Accurate extrinsic and intrinsic peak broadening modelling for time-resolved in situ ball milling reactions via synchrotron powder X-ray diffraction.

The debate on the mechanisms which underpin mechanochemical reactions via ball mill grinding is still open. Our ability to accurately measure the microstructural (crystal size and microstrain) evolution of materials under milling conditions as well as their phase composition as a function of time is key to the in-depth understanding of the kinetics and driving forces of mechanochemical transformations. Furthermore, all ball milling reactions end with a steady state or milling equilibrium - represented by a specific phase composition and relative microstructure - that does not change as long as the milling conditions are maintained. The use of a standard sample is essential to determine the instrumental contribution to the X-ray powder diffraction (XRPD) peak broadening for time-resolved in situ (TRIS) monitoring of mechanochemical reactions under in operando conditions. Using TRIS-XRPD on a ball milling setup, coupled with low-energy synchrotron radiation, we investigated different data acquisition and analysis strategies on a silicon standard powder. The diffraction geometry and the microstructural evolution of the standard itself have been studied to model the instrumental contribution to XRPD peak broadening throughout the grinding activity. Previously proposed functions are here challenged and further developed. Importantly, we show that minor drifts of the jar position do not affect the instrumental resolution function significantly. We here report and discuss the results of such investigations and their application to TRIS-XRPD datasets of inorganic and organic ball mill grinding reactions.

Overcoming the Drawbacks of Sulpiride by Means of New Crystal Forms.

This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride.

On the Mechanism of Cocrystal Mechanochemical Reaction via Low Melting Eutectic: A Time-Resolved In Situ Monitoring Investigation.

Mechanochemistry has become a sustainable and attractive cost-effective synthetic technique, largely used within the frame of crystal engineering. Cocrystals, namely, crystalline compounds made of different chemical entities within the same crystal structure, are typically synthesized in bulk via mechanochemistry; however, whereas the macroscopic aspects of grinding are becoming clear, the fundamental principles that underlie mechanochemical cocrystallization at the microscopic level remain poorly understood. Time-resolved in situ (TRIS) monitoring approaches have opened the door to exceptional detail regarding mechanochemical reactions. We here report a clear example of cocrystallization between two solid coformers that proceeds through the formation of a metastable low melting binary eutectic phase. The overall cocrystallization process has been monitored by time-resolved in situ (TRIS) synchrotron X-ray powder diffraction with a customized ball milling setup, currently available at µSpot beamline at BESSY-II, Helmholtz-Zentrum Berlin. The binary system and the low melting eutectic phase were further characterized via DSC, HSM, and VT-XRPD.

Metal-organic framework-based magnetic dispersive micro-solid-phase extraction for the gas chromatography-mass spectrometry determination of polycyclic aromatic compounds in water samples.

A magnetic hybrid material based on the use of the mixed-ligand Metal-Organic Framework (MOF) PUM198 is proposed for the magnetic dispersive micro solid-phase extraction (MD-µSPE) of the 16 polycyclic aromatic hydrocarbons (PAHs) included in the US-EPA priority pollutants list. PUM198 is a thermally robust MOF characterized by a doubly interpenetrated microporous framework in which Zn2+ ions and carboxylate groups define 2D planes that are pillared by a bis-pyridine-bis amide ligand containing a biphenyl scaffold. PUM198 revealed to be ideal to adsorb PAHs efficiently through non-covalent interactions. A Plackett-Burman Design followed by a Central Composite Design and the multicriteria method of the desirability functions were applied to find the optimal conditions for the extraction of the investigated PAHs, resulting in a reduced solvent consumption, i.e., 50 µL of solvent per extraction for 5 mL of sample, approximatively 3-20 times lower than those reported in previous studies, thus satisfying the principles of green analytical chemistry. Method validation proved the reliability of the method for the determination of PAHs at trace level, obtaining detection limits in the 6.7-27 ng/L range, good precision with RSDs% lower than 19% and recovery rates in the 99 (±13)-126 (±8)% range near the quantitation limit. Finally, the applicability of the method was demonstrated by analyzing underground water samples taken from contaminated sites.

Bis-isonicotinoyl linkers containing polyaromatic scaffolds: synthesis, structure and spectroscopic properties.

