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A combination of density functional theory (DFT) calculations and microkinetic simulations is applied to the study of condensation between N-acyl-hydrazides and aldehydes in acidic media to produce the active pharmaceutical ingredients (API) nitrofurantoin and dantrolene. Previous experimental reports have shown that the use of ball milling conditions leads to a reduction in the reaction time, which is associated with a significant reduction of waste. This result is reproduced by the current calculations, which additionally provide a detailed mechanistic explanation for this behavior.

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To address the growing demand for more sustainable and greener chemistry, mechanochemical methodologies are emerging as key players. However, to date there has been little data highlighting the benefits of these rising mechanochemical technologies with regard to process scale-up activities or implementation in commercial production scale. Herein, we report the first application of bead-mill technology (Dyno®-mill) for the sustainable mechanochemical synthesis of Acetaminophen, known under the brand name Paracetamol. Using the Beckmann rearrangement, the optimized solvent-free methodology delivered a final product on a scale of several tens of grams. In comparison to current production solvent-based process, the proposed process achieves a higher yield while also allowing the removal of solvents in the chemical reaction, hereby reducing one of the extensive drivers to waste generation. The mechanochemical approach was compared to solvent-based process using a combination of green metrics and EcoScale score. The mechanochemical synthesis of paracetamol scores the highest for all the metrics over currently used solution-based processes.

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The development of mechanochemistry is considerably growing. Benign by design, this technology complies with several principles of green chemistry, contributing to the achievement of the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal objectives. Herein, we report the use of mechanochemical processes in batch to prepare kilogram-scale of the Active Pharmaceutical Ingredient (API): Ibuprofen-Nicotinamide (rac-IBP:NCT) co-crystal in an industrial eccentric vibration mill. This scenario shows a sustainable approach to the industrial up-scaling of pharmaceutical co-crystals by a solvent-free mechanochemical process in batch. The quantitative assessment of the greenness of the mechanochemical process against the Twelve Principles of Green Chemistry was performed using the DOZN 2.0 Green Chemistry Evaluator.

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The development of new green methodologies and their broader adoption for promoting sustainable development in chemistry laboratories and industry play a significant role in society, due to the economic importance of chemistry and its widespread presence in everyday life. Therefore, a sustainable approach to chemistry contributes to the well-being of the worldwide population and complies with the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal. The review highlights how batch and continuous mechanochemical methods are an eco-friendly approach for organic synthesis, with a lower environmental footprint in most cases, compared to solution-based procedures. The assessment is objectively based on the use of green metrics (e.g., atom and real atom economy, E-factor, process mass intensity, material parameter recovery, Eco-scale, stoichiometric factor, etc.) and indicators (e.g. DOZN tool and life cycle assessment, LCA, studies) applied to organic transformations such as synthesis of the amide bond, carbamates, heterocycles, active pharmaceutical ingredients (APIs), porphyrins, porous organic polymers (POPs), metal- or acid-catalysed processes, multicomponent and condensation reactions, rearrangements, etc. The generalized absence of bulk solvents, the precise control over the stoichiometry (i.e., using agents in a stoichiometrically rather than in excess), and the more selective reactions enabling simplified work-up procedures are the distinctive factors, marking the superiority of mechanochemical processes over solution-based chemistry.

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There is still a need for synthetic approaches that are much faster, easier to scale up, more robust and efficient for generating gold(I)-thiolates that can be easily converted into gold-thiolate nanoclusters. Mechanochemical methods can offer significantly reduced reaction times, increased yields and straightforward recovery of the product, compared to the solution-based reactions. For the first time, a new simple, rapid and efficient mechanochemical redox method in a ball-mill was developed to produce the highly luminescent, pH-responsive Au(I)-glutathionate, [Au(SG)]n. The efficient productivity of the mechanochemical redox reaction afforded orange luminescent [Au(SG)]n in isolable amounts (mg scale), usually not achieved by more conventional methods in solution. Then, ultrasmall oligomeric Au10-12(SG)10-12 nanoclusters were prepared by pH-triggered dissociation of [Au(SG)]n. The pH-stimulated dissociation of the Au(I)-glutathionate complex provides a time-efficient synthesis of oligomeric Au10-12(SG)10-12 nanoclusters, it avoids high-temperature heating or the addition of harmful reducing agent (e.g., carbon monoxide). Therefore, we present herein a new and eco-friendly methodology to access oligomeric glutathione-based gold nanoclusters, already finding applications in biomedical field as efficient radiosensitizers in cancer radiotherapy.

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Mechanochemical transformations have made chemists enter unknown territories, forcing a different chemistry perspective. While questioning or revisiting familiar concepts belonging to solution chemistry, mechanochemistry has broken new ground, especially in the panorama of organic synthesis. Not only does it foster new "thinking outside the box", but it also has opened new reaction paths, allowing to overcome the weaknesses of traditional chemistry exactly where the use of well-established solution-based methodologies rules out progress. In this Review, the reader is introduced to an intriguing research subject not yet fully explored and waiting for improved understanding. Indeed, the study is mainly focused on organic transformations that, although impossible in solution, become possible under mechanochemical processing conditions, simultaneously entailing innovation and expanding the chemical space.

