according to aspects of the disclosure. Vessel 200 includes a first housing 202 that can be threadably secured to a second housing 204. Housings 202, 204 define a chamber 206 into which an EMB RS (e.g., EMBRS 120) may be inserted. Similar to vessel 100, an O-ring can be inserted between housings 202, 204 to effect a fluid-tight seal therebetween.

[0047] Due to the range of potential reactions and physical and chemical interactions that can be exploited to see differences in reaction results using EMBRS, there is not one single method to apply this system that will work equally well for all mechanochemical reactions. To probe forces specifically, the size of the milling ball can be varied to confine the ball to merely forward and backward motion during the milling process, enabling shear to be confined exclusively to the sides of the vessel where one material predominates and impact / compression to be confined to the end of the vessel with the opposite material. Alternatively, a smaller milling ball can be used to probe changes as opposing forces are allowed to occur in greater extents within the previously inaccessible jar regions. This assumes experiments comparing ball mobility by changing the size within the EMBRS are done with balls of identical mass so that the forces applied are consistent and a sufficiently small reaction scale with sufficient reaction mixing despite ball size.

[0048] To explore the extent to which different regions of the jar drive reaction, reaction yields can be correlated to performance when harder or softer materials are placed in different regions correlating to higher or lower forces. This requires comparison to the reaction when run in the pure materials initially, where differences in yield are observed and assurance that this difference is not due to thermal effects. Alternatively, catalyst can be located in specific regions to selectively drive reaction in different regions so long as catalyst wear is negligible. Thus, success of the device requires proper tuning of the materials utilized to achieve differences in the different regions by considering the physical and chemical properties of the reaction system under study. Knowledge of significant factors driving mechanochemical transformations and carefully planned control experiments are critical for proper implementation. It is desirable to have several potential inner layers to utilize for experiments. The outer layer of the device is largely insignificant in this regard. Future designs can also incorporate multiple rings of materials enabling further specification.114841727 lv 2Docket No. 130466.00333Data Supporting the Described Methodology

[0049] By way of example, the utility of this system utilizing Teflon (PTFE) and stainless steel (SS) inserts was used to study the mechanochemical Knoevenagel condensation between vanillin and barbituric acid. The reaction scheme is shown in FIG. 4 and mechanism shown in FIG. 8. This reaction is known for the formation of a unique condensed state driven by adhesion of the reagent mixture to the SS milling ball during the milling process. It was found that this sticking behavior is comparatively uncommon when performed in PTFE. The preference of the material to adhere to stainless steel can be exploited to probe differences in reaction yields (correlated to reaction kinetics) during the reaction depending on the region in which the product adheres with the milling ball of sufficient size to ensure shear interactions occur along vessel walls and impact / compression occurs at the ends of the vessel. The preliminary results of this study utilizing the EMBRS are shown in FIG. 5A, with FIG. 5B illustrating four different configurations of the EMBRS: stainless steel middle with PTFE ends (case A), PTFE middle with stainless steel ends (case B), all stainless steel (case C), and all PTFE (case D).

[0050] Reaction yield in pure PTFE control showed a reaction mixture that was thoroughly spread out within the jar upon completion due to the poor adhesion of the chemical reagents to the smooth and low surface energy PTFE surface. This high mobility of the reaction powders correlated to high conversion of 97.7%, suggesting enhanced mixing of the reactants within the jar when adhesion is minimized (see FIG. 5 A). In this case, it is likely that both shear and impact / compressive forces occur and determination of which dominates in driving the reaction could not be deduced due to the homogeneity of the milling jar. Comparatively, the reaction when run in the SS control showed poor conversion (29.4%) with reagents packed exclusively at the ends of the milling jar (see FIG. 5A). Here, the decrease in conversion could be due to reduced mixing within the jar or the fact that reagents undergo predominantly impact / compressive forces (as reagent is observed to be located at the ends of the jar).

