Polymer Mechanochemistry in Confined Spaces.

With the development of mechanophores, polymer mechanochemistry has emerged as a powerful tool for creating force-responsive materials with a variety of desired functions, ranging from color change to molecular release. However, it remains challenging to improve the efficiency of mechanochemical activation, especially for mechanophores embedded within polymer networks, which has profound implications for translating mechanochemical responses into materials-centered applications. The physical and chemical conditions under spatial confinement differ significantly from those in the surrounding bulk environment, offering opportunities to facilitate mechanochemical activation. In this Minireview, we discuss and summarize recent progress in polymer mechanochemistry within confined spaces including surfaces/interfaces, polymer assemblies, and other nanostructures, specifically focusing on the effects of spatial confinement on the enhancement of mechanophore activation. We envision that combining confinement effects with advances in molecular and materials engineering will further improve the activation efficiency, capitalizing more fully on the potential of mechanophores toward practical applications.

Divergent Regioselective Synthesis of Functionalized 1,2,3-1H-Triazoles from Nitriles and Arylazides under Metal- and/or Solvent-free Conditions.

Highly selective and divergent syntheses, which are crucial in both organic synthesis and medicinal chemistry, involve significant advancements in compound accessibility. By modifying α-cyano esters into α-cyano ketones, the synthesis pathway broadens to include a diverse range of 4-CN, 5-amino, and 5-arylamino derivatives of 1,2,3-triazoles, which are achieved notably through the Dimroth rearrangement. This versatility extends further with the potential for a triple cascade reaction, leading to the production of carboximidamide compounds, which are facilitated by the Cornforth rearrangement. Advancements in compound accessibility not only expand the repertoire of synthesized molecules but also open new avenues for potential pharmacological agents. Building on these findings, we have developed an innovative and efficient method for the divergent synthesis of functionalized 1,2,3-triazoles. This method strategically utilizes α-cyanocarbonyls and arylazides by harnessing their reactivity and compatibility to orchestrate a variety of molecular transformations. By optimizing these substrates, our goal is to simplify synthetic routes, improve product yields, and accelerate the discovery and development of new chemical entities with promising biological activities.

Impact of Ball Milling on the Microstructure of Polyethylene Terephthalate.

Polyethylene terephthalate (PET) is a semi-crystalline polymer that finds broad use. Consequently, it contributes to the accumulation of plastics in the environment, warranting PET recycling technologies. Ball milling is a commonly used technique for the micronization of plastics before transformation. It has also recently been reported as an efficient mixing strategy for the enzymatic hydrolysis of plastics in moist-solid mixtures. However, the effect of milling on the microstructure of PET has not been systematically investigated. Thus, the primary objective of this study is to characterize the changes to the PET microstructure caused by various ball milling conditions. PET of different forms was examined, including pre- and post-consumer PET, as well as textiles. The material was treated to a range of milling frequencies and duration, before analysis of particle size, crystallinity by differential scanning calorimetry and powder X-ray diffraction, and morphology by scanning electron microscopy. Interestingly, our results suggest the convergence of crystallinity to ~30% within 15 minutes of milling at 30 Hz. These results are consistent with an equilibrium between amorphous and crystalline regions of the polymer being established during ball milling. The combined data constitutes a reference guide for PET milling and recycling research.

Mechanochemical Synthesis of ß-Sulfenylated Ketones and Esters.

For the first time, ball milling has been employed in the solvent-free synthesis of sulfur-functionalized materials from thiols and α,ß-unsaturated ketones and esters, using potassium carbonate as a transition metal-free catalyst. This environmentally friendly protocol makes use of easily accessible reagents to prepare ß-sulfenylated carbonyl compounds with yields exceeding 91% under ambient air and solvent-free conditions. Additionally, this innovative synthetic strategy enables the modification of  chalcones, compounds with significant medicinal and synthetic potential. The reactions are efficient and easily scalable to gram quantities, offering substantial benefits for practical applications.

Mechanochemical Conditions for Intramolecular N-O Couplings via Rhodium Nitrenoids Generated from N-Acyl Sulfonimidamides.

Starting from N-acyl sulfonimidamides, mechanochemically generated rhodium nitrenoids undergo intramolecular N-O couplings to provide unprecedented 1,3,2,4-oxathiadiazole 3-oxides in good to excellent yields. The cyclization proceeds efficiently with a catalyst loading of only 0.5 mol% in the presence of phenyliodine(III) diacetate (PIDA) as oxidant. Neither an inert atmosphere nor additional heating is required in this solvent-free procedure. Under heat or blue light, the newly formed five-membered heterocycles function as nitrene precursors reacting with sulfoxides as exemplified by the imidation of dimethyl sulfoxide.

Mechanochemical Transformations of Pharmaceutical Cocrystals: Polymorphs and Coformer Exchange.

Transformations of solid samples under solvent-free or minimal solvent conditions set the future trend and define a modern strategy for the production of new materials. Of the various technologies tested in recent years, the mechanochemical approach seems to be the most promising. The aim of this review article is to present the current state of art in solid state research on binary systems, which have found numerous applications in the pharmaceutical and materials science industries. This article is divided into three sections. In the first part, we describe the new equipment improvements. A brief description of techniques dedicated to ex-situ and in-situ studies of progress and the mechanism of solid matter transformation  is presented. In the second section, we discuss the problem of cocrystal polymorphism highlighting the issue related with correlation between mechanochemical parameters (time, temperature, energy, molar ratio, liquid assistant, surface energy, crystal size, crystal shape) and preference for the formation of requested polymorph. The last part is devoted to the description of the processes of coformer exchange in binary systems forced by mechanical and/or thermal stimuli. The influence of the thermodynamic factor on the selection of the best-suited partner for the formation of a two-component  structure is presented.

A Mechanochemically-Triggered, Self-Powered Flash Heating Synthesis of Phosphorous/Caron Composites for Li-Ion Batteries.

"Flash heating" that transiently generates high temperatures above 1000 °C has great potential in synthesizing new materials with unprecedently properties. Up to now, the realization of "flash heating" still relies on the external power, which requires sophisticated setups for vast energy input. In this study, a mechanochemically triggered, self-powered flash heating approach is proposed by harnessing the enthalpy from chemical reactions themselves. Through a model reaction between Mg3N2/carbon and P2O5, it is demonstrated that this self-powered flash heating is controllable and compatible with conventional devices. Benefit from the self-powered flash heating, the resulting product has a nanoporous structure with a uniform distribution of phosphorus (P) nanoparticles in carbon (C) nanobowls with strong P─-C bonds. Consequently, the P/C composite demonstrates remarkable energy storage performance in lithium-ion batteries, including high capacity (1417 mAh g-1 at 0.2 A g-1), robust cyclic stability (935 mAh g-1 at 2 A g-1 after 800 cycles, 91.6% retention), high-rate capability (739 mAh g-1 at 20 A g-1), high loading performance (3.6 mAh cm-2 after 100 cycles), and full cell cyclic stability (90% retention after 100 cycles). This work broadens the flash heating concept and can potentially find application in various fields.

Valorization of Protein Materials Through Mechanochemistry and Self-assembly.

The concept of combining mixing of solids by milling (a type of mechanochemistry) with aqueous self-assembly provides interesting possibilities for energy efficient production of advanced nanomaterials. Many proteins are outstanding building blocks for self-assembly, a prominent example being the conversion of proteins into protein nanofibrils (PNFs) - a structure related to amyloid fibrils. PNFs have attractive mechanical properties and have a tendency to form ordered materials. They are accordingly of interest as materials for bioplastics and potentially also for more high-tech applications. In this concept article we highlight our effort on valorization of such proteins with hydrophobic organic compounds such an organic dyes and drug molecules, by developing scalable methodology combining mechanochemistry and self-assembly. Compared to more established methodology, mechanochemical methodology is a valuable complement as it allows potential scalable production of hybrids between e.g. proteins and highly hydrophobic compounds - a class of hybrid material that is difficult to access by other means by conventical means. This may allow for development of sustainable processes for fabrication of advanced protein-based materials derivable from renewable source materials.

On the Valorisation of Chitin-Derived Furans by Milling.

Chitin-derived furans offer a sustainable alternative feedstock for nitrogen appended aromatic compounds. Herein, we address the challenge of using chitin-derived furans, 3-acetamido-5-acetylfuran (3A5AF) and 3-acetamido-5-furfural aldehyde (3A5F), to favour the formation of exo Diels-Alder adducts and 4­acetylaminophthalimides respectively, using a mechanochemical ball-milling technique. Mechanochemical activation is explored through the synthesis of 7-oxa-norbornene backbones with novel substitution pattern from 3A5AF in yields up to 77% and improved exo:endo selectivity compared to solution-phase reactions. The synthesis of 4­acetylaminophthalimides from 3A5F in yields up to 79% is also showcased from hydrazone derivatives.

Liquid nitrogen ball-milled mechanochemical modification of starches with typically selected A, B and C crystal types on multiscale structure and physicochemical properties.

