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Solid-state milling has emerged as an alternative, sustainable approach for preparing virtually all classes of compounds and materials. In situ reaction monitoring is essential to understanding the kinetics and mechanisms of these reactions, but it has proved difficult to use standard analytical techniques to analyze the contents of the closed, rapidly moving reaction chamber (jar). Monitoring by Raman spectroscopy is an attractive choice, because it allows uninterrupted data collection from the outside of a translucent milling jar. It complements the already established in situ monitoring based on powder X-ray diffraction, which has limited accessibility to the wider research community, because it requires a synchrotron X-ray source. The Raman spectroscopy monitoring setup used in this protocol consists of an affordable, small portable spectrometer, a laser source and a Raman probe. Translucent reaction jars, most commonly made from a plastic material, enable interaction of the laser beam with the solid sample residing inside the closed reaction jar and collection of Raman-scattered photons while the ball mill is in operation. Acquired Raman spectra are analyzed using commercial or open-source software for data analysis (e.g., MATLAB, Octave, Python, R). Plotting the Raman spectra versus time enables qualitative analysis of reaction paths. This is demonstrated for an example reaction: the formation in the solid state of a cocrystal between nicotinamide and salicylic acid. A more rigorous data analysis can be achieved using multivariate analysis. This protocol describes how to set up and use Raman spectroscopy for monitoring the course of solid-state reactions in vibratory ball mills, which will help increase our understanding of the mechanisms and kinetics of mechanochemical reactions.

Owing to its efficiency and unique reactivity, mechanochemical processing of bulk solids has developed into a powerful tool for the synthesis and transformation of various classes of materials. Nevertheless, mechanochemistry is primarily based on simple techniques, such as milling in comminution devices. Recently, mechanochemical reactivity has started being combined with other energy sources commonly used in solution-based chemistry. Milling under controlled temperature, light irradiation, sound agitation or electrical impulses in newly developed experimental setups has led to reactions not achievable by conventional mechanochemical processing. This Perspective describes these unique reactivities and the advances in equipment tailored to synthetic mechanochemistry. These techniques — thermo-mechanochemistry, sono-mechanochemistry, electro-mechanochemistry and photo-mechanochemistry — represent a notable advance in modern mechanochemistry and herald a new level of solid-state reactivity: mechanochemistry 2.0. Mechanochemistry is the science of inducing a chemical reaction through the application of mechanical force. This Perspective focuses on combining traditional mechanochemistry with different energy inputs — heat, light, sound or electrical impulses — to advance mechanochemical synthesis.

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. Ball milling chemical reactions are of interest due to their environmental credentials and potential to achieve new reactions and materials. Here, the authors isolate a metastable material with a previously unknown net topology by in situ monitoring of the mechanosynthesis of a metal organic framework.

Copper-catalyzed mechanochemical click reactions using Cu(II), Cu(I) and Cu(0) catalysts have been successfully implemented to provide novel 6-phenyl-2-(trifluoromethyl)quinolines with a phenyl-1,2,3-triazole moiety at O-4 of the quinoline core. Milling procedures proved to be significantly more efficient than the corresponding solution reactions, with up to a 15-fold gain in yield. Efficiency of both solution and milling procedures depended on the p -substituent in the azide reactant, resulting in H < Cl < Br < I reactivity bias. Solid-state catalysis using Cu(II) and Cu(I) catalysts entailed the direct involvement of the copper species in the reaction and generation of highly luminescent compounds which hindered in situ monitoring by Raman spectroscopy. However, in situ monitoring of the milling processes was enabled by using Cu(0) catalysts in the form of brass milling media which offered a direct insight into the reaction pathway of mechanochemical CuAAC reactions, indicating that the catalysis is most likely conducted on the surface of milling balls. Electron spin resonance spectroscopy was used to determine the oxidation and spin states of the respective copper catalysts in bulk products obtained by milling procedures.

Mechanochemical milling of equimolar mixtures of salicylic acid with three hydroxy derivatives of pyridine provided three new phases. With 2-hydroxypyridine, which is in fact present as 2-pyridone, a discrete cocrystal supramolecular assembly is formed. 3-hydroxypyridine and salicylic acid formed a salt and an extended network of hydrogen bonds while the product of the reaction of 4-hydroxypyridine (present as 4-pyridone) and salicylic acid remained structurally uncharacterized. All three hydroxypyridines retain the tautomeric form as in their respective pure phases upon cocrystal formation. Where possible, reaction profiles have been extracted from in situ monitoring via Rietveld refinement to show direct product formation which could be well described using the first-order reaction rate law. Keywords: cocrystal, mechanochemistry, in situ monitoring, salicylic acid, hydroxypyridine.

