Reticular Synthesis of Hydrogen-Bonded Organic Frameworks and Their Derivatives via Mechanochemistry.

Rational synthesis of hydrogen-bonded organic frameworks (HOFs) with predicted structure has been a long-term challenge. Herein, by using the efficient, simple, low-cost, and scalable mechanosynthesis, we demonstrate that reticular chemistry is applicable to HOF assemblies based on building blocks with different geometry, connectivity, and functionality. The obtained crystalline HOFs show uniform nano-sized morphology, which is challenging or unachievable for conventional solution-based methods. Furthermore, the one-pot mechanosynthesis generated a series of Pd@HOF composites with noticeably different CO oxidation activities. In situ DRIFTS studies indicate that the most efficient composite, counterintuitively, shows the weakest CO affinity to Pd sites while the strongest CO affinity to HOF matrix, revealing the vital role of porous matrix to the catalytic performance. This work paves a new avenue for rational synthesis of HOF and HOF-based composites for broad application potential.

Crucial Role of Water in the Mechanosynthesis of CsPbI3 and Other ABX3 Halides.

Mechanochemical synthesis of CsPbI3 , as a model system for ABX3 halides, was studied. Water was shown to strongly promote the kinetics of formation of CsPbI3 from the CsI+PbI2 mixture through increased mobility of the constituting ionic species. Since many binary and ternary halides are hygroscopic, it was concluded that the presence of small, uncontrollable and unintentional additions of water should often occur in both precursor mixtures and synthesized complex halides boosting the kinetics of formation of many, if not all, ternary organic-inorganic hybrid halides such as, for example, MAPbX3 (X=Cl, Br, I). In addition, trace amounts of water should influence the transport characteristics of complex halides. Thus, the presence of water explains, at least partially, the huge scatter in both the reported mechanochemical reaction times necessary for obtaining single-phase APbX3 perovskite halides and the activation energies of ionic diffusion in APbX3 .

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach.

The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion-corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=-2 kJ mol-1 ) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher-order molecular ICCs with functional properties.

Solid-state interaction of ibuprofen with magnesium stearate and product characterization thereof.

Solid-state compatibility of API with excipients is essential step in the preformulation stage of early development of new finished dosage form. Thermal analysis and vibrational spectroscopy are complementary techniques that play a pivotal role to assess the solid-state compatibility of API with excipients. Their coupling and combination with multivariate analysis, provide valuable quantitative aspect to reveal the potential interactions. The impetus of this work was aimed to fully elucidate the solid-state compatibility of ibuprofen and magnesium stearate in binary mixtures comprising pharmaceutically acceptable amounts of magnesium stearate (0.25-5% w/w). Binary mixtures were analyzed before and after exposure at strictly controlled stress conditions (25 °C/60% relative humidity and 40 °C/75% relative humidity). Interaction between ibuprofen and magnesium stearate was unambiguously confirmed. The product of their interaction was synthetized separately, characterized by means of FTIR spectroscopy, DSC, TG/DTG and XRPD for the first time and identified as diibuprofen magnesium. The induced solid-state pseudopolymorphic transition of this product to diibuprofen magnesium tetrahydrate was also studied and discussed.

Particle size effect in the mechanically assisted synthesis of ß-cyclodextrin mesitylene sulfonate.

The mechanically assisted synthesis of organic compounds has recently focused considerable attention as it may be unique in features to selectively direct the reaction pathway. In the continuation of our work on the synthesis of modified cyclodextrins (CDs) via mechanochemical activation, we sought to discriminate the contribution of supramolecular effects and grinding during the course of a reaction in the solid state. As such, we recently investigated the influence of the particle size of ß-CD in the synthesis of ß-CD mesitylene sulfonate (ß-CDMts) in the solid state using a vibrating ball-mill. We were particularly interested in the role of the particle size on the kinetics of the reaction. In this study, we show that grinding ß-CD reduces the particles size over time down to a limit of 167 nm. The granulometric composition remains rather invariant for grinding times over 1 h. Each type of ß-CD particles reacted with mesitylenesulfonyl chloride (MtsCl) to produce ß-CDMts. Contrary to what could be intuitively anticipated, smaller particles did not lead to the highest conversions. The impact of grinding on the conversion was limited. Interestingly, the proportion of ß-CDMts mono-substituted on the primary face significantly increased over time when the reaction was carried out in the presence of KOH as a base. The data series were confronted with kinetics models to get insight in the way the reactions proceeded. The diversity of possible models suggests that multiple mechanochemical processes can account for the formation of ß-CDMts in the solid state. Throughout the study, we found that the reactivity depended more upon diffusion phenomena in the crystalline parts of the material than on the increase in the surface area of the CD particles resulting from grinding.

