We report the first cocrystal as an intermediate in a solidstate organic reaction wherein molecules of barbituric acid and vanillin assume a favorable orientation for the subsequent Knoevenagel condensation.The Knoevenagel condensation is an important carbon-carbon bond forming reaction. More than a hundred years after the original report by Knoevenagel, 1 Suzuki 2 and Kaupp 3 demonstrated an efficient and quantitative Knoevenagel condensation in the solid state achieved by milling. Other studies of solvent-free Knoevenagel condensation reactions soon followed. 4-10 The reaction of barbituric acid (barb) and vanillin (van) was even used as a model mechanochemical organic reaction for assessing energetics of milling, 11,12 to test twin-screw extrusion for solid-state organic synthesis, 13 and latest, to reveal a peculiar deviation of solid-state reaction kinetics from the one observed in solution, stemming from changes in the rheology of the milled sample. 14 However, studies of barb-van Knoevenagel condensation were thus far limited to ex situ reaction monitoring by, e.g., solution UV-Vis 11 or NMR spectroscopies. 14 In this work, we employ real-time in situ Raman spectroscopy monitoring 15,16 to reveal that the solid-state Knoevenagel condensation (Scheme 1) of barb and van proceeds through a cocrystal intermediate. In the cocrystal, packing of barb and van is such that molecules of barb are suitably positioned for the nucleophilic

We present a solvent-free, green and rapid mechanochemical route for the synthesis of a series of zirconium metal-organic frameworks (MOFs) comprised of Zr6-cluster nodes, UiO-66, UiO-66-NH2, MOF-801 and MOF-804, both on a laboratory scale and by scalable and flow mechanochemical processing. The methodology, based on the use of a non-conventional

We report herein quantitative in situ monitoring by simultaneous PXRD and Raman spectroscopy of the mechanochemical reaction between benzoic acid and nicotinamide, affording a rich polymorphic system with four new cocrystal polymorphs, multiple phase transformations, and a variety of reaction pathways. After observing polymorphs by in situ monitoring, we were able to isolate and characterize three of the four polymorphs, most of which are not accessible from solution. Relative stabilities among the isolated polymorphs at ambient conditions were established by slurry experiments. Using two complementary methods for in situ monitoring enabled quantitative assessment and kinetic analysis of each studied mechanochemical reaction, even when involving unknown crystal structures, and short-lived intermediates. In situ Raman monitoring was introduced here also as a standalone laboratory technique for quantitative assessment of mechanochemical reactions and understanding of mechanochemical reactivity. Our results provide an important step toward a complete and high-throughput quantitative approach to mechanochemical reaction kinetics and mechanisms, necessary for the development of the mechanistic framework of milling reactions.

Mechanochemical milling reactions have received much attention recently as a green and highly efficient path toward various relevant materials. Control over the fundamental reaction parameters in the milling procedure, such as temperature and pressure of the reactor, is still in its infancy, and the vast majority of milling reactions are done by controlling just the basic parameters such as frequency and milling media weight. We demonstrate here how milling under controlled, prolonged, and variable heating programs accomplished in a new milling reactor introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures and also reduces the time and energy costs of the milling process. The methodology is demonstrated on four varied systems: C−C bondforming Knoevenagel condensation, selective C−N bond formation for amide/urea synthesis, selective double-imine condensation, and solid-state formation of an archetypal open metal-organic framework, MOF-74. The potential of this methodology is best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine, or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even a moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity.

In situ Raman spectroscopy was employed to study the course of a mechanochemical nucleophilic substitution on a carbonyl group. We describe evidence of base catalysis, akin to catalysis in solution, achieved by liquid-assisted grinding.

Using tandem in situ monitoring and isotope-labeled solids, we reveal that mechanochemical ball-milling overcomes inherently slow solid-state diffusion through continuous comminution and growth of milled particles. This process occurs with or without a net chemical reaction and also occurs between solids and liquid additives which can be practically used for highly efficient deuterium labeling of solids. The presented findings reveal a fundamental aspect of milling reactions and also delineate a methodology that should be considered in the study of mechanochemical reaction mechanisms.

We demonstrate a controllable mechanochemical synthesis of cocrystal polymorphs of ascorbic acid (vitamin C) and nicotinamide (vitamin B3) on different scales and without using bulk solvents. Next to the previously described polymorph of the 1:1 cocrystal, which is one of the first cocrystals approved for human consumption, we report here a new, thermodynamically more stable polymorph detected during in situ synchrotron powder X-ray diffraction monitoring of milling reactions. The new polymorph is currently available exclusively by mechanochemical synthesis, and its crystal structure was determined from powder X-ray diffraction data. Laboratory in situ monitoring by Raman spectroscopy provided direct insight into the cocrystals formation and was further used to optimize the manufacturing procedure. Sub-gram synthesis using laboratory mixer mill was transferred to the 10 g scale on a planetary ball mill and continuous manufacturing using a twin-screw extruder. Both cocrystal polymorphs perform excellently in tableting, thus alleviating the notoriously poor compactible properties of vitamin C, while the mechanochemical cocrystallization does not harm its antioxidant properties. File list (3) download file view on ChemRxiv Stolar_manuscript_control of cocrystal polymorphism.pdf (1.52 MiB) download file view on ChemRxiv Stolar_SI_control of cocrystal polymorphism.pdf (814.41 KiB) download file view on ChemRxiv TOC.tif (115.72 KiB) Control of pharmaceutical cocrystal polymorphism on various scales by mechanochemistry: transfer from the laboratory batch-to the large-scale extrusion processing

Mechanochemical milling reactions gained a lot of attention lately as a green and highly efficient path towards various relevant materials. The control over the fundamental reaction parameters in milling procedure, such as temperature and pressure of the reactor, is still in infancy and the vast majority of milling reactions is done with controlling just the basic parameters such as frequency and milling media weight. We demonstrate here how the milling under controlled, prolonged and variable heating programs accomplished in a new milling reactor introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures, and also reduces the time and energy costs of the milling process. The methodology is demonstrated on four varied systems: C–C bond forming Knoevenagel condensation, selective C–N bond formation for amide/urea synthesis, selective double-imine condensation, and solid-state formation of an archetypal open metal-organic framework, MOF-74. The potential of this methodology is best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even the moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity.