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We developed an environmentally friendly mechanochemical protocol to induce an effective Fischer indolisation to synthesize indoles and indolines taking advantage of oxalic acid and dimethylurea.

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 and widespread presence in everyday life. Therefore, a sustainable approach to chemistry contributes to the well-being of worldwide population and comply with the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal. The review highlights how mechanochemical methods in batch and in continuous 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 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.

International audience

We present a crystallographic and computational study of three hydantoin-based active pharmaceutical ingredients nitrofurantoin, furazidin, and dantrolene aimed at identifying factors resulting in different propensities of these compounds to form polymorphs, hydrates, solvates, and solvate hydrates. This study is a continuation of our research towards understanding how small structural differences in closely related compounds affect their propensity to form different crystal phases, as all three compounds contain an imidazolidine-2,4-dione scaffold and a N-acyl hydrazone moiety and all form multiple crystalline phases. Crystallographic and computational analysis of the already known and newly obtained nitrofurantoin, furazidin and dantrolene crystal structures was performed by dissecting the properties of individual molecules and searching for the differences in tendency to form hydrogen bonding patterns and characteristic packing features. The propensity to form solvates was found to correlate with the relative packing efficiency of neat polymorphs and solvates and the ability of molecules to pack efficiently in several different ways. Additionally, the differences in propensity to form solvate-hydrates were attributed to the different stability of the hydrate phases.

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.

The extraordinary impact of metal-based complexes on synthetic methods is still recognized nowadays, and attempts are currently undertaken to further extend the use of metal-assisted chemistry to e...

Chemistry - a European journal 28(13), e202104409 (2022). doi:10.1002/chem.202104409, Published by Wiley-VCH, Weinheim

The scale-up of mechanochemical methods could play a transformative role in making manufacturing processes in the pharmaceutical industry greener by eliminating solvent use and recovery. Combined with energy-efficient continuous processing that consolidates reaction steps, mechanochemistry’s environmental and economic benefits may translate across product supply chains. Here, we evaluate numerous sustainability and green chemistry metrics for producing nitrofurantoin, an active pharmaceutical ingredient (API), via mechanochemical continuous twin-screw extrusion (TSE) and conventional solvent-batch synthesis methods. We find a significant reduction in all metrics for TSE including energy, climate change, and human and ecological health, as well as cost due to reducing excess reactant consumption and eliminating solvents while maintaining high product selectivity. In addition, replacing the direct energy source to drive the chemical reaction from mostly thermal to electrical sources does not increase the net life cycle energy consumed to produce functionally equivalent API. We conclude that mechanochemical synthesis via TSE holds multiple sustainability benefits for manufacturing APIs and potentially other chemical products.

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 beta-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. Funding Agencies|COST (European Cooperation on Science and Technology) [CA18112]; Region Occitanie (France) [ESR_PREMAT-00262]; China Scholarship CouncilChina Scholarship Council

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.

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.

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.

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.

The implementation of environmentally friendly, solvent-free mechanochemical synthesis in an undergraduate chemistry teaching laboratory is described. As a model reaction, the experiment addresses the catalytic mechanochemical synthesis of a small library of sulfonylureas, including a known active pharmaceutical ingredient, tolbutamide. The experiment introduces students to mechanochemistry, and the use of automated ball milling as a solvent-free synthetic methodology with a choice of two instruments: a mixer mill and a planetary ball mill. The isolation and purification of final products is achieved simply by washing with water and characterization is performed through powder X-ray diffraction. As milling reactions under wet and dry conditions lead to the formation of two diverse polymorphs of tolbutamide, this experiment also provides an opportunity to discuss topics relevant to solid-state pharmaceutical materials science, such as crystal packing of molecules and polymorphism, and it is an illustration...

Mechanochemistry provides an environmentally sustainable approach to prepare and process molecules and materials and offers a new research space full of opportunities. However, its full industrial potential has not yet been realized. Herein, we discuss opportunities offered and challenges laying ahead for the adoption of mechanochemical manufacturing technologies into industry.

Discovered over a century ago, Beckmann rearrangement is still today fully compliant with all the green chemistry principles and consistent with the key aspects of sustainable development. Herein, ...

The advantages of alternative energy inputs in the preparation of several hydantoins are herein illustrated through examples encompassing traditional methods and new synthetic strategies. When possible, for the same transformation, the advantages and disadvantages of each enabling technology are critically discussed and compared. Special emphasis is given to mechanochemical procedures involving the preparation of hydantoin-based active pharmaceutical ingredients (APIs), commodity chemicals for the industry, and nanohybrid materials for potentially new biomedical applications.

International audience; 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.

Twin-screw extrusion (TSE) was used to synthesize hydantoin-based active pharmaceutical ingredients (APIs) such as nitrofurantoin and dantrolene, employing minimal or no solvent. Postsynthetic workup was not required. This work demonstrates that solvent-free synthesis can be conducted in a continuous manner for pharmaceutical products.

International audience; Allyl alcohol (AA) was obtained by the deoxydehydration (DODH) of glycerol performed in the presence of a number of Re compounds (oxides, phosphine and halide derivatives) in alcoholic solvent or in neat conditions. Independently of starting Re species, the resulting catalytic process featured a delay time, necessary to start the formation of both AA and an Re-alkoxide precipitate. However, no delay time was detected by operating DODH using a preformed precipitate obtained by either Re source. As a consequence, and based on IR spectral analysis, it was hypothesized that the Re precipitate is the actual catalyst of DODH. The mechanism of DODH catalysis operated by methyltrioxorhenium (MTO) was studied by experimental and theoretical approaches. The results suggest that MTO releases methane with the formation of an ReVII alkoxide that subsequently aggregates by yielding the precipitate. The ReVII centre precipitate surface then undergoes reduction by forming ReV catalytic spots. The calculated kinetics also indicate that the detected latency can be ascribed to the presence of two high barriers, i.e. methane release and ReVII → ReV reduction, whereas the downstream processes, i.e. glycation and AA release, are not rate determining.

