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Yes / Grinding solid reagents under solvent-free or low-solvent conditions (mechanochemistry) is emerging as a general synthetic technique which is an alternative to conventional solvent-intensive methods. However, it is essential to find ways to scale-up this type of synthesis if its promise of cleaner manufacturing is to be realised. Here, we demonstrate the use of twin screw and single screw extruders for the continuous synthesis of various metal complexes, including Ni(salen), Ni(NCS)2(PPh3)2 as well as the commercially important metal organic frameworks (MOFs) Cu3(BTC)2 (HKUST-1), Zn(2-methylimidazolate)2 (ZIF-8, MAF-4) and Al(fumarate)(OH). Notably, Al(fumarate)(OH) has not previously been synthesised mechanochemically. Quantitative conversions occur to give products at kg h−1 rates which, after activation, exhibit surface areas and pore volumes equivalent to those of materials produced by conventional solvent-based methods. Some reactions can be performed either under completely solvent-free conditions whereas others require the addition of small amounts of solvent (typically 3–4 mol equivalents). Continuous neat melt phase synthesis is also successfully demonstrated by both twin screw and single screw extrusion for ZIF-8. The latter technique provided ZIF-8 at 4 kg h−1. The space time yields (STYs) for these methods of up to 144 × 103 kg per m3 per day are orders of magnitude greater than STYs for other methods of making MOFs. Extrusion methods clearly enable scaling of mechanochemical and melt phase synthesis under solvent-free or low-solvent conditions, and may also be applied in synthesis more generally. / EPSRC (EP/L019655/1)

Im Vergleich zu herkömmlichen, lösungsmittelbasierten Methoden bietet die Mechanochemie eine einzigartige Möglichkeit, die entstehende Kristallstruktur zu kontrollieren und neue sowie metastabile Kristallstrukturen zu erhalten. Frühere Studien haben gezeigt, dass die Mechanochemie zur selektiven Synthese von Polymorphen unter Verwendung verschiedener Lösungsmittel eingesetzt werden kann. Um den Prozess umweltfreundlicher zu gestalten, ist es erforderlich, auf den Einsatz von Lösungsmitteln zur selektiven Herstellung von Polymorphen mittels Mechanochemie zu verzichten. Bisher wurde nicht systematisch untersucht, ob eine mechanochemische Polymorphkontrolle ohne den Zusatz von Lösungsmitteln möglich ist. Um zu untersuchen, ob eine Kontrolle von Polymorphen ohne Lösungsmittel Zusatz erreicht werden kann, wurden verschiedene Kokristallsysteme unter Verwendung unterschiedlicher Mahlparameter (Energieeintrag, Bechermaterial und Mühlentemperatur) getestet. Zu diesem Zweck wurde die Cokristalle von drei pharmazeutischen Modellsystemen untersucht. Die untersuchten Systeme waren: (1) Isonicotinamid + Carbamazepin, (2) Isonicotinamid + Glutarsäure sowie (3) Nicotinamid + Pimelinsäure. Jedes System bildet polymorphe Kokristallprodukte. Im Verlauf dieser Arbeit wurde die Stabilität der Polymorphe mittels DFT-Simulationen, DSC und VT-PXRD-Experimenten untersucht. Es wurde gezeigt, dass der Energieeintrag und die Mühlentemperatur eine wichtige Rolle für das mechanochemische Produkt spielen. Eine Kombination aus Energieeintrag und Mühlentemperatur kann sogar hoch Temperatur Polymorphe bei niedriger Temperatur stabilisieren. Basierend auf diesen Ergebnissen können die mechanochemischen Parameter genutzt werden, um die Energiebarrieren für Festkörperübergänge zu senken. Diese Erkenntnisse werden für künftige Untersuchungen von mechanochemischen Prozessen in verschiedenen Materialien und deren Erscheinungsformen wertvoll sein. / Mechanochemistry provides a unique opportunity to control the emerging crystal structure and obtain new and metastable crystal structures, compared to conventional solvent-based methods. However, many factors in mechanochemistry remain largely unexplored despite its potential for polymorph control. Polymorphs can be synthesized selectively using different solvents via mechanochemistry. To achieve environmentally friendly processes, it is necessary to explore methods for producing selective polymorphs through mechanochemical reactions without the use of solvents. It has not yet been systematically investigated whether mechanochemical polymorph control is possible without the addition of solvents. The purpose of this study was to investigate whether polymorph control can be achieved without solvents. To achieve this, different cocrystal systems were tested using various milling parameters (energy input, jar material, and milling temperature). Specifically, the cocrystallisation of three pharmaceutical model systems was investigated by ball milling. These systems included: (1) isonicotinamide + carbamazepine, (2) isonicotinamide + glutaric acid, and (3) nicotinamide + pimelic acid. Each system produces polymorphic cocrystal products. In the process of this work, the stability of the polymorphs were investigated using DFT simulations, DSC and VTPXRD experiments to determine the stability at elevated temperatures. Mechanochemical outcomes of ball milling reactions are influenced by both energy input and milling temperature. The combination of energy input and milling temperature can also stabilize high-temperature polymorphs at low temperatures. These results suggest that mechanochemical parameters can lower the energy barriers for solid-state transitions and provide new insights into controlling polymorphism through mechanochemistry. These findings will be useful for future investigations of mechanochemical processes in various materials and their manifestations.

