Ivan Halasz

Real-time and in situ monitoring of mechanochemical milling reactions

Chemical and structural transformations have long been carried out by milling. Such mechanochemical steps are now ubiquitous in a number of industries (such as the pharmaceutical, chemical and metallurgical industries), and are emerging as excellent environmentally friendly alternatives to solution-based syntheses. However, mechanochemical transformations are typically difficult to monitor in real time, which leaves a large gap in the mechanistic understanding required for their development. We now report the real-time study of mechanochemical transformations in a ball mill by means of in situ diffraction of high-energy synchrotron X-rays. Focusing on the mechanosynthesis of metal-organic frameworks, we have directly monitored reaction profiles, the formation of intermediates, and interconversions of framework topologies. Our results reveal that mechanochemistry is highly dynamic, with reaction rates comparable to or greater than those in solution. The technique also enabled us to probe directly how catalytic additives recently introduced in the mechanosynthesis of metal-organic frameworks, such as organic liquids or ionic species, change the reactivity pathways and kinetics.

In situ X-ray diffraction monitoring of a mechanochemical reaction reveals a unique topology metal-organic framework.

Chemical and physical transformations by milling are attracting enormous interest for their ability to access new materials and clean reactivity, and are central to a number of core industries, from mineral processing to pharmaceutical manufacturing. While continuous mechanical stress during milling is thought to create an environment supporting nonconventional reactivity and exotic intermediates, such speculations have remained without proof. Here we use in situ, real-time powder X-ray diffraction monitoring to discover and capture a metastable, novel-topology intermediate of a mechanochemical transformation. Monitoring the mechanochemical synthesis of an archetypal metal-organic framework ZIF-8 by in situ powder X-ray diffraction reveals unexpected amorphization, and on further milling recrystallization into a non-porous material via a metastable intermediate based on a previously unreported topology, herein named katsenite (kat). The discovery of this phase and topology provides direct evidence that milling transformations can involve short-lived, structurally unusual phases not yet accessed by conventional chemistry.

Real-time in situ powder X-ray diffraction monitoring of mechanochemical synthesis of pharmaceutical cocrystals.

Looking in: The penetrating power of high-energy X-rays provides a means to monitor in situ and in real time the course of ball-milling reactions of organic pharmaceutical solids by detecting crystalline phases and assessing the evolution of their particle sizes. Upon switching from neat grinding to liquid-assisted grinding, cocrystal formation is enabled or tremendously accelerated, while the reaction mechanism alters its course.

Mechanosynthesis of the Metallodrug Bismuth Subsalicylate from Bi2O3 and Structure of Bismuth Salicylate without Auxiliary Organic Ligands

Mechanochemical reactions are versatile for the synthesis of new pharmaceutical forms, particularly cocrystals, salts and, since very recently, coordination complexes. Mechanochemistry can be very efficient for the synthesis of metal–organic frameworks (MOFs) and magnesium-based pharmaceuticals directly from inexpensive and otherwise inert materials, such as metal oxides or carbonates. In addition to short reaction times and the lack of bulk solvents, oxide-based mechanosynthesis also has the advantage of generating water as the sole byproduct. We now demonstrate how ionand liquid-assisted grinding (ILAG), previously utilized for the mechanosynthesis of large-pore MOFs and zeolitic imidazolate frameworks 6] based on zinc, can be extended to the pharmaceutical chemistry of bismuth oxide. We demonstrate the rapid and efficient conversion of Bi2O3 into a variety of bismuth salicylate complexes, including the commercial active pharmaceutical ingredient (API) bismuth subsalicylate (1), marketed under the trade name Pepto-Bismol. The pharmaceutical value of bismuth complexes with salicylic acid (H2sal) has been established over a century ago and still remains an area of active research. At least three different forms of bismuth salicylate, which differ in the stoichiometric ratio of bismuth and H2sal, have been reported. These are the API bismuth subsalicylate BiO(Hsal), the disalicylate (2) with assigned formula Bi2O(Hsal)4, [8] and the trisalicylate (3) involving bismuth and salicylic acid in the 1:3 stoichiometric ratio. Until now, the structure for any of these materials has remained unknown. Models for 1 and its biological activity were initially devised by Thurston et al. who used auxiliary chelating ligands to trap discrete oligonuclear clusters of Bi and salicylate anions (Hsal ), and by Burford et al. who explored complexation of Bi with thiosalicylic acid. The potential of mechanochemistry to generate bismuth carboxylates was revealed by Andrews and co-workers, 12] who investigated combined mechanoand thermochemical routes involving carboxylic acids and triphenylbismuth. With H2sal this approach provides different organobismuth salicylates unless the ratio of Bi to acid is 1:3, in which case it leads to the tricarboxylate 3 (Figure 1a). Recrystallization of 3 from acetone yielded metal–organic clusters containing coordinated solvent that are currently the best models for the structure of 1 (Figure 1b). Unfortunately, this synthetic pathway is of limited use due to regulatory aspects of organobismuth precursor and the formation of aromatic hydrocarbon byproducts.