[0051] Upon isolating PTFE to the ends of the jar and SS to the middle, the reagents proceed to either 1) adhere exclusively to the SS in the middle or 2) spread throughout the jar. In the first case, reagents likely predominantly undergo shear forces as the ball slides across the trapped reagent. This resulted in yields of 72.1 %, still lower than the yield with pure PTFE j ars suggesting mobility loss results in some reduction compared to a milling environment where the materials can be spread more easily. In the second case, the conversion % remains low at 36.0%, matching the yields observed in pure SS where reagents appeared to congregate at the 124841727 lv 2Docket No. 130466.00333ends of the jar. This suggests that, while not adhered at the ends of the jar, the reagents are likely undergoing more impact / compressive forces than shear forces (as evidenced by the reduced yield compared to the second case). Upon isolating PTFE to the middle of the jar, product is found to predominantly stick to the SS ends. This again results in slightly higher conversions than in pure SS jars of 39% (see FIG. 5A), suggesting the low adhesion middle of PTFE may act to slightly enhance reagent mixing even though reagents end up confined to the impact / compressive regions. If the reagents exclusively build up in one end of the jar, this conversion is significantly reduced further to -12% which is likely a result of reduced reaction forces when the reagent layer is thicker (see FIG. 5A). On rare occasion, reagent was observed to adhere exclusively to the PTFE in the middle of the jar, resulting in high reaction conversion at 72.4% (see FIG. 5A). This again supports the preference for the reaction to be driven by shear forces over impact / compressive forces. Within error, this result also matches the high conversion of 65.5% observed when reagents do not adhere preferentially to SS or PTFE (see FIG. 5 A). These higher yields indicate location of slippery PTFE in the middle of the jar can facilitate better mixing than when the entire jar is merely SS or when the middle of the jar is SS, but the presence of SS at the ends of the jar still results in some hampenng of reagent movement during the milling process as the yield is lower than when performed in PTFE alone. These results demonstrate the power of the EMBRS methodology7to reveal the critical forces / adhesive properties that enable the reaction to progress.

[0052] The materials and methods employed for all of the above results are described here.

[0053] Chemicals were purchased from BeanTown Chemical and used without further purification. Vanillin was stored under nitrogen gas after each use to help prevent degradation.Nuclear magnetic resonance

[0054] 1HNMR spectra were obtained with either (1) a Bruker Advance Neo 400 instrument equipped with a 400 MHz Ascend magnet, an automated tuning 5 mm broadband iProbe, and a 60 position SampleXpress sample changer or (2) a 500 MHz Varian system equipped using a Varian VnmrS console equipped with an Oxford magnet, and 5 mm 'H [X] broadband and ['H / ^F] [X] switchable probes.Powder X-rav diffraction134841727 lv 2Docket No. 130466.00333

[0055] The sample was placed in the sample holder of a two-circle goniometer, enclosed in a radiation safety enclosure. The X-ray source was a IkW Cu X-ray tube, maintained at an operating current of 40 kV and 25 mA. The X-ray optics were the standard Bragg-Brentano para-focusing mode with the X-ray diverging from a DS slit (1mm) at the tube to strike the sample and then converging at a position sensitive X-ray Detector (Lynx-Eye, Bruker-AXS). The two-circle 218 mm diameter 0-0 goniometer was computer-controlled with independent stepper motors and optical encoders for the 0 circle, with the smallest angular step size of 0.0001 to 20. The software suite for data collection and evaluation is Windows-based. Data collection is automated by the COMMANDER program by employing a DQL file. Data is analyzed by the program EVA.Milling jar material specifications