In this study, a new series of extended linkers containing different polyaromatic chromophores (biphenyl, naphthalene, anthracene, fluorene, 9,9-dimethylfluorene and fluorenone) functionalized with isonicotinoyl moieties have been synthesized by Pd-catalyzed cross-coupling reactions involving isonicotinamide and the appropriate aromatic dibromide. The optimized protocol led to the isolation of the target molecules in good yield and with high purity. These were characterized by 1H NMR, FTIR, MS, and elemental analysis and their solid state structures were solved by single-crystal X-ray diffraction analysis. Electronic absorption and emission spectra were collected both in solution (DMF) and in the solid state. TDDFT calculations were carried out to investigate the effect of the isonicotinoyl moieties on the spectral features of the central chromophores. Although in solution only the linker containing a fluorenone scaffold shows a weak fluorescence, all the isolated linkers turned out to be fluorescent in the solid state, thus paving the way for their use for the fabrication of fluorescent MOFs.

Changing the game of time resolved X-ray diffraction on the mechanochemistry playground by downsizing.

Time resolved in situ (TRIS) monitoring has revolutionised the study of mechanochemical transformations but has been limited by available data quality. Here we report how a combination of miniaturised grinding jars together with innovations in X-ray powder diffraction data collection and state-of-the-art analysis strategies transform the power of TRIS synchrotron mechanochemical experiments. Accurate phase compositions, comparable to those obtained by ex situ measurements, can be obtained with small sample loadings. Moreover, microstructural parameters (crystal size and microstrain) can be also determined with high confidence. This strategy applies to all chemistries, is readily implemented, and yields high-quality diffraction data even using a low energy synchrotron source. This offers a direct avenue towards the mechanochemical investigation of reactions comprising scarce, expensive, or toxic compounds. Our strategy is applied to model systems, including inorganic, metal-organic, and organic mechanosyntheses, resolves previously misinterpreted mechanisms in mechanochemical syntheses, and promises broad, new directions for mechanochemical research.

On the nature of recurrent Au⋯π motifs in tris(2,2'-bipyridine)M(II) (M = Fe, Co and Ni) dicyanoaurate(I) salts: X-ray analysis and theoretical rationalization.

This manuscript reports the synthesis, X-ray characterization and DFT study of three new [M(bipy)3]2[Au(CN)2]3(X) (M = Fe, Co, and Ni; bipy = 2,2'-bipyridine; X = anion) ionic compounds. These salts are composed of [M(bipy)3]2+ dications and [Au(CN)2]- anions in a 2 : 3 ratio. The positive charge is compensated by X = Cl- anions in compounds 1 (M = Fe) and 2 (M = Co) and X = OH- in 3 (M = Ni). The three tridentate bipyridine ligands define the coordination of the M2+ cation, resulting in a nearly octahedral coordination sphere. The linear dicyanoaurate(I) anions are completely surrounded by a cradle of aromatic rings with Au-ring centroid distances below the sum of van der Waals radii, evidencing the existence of a specific Au⋯π attraction. This interaction has been analyzed in terms of the role of the Au-atom (Lewis acid or Lewis base) using DFT calculations combined with the quantum theory of atoms in molecules (QTAIM), noncovalent interaction plot index (NCIplot) and natural bond orbital (NBO) computational tools. The NBO suggests that the Au⋯π interaction is an example of a coinage bond in spite of the anionic nature of the acceptor and the cationic nature of the donor.

Mechanochemical Preparation of Dipyridyl-Naphthalenediimide Cocrystals: Relative Role of Halogen-Bond and π-π Interactions.

Naphthalenediimide derivates are a class of π-conjugated molecules largely investigated in the literature and used as building blocks for metal-organic frameworks or coformers for hydrogen-bond-based cocrystals. However, their tendency to establish halogen-bond interactions remains unexplored. By using a crystalline engineering approach, we report here four new cocrystals with N,N'-di(4-pyrydyl)-naphthalene-1,4,5,8-tetracarboxidiimide and diiodo-substituted coformers, easily obtained via a mechanochemical protocol. Cocrystals were characterized via NMR, electron ionization mass spectrometry, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction. Crystallographic structures were then finely examined and correlated with energy framework calculations to understand the relative contribution of halogen-bond and π-π interactions toward framework stabilization.

Synthesis, characterization, antimicrobial and cytotoxic activity and DNA-binding properties of d-metal complexes with hydrazones of Girard's T and P reagents.