Laboratory Real‐Time and In Situ Monitoring of Mechanochemical Milling Reactions by Raman Spectroscopy

Mechanistic understanding of mechanochemical reactions is sparse and has been acquired mostly by stepwise ex situ analysis. We describe herein an unprecedented laboratory technique to monitor the course of mechanochemical transformations at the molecular level in situ and in real time by using Raman spectroscopy. The technique, in which translucent milling vessels are used that enable the collection of a Raman scattering signal from the sample as it is being milled, was validated on mechanochemical reactions to form coordination polymers and organic cocrystals. The technique enabled the assessment of the reaction dynamics and course under different reaction conditions as well as, for the first time, direct insight into the behavior of liquid additives during liquid-assisted grinding.

The curious case of (caffeine)·(benzoic acid): How heteronuclear seeding allowed the formation of an elusive cocrystal

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals, yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)·(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, hence to identify appropriate heteronuclear seeds for cocrystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly they (or seeds of the product cocrystal) continued to act as long-lasting laboratory “contaminants”, which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research.

A model for a solvent-free synthetic organic research laboratory: click-mechanosynthesis and structural characterization of thioureas without bulk solvents

The mechanochemical click coupling of isothiocyanates and amines has been used as a model reaction to demonstrate that the concept of a solvent-free research laboratory, which eliminates the use of bulk solvents for either chemical synthesis or structural characterization, is applicable to the synthesis of small organic molecules. Whereas the click coupling is achieved in high yields by simple manual grinding of reactants, the use of an electrical, digitally controllable laboratory mill provides a rapid, quantitative and general route to symmetrical and non-symmetrical aromatic or aromatic–aliphatic thioureas. The enhanced efficiency of electrical ball milling techniques, neat grinding or liquid-assisted grinding, over manual mortar-and-pestle synthesis is demonstrated in the synthesis of 49 different thiourea derivatives. Comparison of powder X-ray diffraction data of mechanochemical products with structural information found in the Cambridge Structural Database (CSD), or obtained herein through single crystal X-ray diffraction, indicates that the mechanochemically obtained thiourea derivatives are pure in a chemical sense, but can also demonstrate purity in a supramolecular sense, i.e. in all structurally explored cases the product consisted of a single polymorph. As an extension of our previous work on solvent-free synthesis of coordination polymers, it is now demonstrated that such polymorphic and chemical purity of selected thiourea derivatives, the latter being evidenced through quantitative reaction yields, can enable the direct solvent-free structural characterization of mechanochemical products through powder X-ray diffraction aided by solid-state NMR spectroscopy.

In situ and real-time monitoring of mechanochemical milling reactions using synchrotron X-ray diffraction

We describe the only currently available protocol for in situ, real-time monitoring of mechanochemical reactions and intermediates by X-ray powder diffraction. Although mechanochemical reactions (inducing transformations by mechanical forces such as grinding and milling) are normally performed in commercially available milling assemblies, such equipment does not permit direct reaction monitoring. We now describe the design and in-house modification of milling equipment that allows the reaction jars of the operating mill to be placed in the path of a high-energy (∼90 keV) synchrotron X-ray beam while the reaction is taking place. Resulting data are analyzed using conventional software, such as TOPAS. Reaction intermediates and products are identified using the Cambridge Structural Database or Inorganic Crystal Structure Database. Reactions are analyzed by fitting the time-resolved diffractograms using structureless Pawley refinement for crystalline phases that are not fully structurally characterized (such as porous frameworks with disordered guests), or the Rietveld method for solids with fully determined crystal structures (metal oxides, coordination polymers).

Mechanosynthesis of nitrosobenzenes: a proof-of-principle study in combining solvent-free synthesis with solvent-free separations

Mechanochemical Oxone oxidation of selected para-substituted anilines was used as a rapid and solvent-free route to nitrosobenzenes; besides avoiding bulk solvents and short reaction times, this method exploits high vapour pressures of nitrosobenzenes for the solvent-free separation of the product by sublimation, demonstrating an entirely solvent-free route to chemical synthesis and product isolation.

Dynamic Molecular Recognition in Solid State for Separating Mixtures of Isomeric Dicarboxylic Acids

Molecular recognition emerges from non-covalent interactions and is of paramount importance for understanding of biological processes, ranging from enzymatic activity to DNA base pairing, as well as in the design of functional supramolecular systems, for example, molecular motors, sensors, ion receptors, or systems used in waste management. In the specific area of selective anion binding, numerous anion receptors (hosts) and sensors have been developed. The study of anion binding has traditionally been performed in solution where the host often experiences conformational freedom to form complexes with a wide range of guests. However, selectivity in separation has usually been achieved only upon crystallization, emphasizing the importance of intermolecular interactions in rigid crystal environment which lock the conformation of the host giving rise to its selectivity. In this context, recent advances in chemical reactivity achieved using mechanochemistry indicate that the concepts of supramolecular chemistry, such as templating, may be applicable also to solvent-free reactions. Mechanochemical reactivity can be highly dynamic and has thus far been employed for solid-state differentiation between enantiomers, supramolecular metathesis reactions, and for thermodynamic product selection. Although these reactions show specific interaction patterns between molecules comprising their respective solid phases, the possibility of selective binding and separation of target guest molecules from solid mixtures is, besides the pioneering studies by Etter and Caira, still an unexplored area. Here we focus on recognition and separation of isomeric or geometrically similar dicarboxylic acids (Scheme 1) from either their solid or solution mixtures using principles of supramolecular chemistry. The chosen acids belong to a class of guests of high biological and industrial relevance, and a considerable effort has been put into developing their sensors and receptors. Typically, the receptor for each dicarboxylate had to be meticulously designed because of the specific geometry of each acid molecule and their differing physicochemical properties. The importance of separation of the maleic/fumaric acid (H2mal/H2fum) stereoisomeric pair is not only related to the specific diastereomer recognition, but also arises from their conflicting biochemical behavior and abundant use of H2fum in food and pharmaceutical industry. We show here that the flexible polyamine receptor L (Scheme 1) discriminates among H2mal/H2fum diastereomers, succinic acid (H2suc), and three isomers of benzenedicarboxylic acid, by adapting its conformation and finally forming different solid hydrogenbonded (HB) frameworks. Regardless of whether the recognition takes place in the solid state by milling or by crystallization from solution, the resulting supramolecular complexes are the same and the selectivity bias of L towards the guest acids is fully retained. Milling improved yields to quantitative and almost eliminated the use of solvent. L proved to be an exceptional receptor for H2mal, also on the gram scale, excluding it from solid mixtures with even five other acids or from mixtures where there is a large surplus of a competing acid. Reacting L and H2mal in methanol (MeOH) or ethanol (EtOH) solutions yielded isoskeletal solvated solids, 1a (Table 1 and Section S.2 in the Supporting Information), Scheme 1. Dicarboxylic acids and the polyamine host L. The host binds anions as a cation (HL) resulting from protonation of the central amino group.