Alumina (Al2O3) is one of the most widely used engineering ceramic. It can be used in a wide range of applications like electrical/thermal insulation, wear resistance, structural refractories, cutting tools, abrasives, catalyst carriers and coatings. A traditional ceramic process has several steps (i.e. powder synthesis and processing, shape forming, drying, organic burnout and densification). Accessing powders with sizes in the range of a couple of micrometers down to several tens of nanometers is considered critical in attaining higher densities in the final ceramic bodies. Besides since significant shrinkage can be observed in the thermal treatment steps due to the excessive use of additives (e.g. binders, solvents and plasticizers) in the powder processing and forming steps, it is important to take remedies that would increase the solids loading in the initial mixtures. In addition, most of the conventional additives and solvents used in these steps are toxic and it is necessary to replace them with the environmentally benign aqueous-based alternatives. Alumoxanes could be used as a benign aqueous-based alternative to be used as a ceramic precursor or an agent. They are a group of compounds that have nano sized boehmite cores encapsulated with the organic groups used in its production steps. In this research work, alumoxane nano particles which can be used as precursors for nano-alumina were developed starting from aluminum trihydroxide. As a preconditioning step, grinding was applied to decrease the aluminum hydroxide particle size (&amp / #8804 / 60 &amp / #956 / m) to submicron sizes. This process was followed by the glycothermal ageing step, and organic derivative of boehmite was obtained. The amorphous particles thus obtained were further treated mechanochemically in a high energy ball mill with organic chemicals like acetic acid, methoxy acetic acid, stearic acid and L-lysine. After this step the observed sizes of the particles were as low as 10-100 nm. The effects of organic molecules used in each step were studied by FTIR spectroscopy and their effectiveness in exfoliation of hydroxide layers were identified with dynamic light scattering from processing solutions dispersed in aqueous medium. Moreover, in each step, structural analyses were carried out by XRD.