We describe herein an unprecedented mechanochemical "parallel synthesis" of 3,4-dihydro-2H-benzo[e][1,3]oxazine derivatives via a one pot three component reaction. The new milling system uses a multiposition jar (variable sizes are possible), allowing for the processing of up to 12 samples simultaneously, leading to the formation of a fungicide and a building block for polymer preparation with higher throughput compared to standard milling devices.

Hybrid nanoparticles with a large bridging organic group were prepared by mechanochemical-assisted sol–gel reaction. Planetary ball mill (PBM) was used for the first time to access the bis-silylated precursors, containing complex functionalities (such as hydantoins or a symmetrical urea obtained from α-amino esters). The process is based on a sequential reaction pathway involving liquid-assisted grinding (LAG) and 1,1′-carbonyldimidazole (CDI)-mediated one-pot/two-step reactions. Then hydantoins and the symmetric urea were used for the one-pot preparation of the corresponding bis-silylated compounds in a vibrational ball mill (VBM), followed by the mechanochemical sol–gel preparation of biohybrid bridged silsesquioxane nanospheres of uniform size.

The present work focuses on the mechanochemical preparation of industrially important β-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.

International audience; 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.

Few decades ago, the expertise gained from well-established extraction, processing and degradation techniques, paved the way for the use of ultrasounds as an alternative energy source in chemistry. Among other peculiar features, the locally extreme temperatures and pressures resulting from cavitation, proved to efficiently trigger reactions while maintaining mild average conditions, enhancing rates and yields and, hence, contributing to increase the popularity of sonochemistry up to the present level. The physical properties of the irradiated mixture are crucial for the effectiveness of cavitation, as well as for the proper transfer of acoustic energy to reactants. Therefore, the choice of a solvent that meets these requirements, while minimizing the environmental impact of the process is a fundamental one. Studies that combine sonochemistry with green, non-conventional solvents or with no solvents are surveyed in this review, evidencing how the most frequently investigated options are water phase, ionic liquids, followed by ethylene glycol and its oligomers, glycerol and few other biomass-based solvents. Numerous solvent-free, ultrasound-promoted procedures are also reported in the literature and are included in this contribution. The vast majority of the examples gathered here describe organic reactions, syntheses of nanosystems and polymerizations.

α-Aminophosphonates are an important class of biologically active compounds, attracting considerable attention in medicinal chemistry, by inhibiting enzymes involved in amino acid metabolism. Herein, the Kabachnik–Fields domino reaction was investigated by mechanochemistry for the first-time preparation of α- aminophosphonate derivatives in high yields and with full selectivity, outperforming comparable solution procedures. The reaction occurs without the addition of any external catalyst, possibly via a metal-mediated process occurring on the surface of the jar (zirconium oxide was used as the milling media). The mechanism of the mechanochemical reaction was also investigated by in situ Raman spectroscopy, and the kinetic behavior was disclosed. The solid- state structures of two representative compounds have been determined by single- crystal X-ray diffraction.

In recent years, research on enabling energy sources capable of promoting chemical reactions with low environmental impact and useful to drive the development of innovative, green, and sustainable processes has been continuously growing. We report herein selected examples based on the use of mechanochemistry as a valid and reliable alternative to chemistry in solution for the preparation of pharmaceutical materials, active co-crystals, or hybrid nanoparticles.

International audience; An environmentally friendly mechanochemical strategy for the preparation of unsymmetrical ureas and 3,5-disubstituted hydantoins by using safe starting materials in place of hazardous and toxic isocyanates has been designed. For the first time, the Lossen rearrangement was successfully applied to prepare a collection of relevant structures in medicinal chemistry via a one-pot mechanochemical approach and without a single drop of organic solvent including during the workup. The procedure was effective for the preparation of the Active Pharmaceutical Ingredient (API) ethotoin.

International audience; The preparation of hydantoin scaffolds using modern non-conventional activation methods is herein described. Special attention is devoted to the preparation of hydantoin-based Active Pharmaceutical Ingredients (APIs) by mechanochemistry, highlighting its advantages compared to classical solution procedures, opening new perspectives in the sustainable preparation of useful scaffolds for the pharmaceutical industry.

International audience; 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.

International audience; SynopsisMicrowave-assisted reductive amination with aqueous ammonia: sustainable pathway using a recyclable magnetic nickel based nanocatalyst.AbstractThe development of sustainable protocols for the reductive amination is a highly desirable pursuit in the domain of green synthesis. Magnetic nanocatalysts have found a unique niche in chemical synthesis in recent years as the recovery of expensive and/or toxic catalysts after their use are some of the salient features of these greener processes. Herein, we report the application of a recyclable nickel silica eggshell iron-based magnetic nanoparticles (Fe3O4@SiO2-Ni) for the expeditious microwave-assisted reductive amination of aryl aldehydes and ketones in aqueous ammonia; several desired primary amines were produced in good-to-excellent conversions. Extensive characterization of both, fresh and recycled Fe3O4@SiO2-Ni catalysts, showed that the Ni nanoparticles are highly dispersed on the silica shell and that the metal active phase is highly stable as the core–shell morphology is maintained after reaction, indeed the catalyst is recyclable up to six runs without deactivating. A synergic effect between the Ni nanoparticles and the silica support has been hypothesized wherein the Fe3O4@SiO2-Ni system worked as a bifunctional catalyst; support facilitates the activation of the substrate, and the metal nanoparticles promote the subsequent imine hydrogenation.