Several phenylenediamine derivatives of dehydroacetic acid, 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one have been synthesized and their structure elucidated by using NMR and IR spectroscopies and mass spectrometry. Spectral analyses have pointed toward the localized keto-amine form as the predominant tautomeric form in solution and solid-state which was in agreement with X-ray data. The relatively broad N-H stretching bands observed in IR spectra and significant N-H proton down-field and keto C=O up-field shifts in NMR spectra indicated the presence of intra-molecular hydrogen bonds in all studied compounds. In order to gain further insights into nature of these interactions in solution deuterated isotopomers have been prepared and deuterium isotope effects in ^sup 13^C NMR spectra have been determined and analyzed. The magnitude and sign of isotope effects have confirmed the existence of intra-molecular hydrogen bonds. Observed differences in isotope effects reflected different hydrogen bond structure and dynamics in studied compounds. The results presented in this paper might help in better understanding of biological properties of the related compounds. [PUBLICATION ABSTRACT]

For the first time, we directly measured the onset and completion temperatures of polymorphic transitions in thermo-mechanochemical reactions by simultaneous in situ synchrotron powder X-ray diffraction and temperature monitoring. We determined the thermo-mechanochemical polymorphic transition temperature in 1-adamantyl-1-diamantyl ether to be 31 °C lower than the transition temperature determined by DSC.

Direct amide bond formation involving carboxylic acids and amines predominantly involves solution-based reactions with coupling reagents and catalysts that result in poor sustainability performance. Here, we present a conceptually different approach, which includes simultaneous mechanical and thermal activation. Such an approach enables direct and quantitative conversion to amides starting from carboxylic acids and amines and avoids using activators and additives. As a model reaction, we studied the thermo-mechanochemical condensation of benzoic acid and p-toluidine, which gave N-(p-tolyl)benzamide almost quantitatively in gram-scale. We show that crystalline supramolecular arrangements between reactants act as intermediates that precede the formation of amides. The applicability of the methodology was demonstrated by a quantitative synthesis of moclobemide, a valuable active pharmaceutical ingredient. Finally, the sustainability assessment by green chemistry metrics highlights the atom-efficiency of our methodology.

The information molecule of the first life on Earth is presumably ribonucleic acid (RNA). RNA is a polymer built out of four canonical nucleobases: adenine (A), uracil(U), guanine (G), and cytosine (C). However, it remains unclear how canonical nucleobases got selected from the hundreds available in nature. Here, we show that the non-canonical nucleobase 2,6-diaminopurine (D) base pairs with U in water and the solid state without the need to be attached to the ribose-phosphate backbone. Dependingon the temperature and water availability in the system, D and U assemble in thermodynamically stable hydrated and anhydrated D-U base-paired cocrystals. Structural studies show that the water molecules contribute favorably to the stabilization energies in D-U cocrystal hydrate due to the role of water in forming inter-layer hydrogen bonds. In the anhydrate cocrystal form, D and U molecules exhibit advantageous homomeric stacking interactions and hydrogen bonding. Under UV irradiation, an aqueous solution of D-U base-pair undergoes photochemical degradation, while a pure aqueous solution of U does not, thus demonstrating that base-pairing alters the photostability of U. To understand this decreased photostability of U, we model the main channel forU photodestruction, i.e., covalent photodimerization. Our simulations suggest that D may trigger the U photodimerization because of its ability to form hydrogen bonds with π-stacking dimers of U. Our results indicate that complementary base-pairing of D and U in prebiotic surface environments may have played a role in chemical evolution. In a broader context, supramolecular interactions between small biological building blocks may offer new insights into the origin of life.

In this work the problem of characterizing matrix material structure from embedded electron spin decoherence is studied both theoretically and experimentally. Theoretical calculation using nuclear spin bath model and cluster correlation expansion method shows that the positions of decoherence time scale extremums among single crystal orientations of the matrix material coincide with those of the nearest neighbour proton dipolar couplings. This finding is confirmed by single crystal pulsed EPR experiment performed on \\(\\)-irradiated malonic acid (MA). Electron spin decoherence decay profile in polycrystalline matrix material is obtained from the orientation dependence as an average over sampled orientations on a Fibonacci grid. In addition, it is pointed out theoretically that a further removal of crystal ordering in the nuclear spin bath can reduce decoherence time scale from the polycrystalline value. This prediction is verified experimentally by the Hahn echo time decay scale in a new amorphous polymorph of MA, obtained for the first time by mechanical milling. Thus the embedded electron spin decoherence can be viewed as a quantitative indicator for studying structures and/or structure changes of the matrix material.