This study investigated the effect of liquid nitrogen ball-milled mechanochemical treatment on multiscale structure and physicochemical properties of starches with typically selected A (rice starch, ReS), B (potato starch, PtS) and C (pea starch, PeS) crystal types. The morphology of starch samples changed from integral granules to irregular fragments, and the interaction between the exposure OH bonds led to a serious agglomeration. As the treatment times extended, the crystalline structure of starch samples was gradually destroyed, and the excessive treatment approached amorphization. Moreover, the thermal stability of starch samples showed the downward tendency; and with amorphization increased, the swelling power (SP), solubility (S), water absorption capacity (WAC), oil absorption capacity (OAC) and hydrolysis rate of starch samples gradually increased. The obtained results provided a theoretical foundation for broadening the application range of ball-milled starches with different crystal types.

Mechanochemical Thioglycolate Modification of Microscale Zero-Valent Iron for Superior Heavy Metal Removal.

Microscale zero-valent iron (mZVI) is widely used for water pollutant control and environmental remediation, yet its reactivity is still constrained by the inert oxide shell. Herein, we demonstrate that mechanochemical thioglycolate (TG) modification can dramatically enhance heavy metal (NiII, CrVI, CdII, PbII, HgII, and SbIII) removal rates of mZVI by times of 16.7 to 88.0. Compared with conventional impregnation (wet chemical process), this dry mechanochemical process could construct more robust covalent bonding between TG and the inert oxide shell of mZVI through its electron-withdrawing carboxylate group to accelerate the electron release from the iron core, and more effectively strengthen the surface heavy metal adsorption through metal(d)-sulfur(p) orbital hybridization between its thiol group and heavy metal ions. Impressively, this mechanochemically TG-modified mZVI exhibited an unprecedented NiII removal capacity of 580.4 mg Ni g-1 Fe, 17.1 and 9.5 times those of mZVI and wet chemically TG-modified mZVI, respectively. Its application potential was further validated by more than 10 days of stable groundwater NiII removal in a column flow reactor. This study offers a promising strategy to enhance the reactivity of mZVI, and also emphasizes the importance of the modification strategy in optimizing its performance for environmental applications.

Exploring Enzyme Encapsulation Efficiency in MOFs Using Eco-friendly Approaches.

The encapsulation of protein enzymes in metal-organic frameworks (MOFs) has been recognized as an effective enzyme immobilization approach. In this study, we demonstrated the influence of enzyme amount and the isoelectric points (pI) of different enzymes on the enzyme loading capacity in both mechanochemical (ball-milling) and water-based approaches. We found that increasing enzyme amounts enhances MOF enzyme loading without compromising activity, while the MOF shell protects encapsulated enzymes from proteinase K degradation through its size-sheltering mechanism. However, an excess of enzymes can hinder the formation of ZIF-90. Moreover, enzymes with low pI values (e.g., catalase, pI 5.4) facilitate encapsulation in MOFs, whereas enzymes with high pI values (e.g., lysozyme, pI 11.35) are more challenging to encapsulate. The simulation results revealed that increasing the enzyme amounts and pI values raises the activation energy necessary for MOF formation. This study highlights the crucial role of enzyme properties in the encapsulation process within MOFs, providing valuable insights for fabricating enzyme-MOF biocomposites for diverse applications, such as protein drug delivery.

Solvent Minimized Synthesis of Amides by Reactive Extrusion.

Herein, we report on the translation of a small scale ball-milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin-screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid-liquid, solid-liquid and solid-solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7-hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).

Mechanochemistry in Glycation Research.

Mechanochemistry by milling has recently attracted considerable interest for its ability to drive solvent-free chemical transformations exclusively through mechanical energy and at ambient temperatures. Despite its popularity and expanding applications in different fields of chemistry, its impact on Food Science remains limited. This review aims to demonstrate the specific benefits that mechanochemistry can provide in performing controlled glycation, and in "activating" sugar and amino acid mixtures, thereby allowing for continued generation of colors and aromas even after termination of milling. The generated mechanical energy can be tuned under specific conditions either to form only the corresponding Schiff bases and Amadori compounds or to generate their degradation products, as a function of the frequency of the oscillations in combination with the reactivity of the selected substrates. Similarly, its ability to initiate the Strecker degradation and generate pyrazines and Strecker aldehydes was also demonstrated when proteogenic amino acids were milled with glyoxal.

Meeting the UN Sustainable Development Goals with Mechanochemistry.