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

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Mechanochemistry is a versatile methodology that can be employed both for covalent bond formation in organic synthesis as well as a mediator to allow preparation novel colloidal dispersions for drug delivery. Herein, ball-milling was employed for the solid-state preparation of fluorescent hydrophobic hydantoins, followed by the unprecedented mechanochemically-mediated complexation of hydrophobic hydantoins within hydrophilic protein ß-lactoglobulin (BLG) and BLG nanofibrils (BLGNFs). These hydantoin:protein materials were in turn incorporated into hydrogels. The effect of incorporation of hydantoins into proteins, as well as the effect of protein structure, on the release properties were then investigated. The conversion of BLG to BLGNFs led to a more sustained release demonstrating that heat treatment of BLG into BLGNFs could be employed to modify release properties. To the best of our knowledge, this is the first example where protein : hydantoin complexes were prepared by mechanochemical methodology and mechanochemistry was combined with self-assembly in order to prepare protein nanomaterials for drug-delivery applications. In addition, the use of the developed protein materials is not limited to delivery of drugs but can for example be employed as components of smart food (delivery of nutrients) or release systems of pesticides.

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A mechanochemical method is reported for the synthesis of Au(diphos)X complexes of diphosphine (diphos = XantPhos and N-XantPhos) ligands and halide ions (X = Cl and I). The Au(XantPhos)X (1: X = Cl; 2: X = I) and Au(N-XantPhos)Cl (3) complexes exhibited either yellowish green (1) or bluish green (2) emission, whereas 3 was seemingly non-emissive in the solid state at room temperature. Blue- (2B) and bluish green (2G) luminescent concomitant solvates of 2 were obtained by recrystallization. Luminescent colour changes from blue (2B) or bluish green (2G) to yellow were observed when these forms were subjected to mechanical stimulus, while the original emission colour can be recovered in the presence of solvent vapours. Moreover, the luminescence of 2B can be reversibly altered between blue and yellow by heating/cooling-cycles. These results demonstrate the power of mechanochemistry in the rapid (4 min reaction time), efficient (up to 98% yield) and greener synthesis of luminescent and stimuli-responsive gold(I) complexes.

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Molecular rearrangements are a powerful tool for constructing complex structures in an atom- and step-economic manner, translating multistep transformations into an intrinsically more sustainable process. Mechanochemical molecular rearrangements become an even more appealing eco-friendly synthetic approach, especially for preparing active pharmaceutical ingredients (APIs) and natural products. Still in their infancy, rearrangements promoted by mechanochemistry represent a promising approach for chemists to merge molecular diversity and green chemistry perspectives toward more selective and efficient syntheses with a reduced environmental footprint.

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

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The use of mechanical forces to activate and drive chemical transformations in solid particulate is attracting remarkable interest in the light of its promising application in a wide spectrum of strategic areas ranging from materials science to fine chemical synthesis and pharmaceutical ingredient production. The capability of enabling solventless processes and fabricating unique materials inaccessible otherwise has made mechanochemistry one of the ten chemical innovations with the highest potential of changing the world. As in the past, so again now, the development of reliable technologies based on mechanochemical transformations cannot be separated from the understanding of the underlying mechanisms, their description and their control. To this aim, in this work we propose a kinetic model that relates macroscopic and microscopic scales while accounting for the statistical nature of the mechanical processing of powder. We discuss several specific case studies and develop the pertinent kinetic equations, showing how they can be used to best fit the experimental data and obtain insight into the microscopic features of mechanical activation.

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Aimed at eliminating or at least significantly reducing the use of solvents, sodium hypochlorite pentahydrate crystals (NaOCl·5H2O) in the presence of a catalytic amount of a nitrosyl radical (TEMPO or AZADO) have been successfully used to induce mechanochemical oxidative processes on several structurally different primary and secondary alcohols. The proposed redox process is safe, inexpensive and performing effectively, especially on the macroscale. Herein, an Ertalyte® jar has been successfully used, for the first time, in a mechanochemical process.

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The present work focuses on the challenges that emerge in connection with the kinetics of mechanically activated transformations. This is an important topics to comprehend to enable the full exploitation of mechanical processing in a broad spectrum of areas related to chemistry and materials science and engineering. Emerging challenges involve a number of facets regarding materials and material properties, working principles of ball mills and milling conditions, and local changes occurring in series in processed materials. Within this context, it is highly desirable to relate the nature and rate of observed mechanochemical transformations to individual collisions and then to the processes induced by mechanical stresses on the molecular scale. Hence, it is necessary to characterize the milling regimes that can establish in ball mills regarding frequency and energy of collisions, map the relationship between milling dynamics and transformation kinetics, and obtain mechanistic information through proper time-resolved investigations in situ. A few specific hints are provided in this respect.

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The present work focuses on the mechanochemical preparation of industrially important ß-cyclodextrin (CD) derivatives. Activated CDs have been reacted with nitrogen and sulfur nucleophiles using a planetary mill equipped with stainless steel, zirconia and glass milling tools of different sizes. It is shown that the milling frequency and the number as well as the size of the milling balls have an effect on the nucleophilic reaction.

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The present work addresses the development of an eco-friendly and cost-efficient protocol for the oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones by mechanical processing under air. Ball milling was shown to promote the quantitative conversion of a broad set of alcohols into carbonyl compounds with no trace of an over-oxidation to carboxylic acids. The mechanochemical reaction exhibited higher yields and rates than the classical, homogeneous, TEMPO-based oxidation.

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The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates.

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The mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins was investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures.

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5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1'-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.