In this work synthesis, characterization and crystal structures of 1, Zn(II) complex ([ZnL1(NCS)2]), with (E)-1-(2-oxo-2-(2-(quinolin-2-ylmethylene)hydrazinyl)ethyl)pyridin-1-ium chloride (HL1Cl) and 2, Bi(III) complex ([BiHL2Cl4] × 1/2CH3OH), with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(thiazol-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL2Cl), have been reported. Zn(II) complex possesses a distorted trigonal bipyramidal geometry while surroundings around Bi(III) ion are extended pentagonal bipyramidal. Antimicrobial activity, brine shrimp assay and DPPH radical scavenging activity of both complexes, including previously synthesized complexes with HL2Cl ligand (Zn(II) and Ni(II)) and complexes with (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)ethan-1-aminium chloride (HL3Cl) (Zn(II), Cu(II), Cd(II), Co(II), Fe(III), Ni(II)), were evaluated. For the most active complexes, cytotoxic activity against five malignant cancer cell lines (HeLa, A375, MCF7, PC-3 and A549) and normal cell line HaCaT, as well as generation of reactive oxygen species (ROS), was tested.

Two Crystal Forms of a Hydrated 2:1 ß-Cyclodextrin Fluconazole Complex: Single Crystal X-ray Structures, Dehydration Profiles, and Conditions for Their Individual Isolation.

Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between ß-cyclodextrin (ß-CD) and the antifungal API fluconazole (FLU) as well as temperature-concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ.

Development of novel cocrystal-based active food packaging by a Quality by Design approach.

A way to reduce food waste is related to the increase of the shelf-life of food as a result of improving the package type. An innovative active food packaging material based on cocrystallization of microbiologically active compounds present in essential oils i.e. carvacrol, thymol and cinnamaldehyde was developed following the Quality by Design principles. The selected active components were used to produce antimicrobial plastic films with solidified active ingredients on their surface characterized by antimicrobial properties against four bacterial strains involved in fruit and vegetable spoilage. The developed packaging prototypes exhibited good antimicrobial activity in vitro providing inhibition percentage of 69 (±15)% by contact and inhibition diameters of 32 (±6) mm in the gas phase, along with a prolonged release of the active components. Finally, the prolonged shelf-life of grape samples up to 7 days at room temperature was demonstrated.

Deciphering the Supramolecular Organization of Multiple Guests Inside a Microporous MOF to Understand their Release Profile.

Metal-organic frameworks (MOFs) give the opportunity of confining guest molecules into their pores even by a post-synthetic protocol. PUM168 is a Zn-based MOF characterized by microporous cavities that allows the encapsulation of a significant number of guest molecules. The pores engineered with different binding sites show a remarkable guest affinity towards a series of natural essential oils components, such as eugenol, thymol and carvacrol, relevant for environmental applications. Exploiting single crystal X-ray diffraction, it was possible to step-wisely monitor the rather complex three-components guest exchange process involving dimethylformamide (DMF, the pristine solvent) and binary mixtures of the flavoring agents. A picture of the structural evolution of the DMF-to-guest replacement occurring inside the MOF crystal was reached by a detailed single-crystal-to-single-crystal monitoring. The relation of the supramolecular arrangement in the pores with selective guests release was then investigated as a function of time and temperature by static headspace GC-MS analysis.

The Chiral 1:2 Adduct (S)S(S)C(-)589-Ethyl 2-Phenylbutyl Sulphide-Mercury (II) Chloride:(-)589[(S)S(S)C-Et(2-PhBu)S.(HgCl2)2]. Stereoselective Synthesis, Asymmetric Oxidation, Crystal and Molecular Structure and Circular Dichroism Spectra.

Optically active (-)589ethyl (S)-2-phenylbutyl thioether, (-)(S)C-Et(PhBu)S (I), and its new diastereoisomeric mercury (II) chloride adduct, 1:2, (-)[(S)S(S)C-Et(PhBu)S.(HgCl2)2]2, (II) were stereoselectively synthesized; the absorbance (UV) and circular dichroism (CD) spectra were measured and the crystal and molecular structure of complex (II) was determined by single-crystal X-ray diffraction. Two different Hg centres are present whose coordination environments are built by two short bonds to chloride ligands in one case, and to one chloride and one sulphur in the other one. These originate digonal units. Electroneutrality is achieved by a further chlorine, which can be considered prevalently ionic and bonded to the two Hg centres, forming square bridging systems nearly perpendicular to the digonal molecules. The coordination polyhedra can be interpreted as 2 + 4 tetragonally-compressed octahedra with the four longer contacts lying in the equatorial plane. IR spectroscopic data are consistent with the presence of one bent and one linear Cl-Hg-Cl moiety. The absolute configurations at both stereogenic centres of the formed diastereoisomeric complex (II) are (S). The (S)S absolute configuration at the stereogenic sulphur atom bonded to the mercury(II) atom in complex (II) has been related with the negative Cotton effect assigned in its circular dichroism (CD) spectrum to a charge-transfer transition at ca. 230 nm. The stereoselective oxidation of (I) and (II) with hydrogen peroxide, induced by the stereogenic carbon atom (S)C of the enantiopure sulphide, gave (-)598ethyl (S)C-2-phenylbutyl(S)S-sulphoxide, (-)598[(S)S(S)C-Et(PhBu)SO], (III), having 18.1% de. Oxidations carried out in the presence of a 200 molar excess of mercury(II) chloride gave (-)598ethyl (S)C-2-phenylbutyl(R)S-sulphoxide, (-) 598[(R)S(S)C-Et(PhBu)SO], (IV) with 31% de, showing the cooperative influence of mercury(II) chloride on the selectivity of the oxidation reaction.