Design and Synthesis of a New Soluble Natural ß-Carboline Derivative for Preclinical Study by Intravenous Injection.

Harmine is a natural ß-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection.

Hydroformylation of Alkenes in a Planetary Ball Mill: From Additive-Controlled Reactivity to Supramolecular Control of Regioselectivity.

The Rh-catalyzed hydroformylation of aromatic-substituted alkenes is performed in a planetary ball mill under CO/H2 pressure. The dispersion of the substrate molecules and the Rh-catalyst into the grinding jar is ensured by saccharides: methyl-α-d-glucopyranoside, acyclic dextrins, or cyclodextrins (CDs, cyclic oligosaccharides). The reaction affords the exclusive formation of aldehydes whatever the saccharide. Acyclic saccharides disperse the components within the solid mixture leading to high conversions of alkenes. However, they showed typical selectivity for α-aldehyde products. If CDs are the dispersing additive, the steric hindrance exerted by the CDs on the primary coordination sphere of the metal modifies the selectivity so that the ß-aldehydes were also formed in non-negligible proportions. Such through-space control via hydrophobic effects over reactivity and regioselectivity reveals the potential of such solventless process for catalysis in solid state.

Development of C-N coupling using mechanochemistry: catalytic coupling of arylsulfonamides and carbodiimides.

Reported herein is the mechanochemical synthesis of sulfonyl guanidines, a family of molecules which are relevant as pharmaceuticals and herbicides, by direct coupling of sulfonamides and aromatic or aliphatic carbodiimides. Attempts to conduct the coupling in solution have either failed or given very low conversions, thus demonstrating mechanochemistry as the necessary component for the discovery of this synthetic strategy.

Comparative Study of the Structural, Microstructural, and Mechanical Properties of Geopolymer Pastes Obtained from Ready-to-Use Metakaolin-Quicklime Powders and Classic Geopolymers.

This study compares the structural, microstructural, thermal, and mechanical properties of geopolymer pastes (GPs) created through traditional methods and those derived from ready-to-use powders for geopolymer (RUPG) materials. The metakaolin (MK) precursor was activated using a sodium silicate solution or CaO and MOH (where M is Na or K). Various ratios of precursor/activator and Na2SiO3 or CaO/MOH were tested to determine the optimal combination. For RUPG, the MK precursor was activated by replacing the sodium silicate solution with quicklime. Metakaolin, alkaline hydroxide, and quicklime powders were mixed at different CaO ratios (wt%) and subjected to extensive ball milling to produce RUPG. The RUPG was then hydrated, molded, and cured at 20 °C and 50% relative humidity until testing. Analytical methods were used to characterize the raw and synthesized materials. Classic geopolymers (CGPs) activated with quicklime burst after one hour of molding. The results indicated slight amorphization of GP compared to raw MK, as confirmed by X-ray diffraction analysis, showing N(K)-A-S-H in CGP and N(K)-A-S-H with calcium silicate hydrate (C-S-H/C-A-S-H) in RUPG. The compressive strength of MK-based geopolymers reached 31.45 MPa and 34.92 MPa for GP and CGP, respectively, after 28 days of curing.

Oxide nanoparticles based in magnesium as a potential dental tool to inhibit bacterial activity and promote osteoblast viability.

Functional nano-fillers are commonly used to reduce bacterial colonization in dentistry. This study aimed to synthesize, characterize, and evaluate the biological effects of magnesium oxide (MgO) nanoparticles (NP) obtained by mechanosynthesis. XRD, TEM, FT-IR, and UV-Vis were used to characterize MgO-NP which were subsequently tested for their activity against Staphylococcus aureus, Enterococcus faecalis and Escherichia coli (E. coli). The effects of MgO-NP on osteoblast cells were also analyzed. Three variables were studied: microbial inhibition by optical density (OD; 570-nm), viability estimated by colony-forming-units, and cell proliferation. The characterization of NP is consistent with nanostructures, minimum inhibitory concentration between 1.5-5 mg/mL, and microbial inhibition at 9.75 ug/mL concentration for E. coli were determined. There were different concentration-dependent effects on cell proliferation. Results were observed with 0.156 mg/mL MgO-NP, which increased cell proliferation at 24 and 48 h. The results suggest the antibacterial suitability of MgO-NP, with tolerable viability of mammalian cells for dental applications.

