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Mechanochemistry has become a valuable tool for the synthesis of new molecules, especially in the field of organic chemistry. In the present work, we investigate the kinetic profile of the chlorination reaction of N-3-ethyl-5,5-dimethylhydantoin (EDMH) activated and driven by ball milling. The reaction has been carried out using 2 mm, 4 mm, 5 mm, 6 mm, and 8 mm ball sizes in a new small custom-made Perspex milling jar. The Crystal structure of the starting material EDMH and the 1-chloro-3-ethyl5,5′-dimethyl hydantoin (CEDMH) chlorination product was solved by single-crystal X-ray diffraction. The reaction was monitored, in situ and in real time, by both powder X-ray diffraction (PXRD) and Raman spectroscopy. Our kinetic data show that the reaction progress to equilibrium is similar at all milling ball sizes. The induction period is very short (between 10 and 40 s) when using 4 mm, 5 mm, 6 mm, and 8 mm balls. For the reaction performed with a 2 mm ball, a significantly longer induction period of 9 min was observed. This could indicate that an initial energy accumulation and higher mixing efficiency are necessary before the reaction starts. Using different kinetic models, we found that the amount of powder affected by critical loading conditions during individual impacts is significantly dependent on the ball size used. An almost linear correlation between the rate of the chemical transformations and the ball volume is observed.
The choice of solvents influences crystalline solid formed during the crystallization of active pharmaceutical ingredients (API). The underlying effects are not always well understood because of the complexity of the systems. Theoretical models are often insufficient to describe this phenomenon. In this study, the crystallization behavior of the model drug paracetamol in different solvents was studied based on experimental and molecular dynamics data. The crystallization process was followed in situ using time-resolved Raman spectroscopy. Molecular dynamics with simulated annealing algorithm was used for an atomistic understanding of the underlying processes. The experimental and theoretical data indicate that paracetamol molecules adopt a particular geometry in a given solvent predefining the crystallization of certain polymorphs
We present an in situ triple coupling of synchrotron X-ray diffraction with Raman spectroscopy, and thermography to study milling reactions in real time. This combination of methods allows a correlation of the structural evolution with temperature information. The temperature information is crucial for understanding both the thermodynamics and reaction kinetics. The reaction mechanisms of three prototypical mechanochemical syntheses, a cocrystal formation, a C@C bond formation (Knoevenagel condensation), and the formation
of a manganese-phosphonate, were elucidated. Trends in the temperature development during milling are identified. The heat of reaction and latent heat of crystallization of the product contribute to the overall temperature increase. A decrease in temperature occurs via release of, for example, water as a byproduct.
Solid and liquid intermediates are detected. The influence of the mechanical impact could be separated from temperature effects caused by the reaction.
The process of silicification in plants and the biochemical
effects of silica in plant tissues are largely unknown. To
study the molecular changes occurring in growing cells
that are exposed to higher than normal concentration of
silicic acid, Raman spectra of germinating pollen grains of
three species (Pinus nigra, Picea omorika, and Camellia
japonica) were analyzed in a multivariate classification
approach that takes into account the variation of biochemical
composition due to species, plant tissue structure,
and germination condition. The results of principal
component analyses of the Raman spectra indicate differences
in the utilization of stored lipids, a changed mobilization
of storage carbohydrates in the pollen grain bodies,
and altered composition and/or structure of cellulose of
the developing pollen tube cell walls. These biochemical
changes vary in the different species.
Control of organic polymorph formation: crystallization pathways in acoustically levitated droplets
(2017)
Theoretical and experimental studies indicate that crystal nucleation can take more complex pathways than expected on the ground of the classical nucleation theory. Among these pathways are the formation of pre-nucleation clusters and amorphous precursor phases. A direct in situ observation of the different pathways of nucleation from solution is challenging since the paths can be influenced by heterogeneous nucleation sites, such as container walls. Here, we provide insights into the crystallization process using the in situ combination of an acoustic levitator, Raman spectroscopy, and X-ray scattering. The contactless sample holder enables the observation of homogeneous crystallization processes and the detection of intermediates and final crystalline forms. We provide evidence for the existence of multiple pathways of nucleation based on the investigation of the crystallization of organic molecules from different solvents. Starting from a diluted solution, a supersaturation is reached during the experiment due to the evaporation of the solvent. The highly supersaturated solution reveals different pathways of crystallization. Depending on the degree of supersaturation either the thermodynamically stable or the metastable crystal form is observed.