Chemistry traditionally relies on reactions in solution, but this method is increasingly problematic due to the scale of chemical processes and their economic and environmental impact. Handling residual chemical waste, including solvents, incurs significant costs and environmental pressure. Conversely, novel chemical approaches are needed to address pressing societal issues such as climate change, energy scarcity, food insecurity, and waste pollution. Mechanochemistry, a sustainable chemistry discipline that uses mechanical action to induce chemical reactivity without bulk solvents, is a hot topic in academic research on sustainable and green chemistry. Given its fundamentally different working principles from solution chemistry, mechanochemistry offers more efficient chemical processes and the opportunity to design new chemical reactions. Mechanochemistry has a profound impact on many urgent issues facing our society and it is now necessary to use mechanochemistry to address them. This Minireview aims to provide a guide for using mechanochemistry to meet the United Nations (UN) Sustainable Development Goals (SDGs), thereby contributing to a prosperous society. Detailed analysis shows that mechanochemistry connects with most UN SDGs and offers more cost-efficiency than other approaches together with a superior environmental performance.

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines.

The study presents a novel approach utilizing iminium salt activation and mild enolization of thioesters, offering an efficient and rapid synthesis of Michael adducts with promising stereoselectivity and marking a significant advancement in mechanocatalysis. The stereoselective addition of bisthiomalonates 1-4 to cyclic enones and 4-chlorobenzylideneacetone proceeds stereoselectively under iminium activation conditions secured by chiral primary amines, in contrast to oxo-esters as observed in dibenzyl malonate addition. Mild enolization of thioesters allows for the generation of Michael adducts with good yields and stereoselectivities. Reactions in a ball mill afford product formation with similar efficacy to solution-phase reactions but with slightly reduced enantioselectivity, yet they yield products in just one hour compared to 24 or even 168 hours in solution-based reactions. It is noteworthy that this represents one of the early reports on the application of iminium catalysis using first-generation chiral amines under mechanochemical conditions, along with the utilization of easily enolizable thioesters as nucleophiles in this transformation.

Mechanochemistry: Fundamental Principles and Applications.

Mechanochemistry is an emerging research field at the interface of physics, mechanics, materials science, and chemistry. Complementary to traditional activation methods in chemistry, such as heat, electricity, and light, mechanochemistry focuses on the activation of chemical reactions by directly or indirectly applying mechanical forces. It has evolved as a powerful tool for controlling chemical reactions in solid state systems, sensing and responding to stresses in polymer materials, regulating interfacial adhesions, and stimulating biological processes. By combining theoretical approaches, simulations and experimental techniques, researchers have gained intricate insights into the mechanisms underlying mechanochemistry. In this review, the physical chemistry principles underpinning mechanochemistry are elucidated and a comprehensive overview of recent significant achievements in the discovery of mechanically responsive chemical processes is provided, with a particular emphasis on their applications in materials science. Additionally, The perspectives and insights into potential future directions for this exciting research field are offered.

High-Energy Ball Milling Enables an Ultra-fast Wittig Olefination Under Ambient and Solvent-free Conditions.

30 Seconds to success! - The Wittig reaction, a fundamental and extensively utilized reaction in organic chemistry, enables the efficient conversion of carbonyl compounds to olefins using phosphonium salts. Traditionally, meticulous reaction setup, including the pre-formation of a reactive ylide species via deprotonation of a phosphonium salt, is crucial for achieving high-yielding reactions under classical solution-based conditions. In this report, we present an unprecedented protocol for an ultra-fast mechanically induced Wittig reaction under solvent-free and ambient conditions, often eliminating the need for tedious ylide pre-formation under strict air and moisture exclusion. A range of aldehydes and ketones were reacted with diverse phosphonium salts under high-energy ball milling conditions, frequently giving access to the respective olefins in only 30 seconds.

UPCYCLING OF CHITIN TO CROSS-COUPLING CATALYSTS: TAILORED SUPPORTS AND OPPORTUNITIES IN MECHANOCHEMISTRY.

In this study chitin derived from shrimp shells was used in the design of heterogeneous Pd-based catalysts for Heck and Suzuki-Miyaura cross-coupling reactions. The synthesis of Pd nanoparticles supported on N-doped carbons was performed through different approaches, including a sustainable mechanochemical approach, by using a twin-screw extruder. All catalytic systems were characterized by a multitechnique approach and the effect of nanoparticles size, N-doping on the support, and their synergistic interactions were elucidated. Specifically, Kelvin Probe Atomic Force Microscopy provided valuable insights on charge transfer and metal-support interactions. The catalytic behaviour of the samples was investigated in cross-coupling reactions under batch conditions and under semi-continuous flow solvent-free conditions, respectively obtaining a quantitative yield and a noteworthy productivity of 8.7 mol/(gPdh).

In Situ Eutectic Formation in a Polymeric Matrix via Hot-Melt Reactive Extrusion and the Use of Partial Least Squares Regression Modeling for Reaction Yield Determination.

There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (>12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.