[0056] Trials employed stainless steel (SS) milling jars (25 mL) and associated stainless steel grinding balls (15 mm, 13.40 g) purchased from Retsch, along with grinding balls (12.7 mm, 8.55 g) made of corrosion-resistant 316 stainless steel purchased from McMaster Carr. Zirconia (ZR) jars (25 mL) were made by Retsch, and zirconia grinding balls (12.7 mm, -6.0 g) were purchased from McMaster-Carr. PTFE milling jars (25 mL) and aluminum (AL) milling jars (25 mL) were manufactured in house to match the internal dimensions of the Retsch models using chemical resistant PTFE and multipurpose 6061 aluminum purchased from McMaster Carr; associated milling balls (12.7 mm, 2.99 g (AL) & 2.30 g (PTFE)) of identical material were purchased from McMaster Carr. Inserts for commercial 25 mL vessels made of SS and PTFE with 10 mL internal volumes isolating each material to different regions of the vessel were manufactured in-house using 316 stainless steel and chemical-resistant PTFE purchased from McMaster-Carr.General procedures for reaction kinetics measurements in different milling materials

[0057] Synthesis of 5-(4-hydroxy-3-methoxybenzylidene)pyrimidine-2,4,6(lH,3H,5H)-trione was performed in a Retsch MM400 mixer mill operating at a frequency of 30 Hz or 25 Hz using the materials described above.

[0058] In atypical experiment, the milling jars and balls were first cleaned with acetone, water, and Alconox soap, followed by a rinse with DI water and dry ing. Then, the milling ball, vanillin (1.9 mmol), barbituric acid (1.9 mmol), and water (2.9 mmol, 10 % wt) were loaded into a 25 mL milling jar. Jars were then placed on a Retsch MM400 mill, and milling was performed for 144841727 lv 2Docket No. 130466.00333the desired run time at either 25 Hz or 30 Hz. Upon reaction completion, the mixture in the jars was photographed, and a small amount of crude product (ty pically 5-25 mg) was collected from multiple jar regions and dis-solved in DMSO-d6 (750-800 pL) between 3-7 minutes following the end of the run. Conversion was measured by 'H nuclear magnetic resonance spectroscopy (NMR). This process was repeated until all run times had been measured. While more experimentally costly in terms of time and resources, this methodology ensures that the results are unaffected by cooling or other potential factors that could interfere with the kinetics during milling pauses resulting from periodic sampling. Control experiments revealed that this precaution was well taken as the reaction could continue slowly in the solid state upon pausing the milling process, thus the crude product was dissolved in d6-DMSO within 3-7 mins upon removal from the jar and taken for analysis. The reaction proceeds slowly in solution, with conversion changes of less than 5% observed after a day in solution. Thus, NMR measurements obtained within 12 hours of dissolution are within the methodological error.Defining the onset of the positive feedback period

[0059] Former studies define the beginning of the positive feedback period by visualization of the original % conversion vs time graph. To be more quantitative, it was chosen to define this time using the second derivative of the derived kinetic fit of the data described below and the % conversion reached by the % conversion fit value at that time point.General procedures for reactions confining different materials to specific milling jar regions

[0060] In a typical experiment, in-house designed milling jar inserts (described above) were cleaned with acetone, water, and Alconox soap, followed by a rinse with DI water and drying. Then they were loaded with vanillin (0.76 mmol), barbituric acid (0.76 mmol), water (21 pL, 10 % wt), and a PTFE milling ball (16 mm, 4.40 g), sealed in 25 mL vessels, and milled for 60 min at 30 Hz. Then,1HNMR was prepared according to the methodology described above. Extensions of the Methodology'

[0061] While EMBRS are primarily designed for studies such as those described above, the concept of confining different materials to different milling jar regions can be applied for a number of other scientific purposes as well. This is due to the range of potential reactions and materials that can be accommodated by the EMBRS. An exhaustive list of use cases cannot be154841727 lv 2Docket No. 130466.00333given. However, a few examples and conceptual frameworks for other potential common uses for fundamental and applied science can be provided.

[0062] Direct mechanocatalysis, the concept of catalyzing mechanochemical reactions using metal milling surfaces rather than complex ligand systems has arisen as a significant advance in the field of mechanochemistry offering a more sustainable and cost-effective method for catalysis. In principle, utilizing the EMBRS within a mechanocatalysis framework could enable chemists to perform two (or more) different reactions simultaneously by exploiting the separation of different regions of the jar to catalyze different transformations. For this purpose, one would envision an EMBRS made of a series of rings within the central cylinder in addition to the end caps wherein a series of different metals each catalyzing a unique reaction are present. Once catalyzed, in theory the products of each separate reaction could then be made to further react within the vessel. This concept offers a novel method to transform reactions that would formerly be two or three pot syntheses into one pot transformations, enhancing reaction rates to isolate more complex final products and simplifying the syntheses in question. This could in theory also be achieved with proper understanding of reactions driven by different forces where one reaction is significantly favored to occur in impact / compressive regions of the jar while the other occurs in the shear regions of the jar.

[0063] This concept of designing the EMBRS to enable multiple reaction zones within a single milling jar can also be extended to the realm of photocatalysis. The EMBRS can be designed whereby certain portions of the system are made of an optically transparent material which can allow in light to drive photochemical transformations. This enables specific areas of the milling jar to drive photochemistry, while other regions drive classical mechanochemical reactions, or both simultaneously. By incorporating lights and different metals and materials together, further chemistries driven by material responses to certain lights can also be envisioned. For example, the EMBRS may include a zone of different metals on which light is shone to get different hot electrons out for driving reactivity due to the different work functions of the metals.

[0064] The EMBRS is also useful for in situ catalyst generation, whereby mechanical forces strip materials from the jar surfaces to be incorporated as catalyst in the reaction mixtures. It was demonstrated that by using Cu milling components, the jar surfaces could help drive mechanochemical transformations, for example in the case of the mechanochemical copper164841727 lv 2Docket No. 130466.00333catalyzed coupling between sulfonamides and isocyanates, this can occur by generating the proper Cu catalyst derived from copper worn from the milling jar surface.

[0065] An additional case study for the EMBRS is the study of piezoelectric materials recently utilized by mechanochemists as catalysts to drive redox transformations. Here, applied mechanical force to piezoelectric materials generated electrons that can be used to catalyze reaction, with the energies and yields of electrons generated, dependent upon the mechanical environment of the milling jar. By confining a piezoelectric material to different regions of the jar and ensuring surface areas in shear and impact / compression regions are equivalent, one could observe, based on associated reaction yields, which forces most critically drive activation of the piezoelectric materials when milling. See FIG. 7 for a depiction of this process.The use of EMBRS for mechanocatalysis