Removal of pathogens by ultrafiltration from sea water.

Among water treatment processes, ultrafiltration is known to be efficient for the elimination of micro-organisms (bacteria and viruses). In this study, two pathogens were targeted, a bacterium, Vibrio aestuarianus and a virus, OsHV-1, with the objective to produce high quality water from seawater, in the case of shellfish productions. The retention of those microorganisms by ultrafiltration was evaluated at labscale. In the case of OsHV-1, the protection of oysters was validated by in vivo experiments using oysters spat and larvae, both stages being highly susceptible to the virus. The oysters raised using contaminated seawater which was then subsequently treated by ultrafiltration, had similar mortality to the negative controls. In the case of V. aestuarianus, ultrafiltration allowed a high retention of the bacteria in seawater with concentrations below the detection limits of the 3 analytical methods (flow cytometry, direct seeding and seeding after filtration to 0.22 µm). Thus, the quantity of V. aestuarianus was at least, 400 times inferior to the threshold known to induce mortalities in oysters. Industrial scale experiment on a several months period confirmed the conclusion obtained at lab scale on the Vibrio bacteria retention. Indeed, no bacteria from this genus, potentially harmful for oysters, was detected in permeate and this, whatever the quality of the seawater treated and the bacteria concentration upstream of the membrane. Moreover, the resistance of the process was confirmed with a stability of hydraulic performances over time for two water qualities and even facing an algal bloom. In terms of retention and resistance, ultrafiltration process was validated for the treatment of seawater towards the targeted pathogenic microorganisms, with the aim of biosecuring shellfish productions.

On the entropy cost of making solvates.

We present a simple way of estimating the entropy cost of solvate formation in crystals. The entropy penalty of making solvates can be as low as <1 kJ mol-1 or as high as >9 kJ mol-1 and is entirely dependent on the nature of the liquid component and the temperature of solvate formation. A link is found between a low entropy cost and a higher likelihood for a solvent to make solvates.

Site-Selective Double and Tetracyclization Routes to Fused Polyheterocyclic Structures by Pd-Catalyzed Carbonylation Reactions.

In this contribution, we report novel palladium-catalyzed carbonylative cascade approaches to highly functionalized polyheterocyclic structures. The Pd-catalyzed carbonylative process involves the regioselective insertion of one to three CO molecules and the sequential ordered formation of up to eight new bonds (one C-O, two C-C, five C-N). The exclusive formation of six-membered heterocycles is elucidated by detailed modeling studies.

Stepwise Evolution of Molecular Nanoaggregates Inside the Pores of a Highly Flexible Metal-Organic Framework.

The crystalline sponge method (CSM) is primarily used for structural determination by single-crystal X-ray diffraction of a single analyte encapsulated inside a porous MOF. As the host-guest systems often show severe disorder, reliable crystallographic determination is demanding; thus the dynamics of the guest entering and the formation of nanoconfined molecular aggregates has not been in the spotlight. Now, the concept is investigated of the CSM for monitoring the structural evolution of nanoconfined supramolecular aggregates of eugenol guests with displacement of DMF inside the cavities of the flexible MOF, PUM168. The interpretation of the electron density provides a series of unique detailed snapshots depicting the supramolecular guest aggregation, thus showing the tight interplay between the host flexible skeleton and the molecular guests through the DMF-to-eugenol exchange process.

Synthesis of Imidazolidin-2-ones and Imidazol-2-ones via Base-Catalyzed Intramolecular Hydroamidation of Propargylic Ureas under Ambient Conditions.