Machine-Learning-Assisted Discovery of Mechanosynthesized Lead-Free Metal Halide Perovskites for the Oxidative Photocatalytic Cleavage of Alkenes.

Lead-free metal halide perovskites can potentially be air- and water-stable photocatalysts for organic synthesis, but there are limited studies on them for this application. Separately, machine learning (ML), a critical subfield of artificial intelligence, has played a pivotal role in identifying correlations and formulating predictions based on extensive datasets. Herein, an iterative workflow by incorporating high-throughput experimental data with ML to discover new lead-free metal halide perovskite photocatalysts for the aerobic oxidation of styrene is described. Through six rounds of ML optimization guided by SHapley Additive exPlanations (SHAP) analysis, BA2CsAg0.95Na0.05BiBr7 as a photocatalyst that afforded an 80% yield of benzoic acid under the standard conditions is identified, which is a 13-fold improvement compared to the 6% with when using Cs2AgBiBr6 as the initial photocatalyst benchmark that is started. BA2CsAg0.95Na0.05BiBr7 can tolerate various functional groups with 22 styrene derivatives, highlighting the generality of the photocatalytic properties demonstrated. Radical scavenging studies and density functional theory calculations revealed that the formation of the reactive oxygen species superoxide and singlet oxygen in the presence of BA2CsAg0.95Na0.05BiBr7 are critical for photocatalysis.

Thermodynamic Guidelines for the Mechanosynthesis or Solid-State Synthesis of MnFe2O4 at Relatively Low Temperatures.

Herein, thermodynamic assessment is proposed to screen suitable precursors for the solid-state synthesis of manganese ferrite, by mechanosynthesis at room temperature or by subsequent calcination at relatively low temperatures, and the main findings are validated by experimental results for the representative precursor mixtures MnO + FeO3, MnO2 + Fe2O3, and MnO2 +2FeCO3. Thermodynamic guidelines are provided for the synthesis of manganese ferrite from (i) oxide and/or metallic precursors; (ii) carbonate + carbonate or carbonate + oxide powder mixtures; (iii) other precursors. It is also shown that synthesis from metallic precursors (Mn + 2Fe) requires a controlled oxygen supply in limited redox conditions, which is hardly achieved by reducing gases H2/H2O or CO/CO2. Oxide mixtures with an overall oxygen balance, such as MnO + Fe2O3, act as self-redox buffers and offer prospects for mechanosynthesis for a sufficient time (>9 h) at room temperature. On the contrary, the fully oxidised oxide mixture MnO2 + Fe2O3 requires partial reduction, which prevents synthesis at room temperature and requires subsequent calcination at temperatures above 1100 °C in air or in nominally inert atmospheres above 750 °C. Oxide + carbonate mixtures, such as MnO2 +2FeCO3, also yield suitable oxygen balance by the decomposition of the carbonate precursor and offer prospects for mechanosynthesis at room temperature, and residual fractions of reactants could be converted by firing at relatively low temperatures (≥650 °C).

Core and surface structure and magnetic properties of mechano-synthesized LaFeO3 nanoparticles and their Eu3+-doped and Eu3+/Cr3+-co-doped variants.

The core and surface structure, and magnetism of mechano-synthesized LaFeO3 nanoparticles (30-40 nm), Eu3+-doped (La0.70Eu0.30FeO3), and Eu3+/Cr3+ co-doped (La0.70Eu0.30Fe0.95Cr0.05O3) are reported. Doping results in a transition from the O'-type to the O-type distorted structure. Traces of reactants, intermediate phases, and a small amount of Eu2+ ions were detected on the surfaces of the nanoparticles. The nanoparticles consist of antiferromagnetic cores flanked by ferromagnetic shells. The Eu3+ dopant ions enhance the magnetization values relative to those of the pristine nanoparticles and result in magnetic susceptibilities compatible with the presence of Eu3+ van Vleck paramagnetism of spin-orbit coupling constant (λ = 363 cm-1) and a low temperature Curie-Weiss like behavior associated with the minority Eu2+ ions. Anomalous temperature-dependent magnetic hardening due to competing magnetic anisotropy and magnetoelectric coupling effects together with a temperature-dependent dopant-sensitive exchange bias, caused by thermally activated spin reversals at the core of the nanoparticles, were observed.

