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

Tetratopic porphyrin-based MOFs represent a particularly interesting subclass of zirconium MOFs due to the occurrence of several divergent topologies. The control over the target topology is a demanding task and reports often show products containing phase contamination. We demonstrate how mechanochemistry can be exploited for controlling the polymorphism in 12-coordinated porphyrinic zirconium MOFs, gaining pure hexagonal (shp) PCN-223 and cubic (ftw) MOF-525 phases in 20-60 minutes of milling. The reactions are mainly governed by the milling additives and the zirconium precursor. In situ monitoring by synchrotron powder X-ray diffraction (PXRD) revealed that specific reaction conditions resulted in the formation of MOF-525 as an intermediate, which rapidly converted to PCN-223 upon milling. Electron spin resonance (ESR) measurements revealed significant differences between the spectra of paramagnetic centers in two polymorphs, showing a potential of polymorphic Zr-MOFs as tunable supports in spintronics applications. Metal-organic frameworks (MOFs) received wide attention due to their potential for applications in gas storage 1-3 and separation, 4,5 catalysis, 6,7 drug delivery, 8 light-harvesting, 9,10 and destruction of harmful compounds such as chemical warfare agents. 11 Their superior performance stems from the existence of pores and channels enabling easy access of substrates to the active sites inside the MOF crystals. The use of MOFs as heterogeneous catalysts and catalysts supports is broadened after the introduction of Zr-MOFs based on zirconium [Zr6(OH)4O4] 12+ oxo-clusters and carboxylate linkers, 12 which provided a way to overcome challenges related to the robustness of MOFs under humid, acidic or basic media. 11,13 They also drew significant interest in an area of MOF-polymorphism. Zr-MOFs based on tetratopic tetrakis(4-carboxyphenyl) porphyrin (TCPP) linkers displayed unprecedented flexibility in topological ordering. They are known to exist in six different topologies, 14,15-22 12-connected cubic ftw (MOF-525) 21 and hexagonal shp (PCN-223), 16 8-connected sqc (PCN-225), 17 csq (PCN-222/MOF-545), 19,21 and scu (NU-902), 15 and 6-connected she (PCN-224). 20 Recent studies have been focused on establishing different reaction

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.

PurposeThe assessment of ovarian reserve by antral folicule count (AFC) following electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas. MethodsForty-five patients between 18 and 35 years, with unilateral endometriomas were randomly analyzed. Laparoscopic cystectomy was performed by the stripping method. Ovarian haemostasis was obtained either by suturing (group A, n = 23) or by bipolar electrocoagulation (group B, n = 22). AFC was performed by ultrasound on the third day of the three postoperative menstrual cycles. The sum of AFC was compared between sutured (A1) and electrocoagulated (B1) ovaries, as well as between intact ovaries of both groups (A0 -intact ovaries in sutured group; B0 -intact ovaries in electrocoagulated group). ResultsThe median of AFC was significantly lower in operated ovaries than in intact ovaries in both groups of patients, regardless of suturing (A1 median: 12 (range 9-19) versus A0 median: 21.0 (range 15-27), p<0.05) or electrocoagulation (B1:5.0 (2-10) vrs B0:18.5 (8-29) p<0.05). The median AFC was significantly higher in sutured ovaries than in electrocoagulated ovaries (A1:12 (9-19) vrs B1:5.0 (2-10), p<0.05). ConclusionOur preliminary data show that operation on ovarian endometriomas could reduce ovarian reserve. The AFC value suggests that the ovarian reserve was less reduced in sutured ovaries than in those electrocoagulated. Suturing as a method of haemostasis could be a better choice after stripping ovarian endometriomas.

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Mechanism of C-H bond activation by various Pd catalysts under milling conditions has been studied by in situ Raman spectroscopy. Common Pd precursors, that is PdCl , [Pd(OAc) ] , PdCl (MeCN) and [Pd(MeCN) ][BF ] , have been employed for the activation of one or two C-H bonds in an unsymmetrical azobenzene substrate. The C-H activation was achieved by all used Pd precursors and their reactivity increases in the order [Pd(OAc) ]

The mechanism of mechanochemical Pd II -catalyzed selective bromination of the carbon−hydrogen bond in azobenzene by N-bromosuccinimide (NBS) was investigated using in situ timeresolved Raman spectroscopy and quantum-chemical (density functional theory, DFT) calculations. Raman monitoring of the reactions in the presence of different amounts of Pd(OAc) 2 , ptoluenesulfonic acid (TsOH), and acetonitrile (MeCN) as solid and liquid additives provided direct evidence that the formation of the carbon−halogen bond in the solid state proceeds from catalytically active cyclopalladated intermediates that are monomeric in the presence of MeCN or dimeric without MeCN. The reaction pathway via the monomeric palladacycle is more efficient than the pathway via the dimeric palladacycle for the bromination of azobenzene, offering better yields and faster reactions. Both reaction routes require the presence of TsOH, which is involved in the formation of the active Pd II catalysts and palladacyclic intermediates, as well as in the activation of NBS. Four possible reaction mechanisms for the bromination of cyclopalladated azobenzene were investigated by DFT modeling. Three mechanistic pathways include (i) oxidative addition of the Br to Pd atom and (ii) reductive elimination by the 1,2-displacement of Br to the carbon atom. In one pathway, the transfer of Br to Pd occurs only after the initial displacement of the neutral ligand by NBS. In another, the Pd atom is inserted directly into the N−Br bond of NBS, and in the last one, Br + migrates spontaneously from the protonated NBS to Pd. In all three cases, the subsequent elimination step is remarkably lower in energy. In the fourth mechanism, Br + migrates from free NBS directly to the activated carbon, simultaneously with the Pd−C bond breaking. Besides NBS, the hydrogen bond complex NBS•••TsOH was also considered as the bromine source. None of the considered mechanisms can be definitely rejected on the basis of experimental findings and the current modeling level, and more than one could be operative depending on the reaction conditions.

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