[0066] An additional embodiment of EMBRS is the use of metal components with catalytic properties, and we have established its viability for this by examining the copper-catalyzed mechanochemical synthesis of sulfonyl-(thio)urea-based antidiabetic drugs. Previous studies have shown that this transformation is highly sensitive to the copper oxidation state, atmosphere, and catalyst loading. To that end. using the milling jar itself as the catalyst source is a key advantage for driving this and many other reactions. As a means to control the direct mechanocatalysis using the EMBRS configuration, the location within the milling jars where copper wear would be most prevalent during reaction was evaluated. Through the use of EMBRS jars with Cu end caps vs Cu center pieces, it was determined that the copper metal acted as a pre-catalyst for this reaction, transforming, given the right atmospheric conditions, in situ to catalytically active hydroxide (e.g. Cu(OH)2). This is proven by the loss of metallic Cu° at the milling jar surface, and the formation of surface Cu2+oxide species, which forms only under oxygen exposure, while no reaction occurs under nitrogen environments. The identity of the catalyst was verified through a combination of experimental studies and DFT calculations. Surface oxidation state was identified by X-ray photoelectron spectroscopy. As noted above, these two regions of the milling j ar undergo different types of mechanical stress, with the end caps experiencing more impact, and the central part of the jar experiencing more shear. Consequently, the use of the composite milling jar effectively permits isolating the surface responsible for adding the most to the catalytic activity in either the impact- or the shear-dominated regime of ball-milling. When the reaction was performed in the EMBRS jars, isolating the Cu catalyst production to either the shear or impact / compression regions, the 174841727 lv 2Docket No. 130466.00333resulting wear of Cu metal can be varied, as determined by ICPMS measurements and ratioed with the available surface area in the middle and ends of the jar, to control the amount of catalytic material formed. By analyzing resulting powder mixtures for final Cu content once reaction was completed, it was seen that placing the copper surface at the reactor ends led to more copper wear per unit surface area (85.5 pg mm2g’1), compared to the case in which a copper surface was located in the cylindrical body of the jar (16.4 pg mm2g'1). Despite the difference in copper loss, both EMBRS designs led to similar conversions of -80%, which was likely due to sufficient excess available copper. The observed ratios are given in FIG. 6. Cu is released at the middle of the jar (shear regions) but proportionally more Cu is generated from the impact / compression regions. It should be noted that the condition of the initial copper surface was seen to be inconsequential, as even a robust oxide layer is easily stripped away during milling, leaving the bulk metal and the atmosphere (oxygen and water vapor) as the predominant factors driving further catalyst formation.

[0067] To enable milling under strictly controlled atmospheres, in-house designed air-tight milling jars were manufactured from stainless steel. Briefly, these jars were machined from stainless steel and use KF-25 flange vacuum joints, which can be sealed with a KF-25 toggle clamp and locking pin, and the EMBRS fit as inserts into the jar. By mixing insert caps and cylindrical bodies of different materials, catalytically active metal can be isolated to different jar regions.Summary procedure for Reactions isolating copper metal to different jar regions

[0068] Before each experiment, copper and stainless-steel insert pieces were cleaned using citric acid. Reaction jars were loaded with a SS ball (12.7 mm, -8.54 g), p-toluenesulfonamide (428 mg, 2.5 mmol), and n-butyl isocyanate (278.5 pL, 2.5 mmol). The jars were loaded under humid ambient atmosphere and placed on a Retsch MM400 mill. Milling was conducted for 2 hr at a frequency of 30 Hz. After milling, crude product was collected from multi pie jar regions, dissolved in DMSO-d6, passed through a filter pipette, and crude conversion measured by 'H NMR. Additional crude powder was removed from the vials immediately upon reaction conclusion and analyzed through ICP-MS.Examinations of reactivity with different copper-based catalysts in various atmospheres

[0069] Before each experiment, stainless steel 25 mb atmospherically sealed jars were cleaned. Subsequently, reaction jars were loaded with a stainless-steel ball (15 mm. 13.4 g). p- 184841727 lv 2Docket No. 130466.00333toluenesulfonamide (214 mg, 1.25 mmol), n-butyl isocyanate (140.8 pL. 1.25 mmol), and the copper-based catalyst (5 mol% loading or varies in the case of CuO). The reactions were conducted either neat, or with addition of water (10 pL). The jars were then either: a) purged with 20 psi of dried N2 gas, b) purged with dried air in a Captair Pyramid Portable Glove Bag, or c) placed directly on the mill under humid ambient atmosphere. Complete purging or humidity was confirmed by a hygrometer reading of 0.1% or -30-60%, respectively, and the concentration of O2 was measured using a Forensics NIST calibrated gas monitor. Upon purging,jars w ere sealed, placed on a Retsch MM400 mill, and milling was conducted for 2 hr at a frequency of 30 Hz. After milling, the crude product was collected from multiple jar regions, dissolved in DMSO-d6, passed through a filter pipette, and crude conversion was measured by1H nuclear magnetic resonance spectroscopy (NMR).Procedure for examining oxidation state of milling surface materials by X-rav photoelectron spectroscopy (XPS)

[0070] XPS data were obtained using a SPECS EnviroESCA instrument operating under traditional high vacuum pressure. Copper samples were kept under nitrogen except when loading them into the instrument for analysis (-1-3 min process, an insufficient time for significant oxide formation). To ensure that the potential effects of reduction of the copper surface by X-rays were minimized, Cu(2p3 2) and Cu LMM (Auger electron spectrum that arises from the electronic transitions within the L shell of an atom) spectra were recorded first, followed by the collection of other XPS data.

[0071] Although various embodiments of the present disclosure have been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it will be understood that the present disclosure is not limited to the embodiments disclosed herein, but is capable of numerous rearrangements, modifications, and substitutions without departing from the spirit of the disclosure as set forth herein.

[0072] The term “substantially’ is defined as largely but not necessarily wholly what is specified, as understood by a person of ordinary skill in the art. In any disclosed embodiment, the terms “substantially”, “approximately”, “generally”, and “about” may be substituted with “within [a percentage] of’ what is specified, where the percentage includes 0.1, 1, 5, and 10 percent.194841727 lv 2Docket No. 130466.00333

[0073] The forgoing outlines features of several embodiments so that those skilled in the art may better understand the aspects of the disclosure. Those skilled in the art should appreciate that they may readily use the disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and / or achieving the same advantages of the embodiments introduced herein. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the disclosure. The scope of the invention should be determined only by the language of the claims that follow.

[0074] The term '“comprising’7within the claim is intended to mean “including at least” such that the recited listing of elements in a claim are an open group. The terms “a”, “‘an”, and other singular terms are intended to include the plural forms thereof unless specifically excluded.

[0075] Conditional language used herein, such as, among others, “can”, “might”, “may”, “e g ”, and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements and / or states. Thus, such conditional language is not generally intended to imply that features, elements, and / or states are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without author input or prompting, whether these features, elements, and / or states are included or are to be performed in any particular embodiment.

[0076] While the above detailed description has shown, described, and pointed out novel features as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the devices or algorithms illustrated can be made without departing from the spirit of the disclosure. As will be recognized, the processes described herein can be embodied within a form that does not provide all of the features and benefits set forth herein, as some features can be used or practiced separately from others. The scope of protection is defined by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

[0077] Although various embodiments of the method and apparatus of the present invention have been illustrated in the accompanying Drawings and described in the foregoing Detailed204841727 lv 2Docket No. 130466.00333Description, it will be understood that the invention is not limited to the embodiments disclosed, but is capable of numerous rearrangements, modifications, and substitutions without departing from the spirit of the invention as set forth herein.214841727 lv 2

Claims

Docket No. 130466.00333CLAIMSWhat is claimed is:

1. A mechanochemical ball mill system comprising:an outer casing having a cavity formed therein;a cylinder comprising a first material and configured to fit within the cavit ; and a pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material.

2. The mechanochemical ball mill system of claim 1, wherein each end cap of the pair of end caps is configured to thread onto an end of the cylinder.

3. The mechanochemical ball mill system of claim 1, wherein the first and second materials are different.

4. The mechanochemical ball mill system of claim 1, wherein the cylinder is comprised of at least two rings, the first ring being comprised of the first material and the second ring being comprised of a material that is different than the first material.

5. The mechanochemical ball mill system of claim 4, wherein the cylinder comprises three rings, the first and third rings being disposed on opposite sides of the second ring and being comprised of the first material.

6. The mechanochemical ball mill system of claim 5, wherein the second ring is comprised of the second material.

7. The mechanochemical ball mill system of claim 1, wherein the first material comprises one of stainless steel, copper, zirconia, aluminum, or polytetrafluoroethylene.

8. The mechanochemical ball mill system of claim 7, wherein the second material comprises one of stainless steel, copper, zirconia, aluminum, or polytetrafluoroethylene.