L'un des objectifs des industries chimique et pharmaceutique est de développer des procédés verts évitant ou réduisant l'utilisation de solvants. Mais ne pas utiliser de solvant nécessite souvent des catalyseurs métalliques ou autre, ce qui rend les purifications délicates, comme dans le cas des synthèses de chimie fine permettant l'obtention de principes actifs pharmaceutiques. C'est ainsi que la mécanochimie a émergé en tant que voie durable pour la synthèse chimique, y compris dans le cas des transformations moléculaires organiques sous contrainte mécanique. Malgré les progrès récents de cette méthodologie, certains aspects de l'action mécanique ne sont pas totalement élucidés, en particulier ce qui concerne les mécanismes. Dans cette thèse, trois axes principaux de la mécanochimie ont été explorés. Dans une première partie, le mécanisme moléculaire de la synthèse de deux types de 1,4-diazines, la dibenzo[a,c]phenazine (DBPZ) et la 2,3-diphenylquinoxaline (DPQ), a été investigué. La RMN 13C CP-MAS a permis de mettre en évidence des intermédiaires de cette synthèse, et des mesures calorimétriques ont révélé que deux réactions se poursuivaient après broyage. La possibilité d'une réaction concertée a également été prise en compte dans le cas de la dibenzo[a,c]phenazine. La seconde partie concerne la formation de la 2,3-diphenylquinoxaline. Les paramètres du procédé ont été étudiés, dans le cas d'un broyeur à bille vibrant. L'influence des matériaux de broyage, de la taille et de la masse des billes, la granulométrie des matières premières, ainsi que la température des media de broyage ont été étudiés, permettant de déterminer une énergie d'activation apparente (Ea). Le tracé des courbes selon Arrhenius et Eyring-Polanyi a montré des changement de Ea caractéristiques de modifications au niveau du mécanisme, attribuées à l'apparition d'un possible eutectique fondant au dessus de 30°C, induit mécaniquement. Après cette étude qui a permis la compréhension de certains points fondamentaux, et d'approfondir les procédés de ces réactions modèles, une troisième partie traite de l'application de la mécanochimie à la synthèse en phase solide d'hydrazones d'intérêt pharmaceutique, et à celle catalysée de dérivés de l'isoniazide obtenus par réaction d'aldéhydes et d'hydrazines. D'une manière générale, les durées de réaction sont plus faibles, et les rendements meilleurs, qu'avec les méthodes classiques. L'influence des réactivités électronique et des hydrazines à l'état solide a été discutée. Les essais biologiques ont démontré une activité avérée des dérivés de l'isoniazide dans l'inhibition de Mycobacterium tuberculosis. Les résultats présentés dans cette thèse englobent plusieurs aspects très complémentaires de la mécanochimie. L'approche fondamentale du mécanisme est d'un accès difficile, en raison de la complexité du système, mais des avancées ont été réalisées comme la mise en évidence d'intermédiaires à longue durée de vie. Les paramètres du procédé apportent une contribution à la compréhension du mécanisme mais aussi en vue du scaling-up. Enfin, la mécanosynthèse s'est révélée être une méthode de chimie verte particulièrement adaptée à la synthèse d'hydrazones d'intérêt pharmaceutique, pour le screening de nouvelles entités ou la synthèse durable de produits de grande pureté. / One of the goals of pharmaceutical and chemical industries is the development of green processes that eliminates or reduces the use of solvents. However, avoiding solvents often requires the use of metal catalysts or others, that accelerates chemical reactions, but make the purifications difficult, especially in the case of fine chemical products, such as active pharmaceutical ingredients. The mechanochemistry has emerged as a sustainable way that enables chemical synthesis, including organic molecular transformations, using the mechanical energy. In spite of the recent advances of the methodology, some aspects of the mechanical action still remain to be fully elucidated, mainly concerning the mechanisms. In this thesis, three main axes of mechanochemistry were explored. First, the molecular mechanism of 1,4-diazine mechanosynthesis, mentioning dibenzo[a,c]phenazine (DBPZ) and 2,3-diphenylquinoxaline (DPQ), is investigated by using 13C CP-MAS NMR that reveals intermediate species for DBPZ, and by calorimetric measurements that show continuation of the reaction after grinding for both reactions. The possibility of a concerted mechanism is considered for dibenzo[a,c]phenazine case. The second focus is on 2,3-diphenylquinoxaline product formation. The process parameters for a vibratory ball mill were studied. Grinding material, size and mass of the balls, granulometry of the starting material were assessed, as well as the temperature of the milling media, providing apparent activation energy (Ea). Arrhenius and Eyring-Polanyi plots presented changes in Ea indicating changes in mechanism, which was attributed to a possible mechanically induced eutectic melting after 30°C. Finally, after understanding some fundamentals and processes for those model reactions, the mechanochemical route was successfully applied to solid-state synthesis of pharmaceutically attractive phenolic hydrazones and catalyzed isoniazid derivatives synthesis, by reacting solid aldehydes and hydrazines. In general, the products were obtained in shorter times and in higher yields compared to classical thermal route. The roles of electronic and solid-state reactivity of the hydrazines were discussed. Biological assays demonstrated the great activity of isoniazid derivatives in inhibiting Mycobacterium tuberculosis. The results presented here cover the mechanochemistry at different levels. The fundamental comprehension is still difficult to access due to the complexity of the system, but some advances could be made such as the detection of intermediate species with significant lifetime. The process parameters are equally important to deduce some mechanism, but also for scale up purposes. At last, the mechanosynthesis of hydrazones showed to be a greener route to produce pharmaceuticals, for high screening of new ones, as well as for the synthesis of others, with great purity and waste reduction.