The mechanochemical synthesis of two model compounds, a metal organic framework ([Bi(1,4-bdc)2]*(Im) (bdc = benzene dicarboxylate, Im = imidazole cation)) and a cocrystal (Carbamazepine:Indometacin 1:1) were followed ex situ by combined analytical methods. Powder X-ray diffraction (XRD) and Raman spectroscopy data were evaluated for the synthesis of the metal organic framework. XRD measurements and REM images were analysed for the synthesis of the cocrystal. The measurements revealed that both model compounds were synthesised within minutes. The metal organic framework [Bi(1,4-bdc)2]*(Im) is synthesised via an intermediate structure. The cocrystal Carbamazepine:Indometacin 1:1 is formed within few seconds and afterwards the crystallite size decreases extremely.
Carbamazepine (CBZ) is known for its variety of anhydrous and hydrous polymorphs. Herein, a thorough analysis of the crystallization behavior of CBZ is presented. The influence of the solvent and the concentration on the crystallization behavior under different environmental conditions is investigated by combined in situ XRD and Raman spectroscopy measurements. Crystallization studies conducted via conventional crystallization in glass tubes and in levitated droplets using an acoustic levitator indicate a dependence of the crystallization process from solvent and surface.
The unusually fast crystallization of the organic compound nifedipine has been investigated in detail using different solutions as precursors for the formation of the initial glassy nifedipine films. Starting from these amorphous films the crystallization process was investigated by time-resolved light microscopy at different temperatures around Tg of nifedipine. In all studied cases (acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran) the measured mean crystallization rates are, on average, 10000 times higher than rates reported in previous studies. Such high rates cannot be explained by a classical diffusional crystal growth mechanism of nifedipine. Instead, nifedipine shows a strong propensity for diffusionless growth. Solvent assisted or solvent induced preordering of the glassy modification is suggested to be the most probable driving force behind these fast crystallization processes. The nifedipine crystallization rates can be controlled not only by specific solvent–molecule interactions but also by temperature. Below 40 °C, the temperature dependence of the rates is generally small. Above 40 °C, a slowing down of the crystallization rates with increasing temperatures indicates a kinetic competition between different polymorphs. The molecular dynamics of nifedipine molecules in the amorphous phase as well as the relaxation times are studied by dielectric measurements. The dielectric data corroborate the inherently strong propensity of nifedipine to crystallize diffusionlessly under all conditions.
An unusually fast crystallization of the organic glass former nifedipine has been observed. The crystallization process, starting from an amorphous film to crystalline material, was investigated by time resolved Raman microspectroscopy. The crystallization rates of the initially crystallizing metastable β-form are four orders of magnitude higher than those of previous studies.
A combination of two analytical methods, time-resolved X-ray diffraction (XRD) and Raman spectroscopy, is presented as a novel tool for crystallization studies. An acoustic levitator was employed as sample environment. This setup enables the acquisition of XRD and Raman data in situ simultaneously within a 20 s period and hence permits investigation of polymorphic phase transitions during the crystallization process in different solvents (methanol, ethanol, acetone, dichloromethane, acetonitrile). These real time measurements allow the determination of the phase content from the onset of the first crystalline molecular assemblies to the stable system. To evaluate the capability of this approach, the setup was applied to elucidate the crystallization process of the polymorphic compound nifedipine. The results indicate the existence of solvent-dependent transient phases during the crystallization process. The quality of the data allowed the assignment of the lattice constants of the hitherto unknown crystal structure of the β-polymorph.