9. The mechanochemical ball mill system of claim 1, wherein the first material has a surface adhesion that is less than a surface adhesion of the second material.

10. The mechanochemical ball mill system of claim 1, wherein the first material has a surface adhesion that is greater than a surface adhesion of the second material.224841727 lv 2Docket No. 130466.0033311. The mechanochemical ball mill system of claim 1, wherein at least one of the first material or the second material comprises an optically transparent material comprising a light source to drive photochemical transformations.

12. The mechanochemical ball mill system of claim 1, wherein at least one of the first material or the second material comprises a piezoelectric material to drive redox transformations.

13. The mechanochemical ball mill system of claim 1, wherein at least one of the first material or the second material comprises a catalytically active material, whereby surface catalytical reactions or the mechanical generation of catalytically active particles derived from the catalytic material occurs.

14. An insert for a mechanochemical ball mill system, the insert comprising:a cylinder comprising at least a first material; anda pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material.

15. The insert of claim 14. wherein the cylinder is comprised of at least two rings, the first ring being comprised of the first material and the second ring being comprised of a material that is different than the first material.

16. The insert of claim 15, wherein the cylinder comprises three rings, the first and third rings being disposed on opposite sides of the second ring and being comprised of the first material.

17. The insert of claim 16, wherein the second ring is comprised of the second material.

18. The insert of claim 14, wherein the first material comprises one of stainless steel, copper, zirconia, aluminum, or polytetrafluoroethylene.

19. The insert of claim 18, wherein the second material comprises one of stainless steel, copper, zirconia, aluminum, or polytetrafluoroethylene.

20. The insert of claim 14, wherein the first material has a surface adhesion that is less than a surface adhesion of the second material.234841727 lv 2Docket No. 130466.0033321. The insert of claim 14, wherein the first material has a surface adhesion that is greater than a surface adhesion of the second material.

22. The insert of claim 14, wherein at least one of the first material or the second material comprises an optically transparent material comprising a light source to drive photochemical transformations.

23. The insert of claim 14, wherein at least one of the first material or the second material comprises a piezoelectric material to drive redox transformations.

24. The insert of claim 14, wherein at least one of the first material or the second material comprises a catalytically active material, whereby surface catalytical reactions or the mechanical generation of catalytically active particles derived from the catalytic material occurs.

25. A method of tuning a location of a reaction in a ball milling reactor jar system, the method comprising:providing an outer casing having a cavity formed therein;providing a cylinder comprising a first material and configured to fit within the cavity; andproviding a pair of end caps configured to be removably attached to the cylinder, each end cap being made of a second material,wherein the tuning comprises selecting the first material to be a different material from the second material.

26. The method of claim 25, wherein the tuning comprising selecting regions in the system to place catalytic material to optimize the reaction.

27. The method of claim 25, wherein the cylinder is comprised of at least two rings, the first ring being comprised of the first material and the second ring being comprised of a material that is different than the first material.

28. The method of claim 27, wherein the cylinder comprises three rings, the first and third rings being disposed on opposite sides of the second ring and being comprised of the first material.

29. The method of claim 28, wherein the second ring is comprised of the second material.244841727 lv 2Docket No. 130466.0033330. The method of claim 25, wherein the first material comprises one of stainless steel, copper, zirconia, aluminum, or polytetrafluoroethylene.

31. The method of claim 30, wherein the second material comprises one of stainless steel, copper, zirconia, aluminum, or polytetrafluoroethylene.

32. The method of claim 25, wherein the first material has a surface adhesion that is less than a surface adhesion of the second material.

33. The method of claim 25, wherein the first material has a surface adhesion that is greater than a surface adhesion of the second material.

34. The method of claim 25, wherein at least one of the first material or the second material comprises an optically transparent material comprising a light source to drive photochemical transformations.

35. The method of claim 25, wherein at least one of the first material or the second material comprises a piezoelectric material to drive redox transformations.254841727 lv 2

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