Binary Mixtures of Meloxicam and L-Tartaric Acid for Oral Bioavailability Modulation of Pharmaceutical Dosage Forms.

Binary mixtures of active pharmaceutical ingredients (API) are researched to improve the oral bioavailability of pharmaceutical dosage forms. The purpose of this study was to obtain mixtures of meloxicam and L-tartaric acid because tartaric acid improves intestinal absorption and meloxicam is more soluble in a weakly basic environment. The mixtures in the 0-1 molar fraction range, obtained from solvent-assisted mechanosynthesis, were investigated by differential scanning calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Fourier Transform Raman spectroscopy (FT-Raman), X-ray powder diffraction (XRD) and solubility tests. The physicochemical characteristics of the compounds obtained from DSC data reveal, for the first time, the formation of a co-crystal at meloxicam molar fraction of 0.5. FTIR spectroscopy data show the existence of hydrogen bonds between the co-crystal components meloxicam and L-tartaric acid. FT-Raman spectroscopy was used complementary with FT-IR spectroscopy to analyze the pure APIs and their mixtures, to emphasize the appearance/disappearance and the shifts of the position/intensity of vibrational bands, following the formation of hydrogen-bonded structures or van der Waals interactions, and to especially monitor the crystal lattice vibrations below 400 cm-1. The experimental results obtained by X-ray powder diffraction confirmed the formation of the co-crystal by the loss and, respectively, the apparition of peaks from the single components in the co-crystal diffractogram. The solubility tests showed that the co-crystal product has a lower aqueous solubility due to the acidic character of the other component, tartaric acid. However, when the solubility tests were performed in buffer solution of pH 7.4, the solubility of meloxicam from the co-crystal mixture was increased by 57% compared to that of pure meloxicam. In conclusion, the studied API mixtures may be considered potential biomaterials for improved drug release molecular solids.

Mechanosynthesis of Triazolyl-bis(indolyl)methane Pharmacophores via Gold Catalysis: A Prelude to Their Molecular Electronic Properties and Biological Potency.

Chemical structures possessing both 1,2,3-triazole and bis(indolyl)methane fragments gained considerable interest in drug synthesis owing to their established biological efficacies. However, 1,2,3-triazoles linked at the bridging position of bis(indolyl)methane is a logical and unexplored design approach. In this regard, nine new triazolyl-bis(indolyl)methane conjugates under AuCl catalyzed ball-milling conditions were accomplished. Comparative evaluation on absorptive and emissive properties of the synthesized dyads were also analyzed. To unravel the influence of different peripheral substituents on the electronic structure and π-orbital properties, theoretical investigations were performed. Screening of molecules for free radical scavenging, anti-inflammatory and antidiabetic showed comparable potency against reference drugs. In particular, compounds 7 h, 7 d and 7 a displayed good efficiency of α-amylase inhibition. The DNA gyrase inhibitory potential of all compounds were assessed in silico which revealed high binding affinity (ΔG=-8.99 Kcal/mol) for 7 i followed by 7 h (ΔG=-7.80 Kcal/mol) with the targeted protein.

Synthesis and Optoelectronic Features of Rhodamine-Triazole Dyads as Metallochromic Probes for Copper-Selective Chemosensing.

Rhodamine-based chromic materials have attracted significant interest owing to their cation recognition ability with high sensitivity. However, rhodamine chromophores with controllable sensing selectivity towards transition metal species are only at the advent. Herein, three triazole-conjugated rhodamine dyads with different peripheral substituents were synthesized. The key triazole precursors required for the desired chemistry were prepared by adopting our recently developed CTAB catalyzed mechano-click chemistry. Molecular properties derived from photophysics, electrochemistry and surface morphology of the synthesized dyads were analyzed. Furthermore, frontier molecular orbitals, electronic structure and secondary quantum chemical parameters of dyads were also compared. Screening of dyads for their sensing ability towards an array of alkali, alkaline and transition metal ions exhibited a noticeable naked-eye detection of Cu2+ ions and was confirmed by spectrophotometric titration. The specific binding mode of dyads as probable with Cu2+ over other metal ions attributes to the chemoselectivity.

Step-Economical Mechanosynthesis of Hybrid Azoles: Deciphering Their π-Orbital and Pharmacological Characteristics.