The first organo-catalyzed synthesis of imidazolidin-2-ones and imidazol-2-ones via intramolecular hydroamidation of propargylic ureas is reported. The phosphazene base BEMP turned out to be the most active organo-catalyst compared with guanidine and amidine bases. Excellent chemo- and regioselectivities to five-membered cyclic ureas have been achieved under ambient conditions, with a wide substrate scope and exceptionally short reaction times (down to 1 min). A base-mediated isomerization step to an allenamide intermediate is the most feasible reaction pathway to give imidazol-2-ones, as suggested by DFT studies.

Coordination Driven Capture of Nicotine Inside a Mesoporous MOF.

Metal organic frameworks (MOFs) are a wide class of crystalline porous polymers studied in many fields, ranging from catalysis to gas storage. In the past few years, MOFs have been studied for the encapsulation of organic or organometallic molecules and for the development of potential drug carriers. Here, we report on the study of two structurally-related mesoporous Cu-MOFs, namely PCN-6 and PCN-6' (PCN stands for Porous Coordination Network), for nicotine trapping. Nicotine is a well-known alkaloid liquid molecule at room temperature, whose crystalline structure is still unknown. In this work, the loading process was monitored by electron ionization mass spectrometry by using a direct insertion probe (DIP-EI/MS), infrared (IR), and ultraviolet/visible (UV/VIS) analysis. Both nuclear magnetic resonance (NMR) spectroscopy and thermogravimetric (TGA) analysis showed evidence that nicotine trapping reaches remarkable uptakes up to 40 wt %. In the case of PCN-6@nicotine, X-ray structural resolution revealed that the guest uptake is triggered by coordination of the pyridine ring of nicotine to the copper nuclei of the paddle-wheel units composing the framework of PCN-6.

Ligand-Driven Coordination Sphere-Induced Engineering of Hybride Materials Constructed from PbCl2 and Bis-Pyridyl Organic Linkers for Single-Component Light-Emitting Phosphors.

We report design and structural characterization of six new coordination polymers fabricated from PbCl2 and a series of closely related bis-pyridyl ligands LI and HLII-HLVI, namely, [Pb2(LI)Cl4]n, [Pb(HLII)Cl2]n·nMeOH, [Pb(HLIII)Cl2]n·0.5 nMeOH, [Pb2(LIV)Cl3]n, [Pb(HLV)Cl2]n, and [Pb3(LVI)2Cl4]n·nMeOH. The topology of the obtained networks is dictated by the geometry of the organic ligand. The structure of [Pb2(LI)Cl4]n is constructed from the [PbCl2]n two-dimensional (2D) sheets, linked through organic linkers into a three-dimensional framework, which exhibits a unique binodal 4,7-connected three-periodic topology named by us as sda1. Topological analysis of the 2D metal-organic sheet in [Pb(HLII)Cl2]n·nMeOH discloses a binodal 3,4-connected layer topology, regardless of the presence of tetrel bonds. A one-dimensional (1D) coordination polymer [Pb(HLIII)Cl2]n·0.5 nMeOH is considered as a uninodal 2-connected chain. The overall structure of [Pb2(LIV)Cl3]n is constructed from dimeric tetranuclear [Pb4(µ3-LIV-κ6N:N':N″:µ3-O)2(µ4-Cl)(µ2-Cl)2]3+ cationic blocks linked in a zigzag manner through bridging µ2-Cl- ligands, yielding a 1D polymeric chain. Topological analysis of this chain reveals a unique pentanodal 3,4,4,5,6-connected chain topology named by us as sda2. The structure of [Pb(HLV)Cl2]n exhibits a 1D zigzaglike polymeric chain. Two chains are further linked into a 1D gridlike ribbon through the dimeric [Pb2(µ2-Cl)2Cl2] blocks as bridging nodes. With the bulkiest ligand HLVI, a 2D layered coordination polymer [Pb3(LVI)2Cl4]n·nMeOH is formed, which network, considering all tetrel bonds, reveals a unique heptanodal 3,3,3,3,4,5,5-connected layer topology named by us as sda3. Compounds [Pb2(LI)Cl4]n, [Pb2(LIV)Cl3]n, and [Pb(HLV)Cl2]n were found to be emissive in the solid state at ambient temperature. While blue emission of [Pb2(LI)Cl4]n is due to the ligand-centered transitions, bluish-green and white luminescence of [Pb2(LIV)Cl3]n and [Pb(HLV)Cl2]n, respectively, was assigned to ligand-to-metal charge transfer mixed with metal-centered excited states. Molecular as well as periodic calculations were additionally applied to characterize the obtained polymers.