The search for the ideal, environmentally friendly and preferably cheap solvent has been a persistent topic in general chemistry. Hence, the effort in the development of “green” solvents and processes skyrocketed in the recent past. However, a replacement of solvents does not deal with the problem at hand – it is just a small fix, not a big innovation. Taking this into consideration, what is the big innovation needed in chemistry? If one considers solvents as the problem, then the logical step is to simply get rid of them altogether. One approach to conduct reactions in the absence of solvents is mechanochemistry. Initiated and/or sustained by mechanical energy, mechanochemical reactions offer a sustainable alternative to many wet-chemical methods. Innovative uses thereof have made their way into the fields of pharmaceuticals, material synthesis and, foremost, organic chemistry, where the vast potential of this rediscovered field has been demonstrated. In this context, I have dedicated this thesis to establish mechanochemical protocols for the fields of polymers and nanographenes. Both of those topics are, at the moment, dominated by solution-based synthesis, although the compounds produced are hardly soluble.

No description available.

Die strukturelle Vielfalt von Metallphosphonaten macht sie zu vielversprechenden Kandidaten für vielzählige Anwendungen, erschwert aber zugleich eine planmäßige Synthese. Die Untersuchung der Bildungsmechanismen kristalliner Übergangs-metallphosphonate stellt Zusammenhänge zwischen Synthesebedingungen und resultierender Struktur her. In dieser Arbeit wurden unterschiedliche Phosphonsäuren mit divalenten Metallionen umgesetzt und so verschiedene Metallphosphonate mit diversen Strukturen erhalten. Die Kristallstrukturen neuer Verbindungen wurden mittels Röntgenpulver-diffraktometrie aufgeklärt. Systematische Untersuchungen zeigten einen direkten Zusammenhang zwischen bestimmten Strukturmotiven und Eigenschaften der Verbindungen. Das Bestreben nach umweltfreundlichen und wirtschaftlichen Synthesemethoden wird durch die Mechanochemie erfüllt. Die zugrundeliegenden Reaktions-mechanismen liegen im Dunkeln, sodass Mechanochemie größtenteils als „trial and error“-Methode funktioniert. In situ Untersuchungen mechanochemischer Reaktionen erlauben die Aufklärung der Reaktionswege und weitere Optimierung der Prozesse. Nach der Optimierung des experimentellen Aufbaus wurde in dieser Arbeit eine Kombination der Methoden Röntgenpulverdiffraktometrie und Thermographie zur Aufklärung der Bildungmechanismen von Metallphosphonaten eingesetzt. Die Ergebnisse der in situ Untersuchungen zeigen die Bildung von Metallphosphonaten als dreistufigen Prozess, der über einen nicht-kristallinen Zustand verläuft. / The structural diversity of metal phosphonates makes them promising candidates for numerous applications, but at the same time makes planned synthesis difficult. The study of the formation mechanisms of crystalline transition metal phosphonates establishes correlations between synthesis conditions and resulting structure. In this work, different phosphonic acids were reacted with divalent metal ions to obtain various metal phosphonates with diverse structures. The crystal structures of new compounds were solved by X-ray powder diffraction. Systematic studies showed a direct correlation between certain structural motifs and properties of the compounds. The search for environmentally friendly and economical synthesis methods is met by mechanochemistry. The underlying reaction mechanisms are unclear, so mechanochemistry functions largely as a "trial and error" method. In situ studies of mechanochemical reactions allow the elucidation of reaction pathways and further optimization of processes. After optimizing the experimental setup, a combination of X-ray powder diffraction and thermography methods was used in this work to elucidate the formation mechanisms of metal phosphonates. The results of the in situ investigations show the formation of metal phosphonates as a three-step process proceeding via a non-crystalline state.