A hybrid pharmacophore strategy for unifying 1,2,3-triazole with 1,2,4-triazole cores to prepare mixed triazoles was accomplished by a ball-milling approach. The developed chemistry works under the catalysis of cupric oxide nanoparticles with salient features like one-jar operation, lower number of synthetic steps, catalyst recyclability, time-dependent product control, and good overall yields. π-Orbital properties based on theoretical calculations supported the suitability of these molecules for pharmacological screening. Therefore, the biological potency of the synthesized molecules was evaluated for antioxidant, anti-inflammatory, and anti-diabetic activities. By virtue of their proton-donating tendency, all compounds showed promising radical-scavenging activity with the inhibition level reaching up to 90 %. These molecular hybrids also exhibited anti-inflammatory and anti-diabetic potencies similar to those of standard compounds, owing to their electron-rich nature. Finally, α-amylase inhibitory potential was demonstrated in silico; significant regions necessary for enzyme inhibition were identified by hydrogen bonding interactions.

The Mechanochemical Synthesis and Activation of Carbon-Rich π-Conjugated Materials.

Mechanochemistry uses mechanical force to break, form, and manipulate chemical bonds to achieve functional transformations and syntheses. Over the last years, many innovative applications of mechanochemistry have been developed. Specifically for the synthesis and activation of carbon-rich π-conjugated materials, mechanochemistry offers reaction pathways that either are inaccessible with other stimuli, such as light and heat, or improve reaction yields, energy consumption, and substrate scope. Therefore, this review summarizes the recent advances in this research field combining the viewpoints of polymer and trituration mechanochemistry. The highlighted mechanochemical transformations include π-conjugated materials as optical force probes, the force-induced release of small dye molecules, and the mechanochemical synthesis of polyacetylene, carbon allotropes, and other π-conjugated materials.

Low Temperature Magnetic Transition of BiFeO3 Ceramics Sintered by Electric Field-Assisted Methods: Flash and Spark Plasma Sintering.

Low temperature magnetic properties of BiFeO3 powders sintered by flash and spark plasma sintering were studied. An anomaly observed in the magnetic measurements at 250 K proves the clear existence of a phase transition. This transformation, which becomes less well-defined as the grain sizes are reduced to nanometer scale, was described with regard to a magneto-elastic coupling. Furthermore, the samples exhibited enhanced ferromagnetic properties as compared with those of a pellet prepared by the conventional solid-state technique, with both a higher coercivity field and remnant magnetization, reaching a maximum value of 1.17 kOe and 8.5 10-3 emu/g, respectively, for the specimen sintered by flash sintering, which possesses the smallest grains. The specimens also show more significant exchange bias, from 22 to 177 Oe for the specimen prepared by the solid-state method and flash sintering technique, respectively. The observed increase in this parameter is explained in terms of a stronger exchange interaction between ferromagnetic and antiferromagnetic grains in the case of the pellet sintered by flash sintering.

Sustainable Synthesis of Cadmium Sulfide, with Applicability in Photocatalysis, Hydrogen Production, and as an Antibacterial Agent, Using Two Mechanochemical Protocols.

CdS nanoparticles were successfully synthesized using cadmium acetate and sodium sulfide as Cd and S precursors, respectively. The effect of using sodium thiosulfate as an additional sulfur precursor was also investigated (combined milling). The samples were characterized by XRD, Raman spectroscopy, XPS, UV-Vis spectroscopy, PL spectroscopy, DLS, and TEM. Photocatalytic activities of both CdS samples were compared. The photocatalytic activity of CdS, which is produced by combined milling, was superior to that of CdS, and was obtained by an acetate route in the degradation of Orange II under visible light irradiation. Better results for CdS prepared using a combined approach were also evidenced in photocatalytic experiments on hydrogen generation. The antibacterial potential of mechanochemically prepared CdS nanocrystals was also tested on reference strains of E. coli and S. aureus. Susceptibility tests included a 24-h toxicity test, a disk diffusion assay, and respiration monitoring. Bacterial growth was not completely inhibited by the presence of neither nanomaterial in the growth environment. However, the experiments have confirmed that the nanoparticles have some capability to inhibit bacterial growth during the logarithmic growth phase, with a more substantial effect coming from CdS nanoparticles prepared in the absence of sodium thiosulfate. The present research demonstrated the solvent-free, facile, and sustainable character of mechanochemical synthesis to produce semiconductor nanocrystals with multidisciplinary application.