Interactions and reactivity in crystalline intermediates of mechanochemical cyclorhodation reactions.

There is experimental evidence that solid mixtures of the rhodium dimer [Cp*RhCl2]2 and benzo[h] quinoline (BHQ) produce two different polymorphic molecular cocrystals called 4α and 4ß under ball milling conditions. The addition of NaOAc to the mixture leads to the formation of the rhodacycle [Cp*Rh-(BHQ)Cl], where the central Rh atom retains its tetracoordinate character. Isolate 4ß reacts with NaOAc leading to the same rhodacycle while isolate 4α does not under the same conditions. We show that the puzzling difference in reactivity between the two cocrystals can be traced back to fundamental aspects of the intermolecular interactions between the BHQ and [Cp*RhCl2]2 fragments in the crystalline environment. To support this view, we report a number of descriptors of the nature and strength of chemical bonds and intermolecular interactions in the extended solids and in a cluster model. We calculate formal quantum mechanical descriptors based on electronic structure, electron density, and binding and interaction energies including an energy decomposition analysis. Without exception, all descriptors point to 4ß being a transient structure higher in energy than 4α with larger local and global electrophilic and nucleophilic powers, a more favorable spatial and energetic distribution of the frontier orbitals, and a more fragile crystal structure.

Intermediates in Mechanochemical Reactions.

Mechanochemical reactions offer methodological and environmental advantages for chemical synthesis, constantly attracting attention within the scientific community. Besides unmistakable sustainability advantages, the conditions under which mechanochemical reactions occur, namely solventless conditions, sometimes facilitate the isolation of otherwise labile or inaccessible products. Despite these advantages, limited knowledge exists regarding the mechanisms of these reactions and the types of intermediates involved. Nevertheless, in an expanding number of cases, ex situ and in situ monitoring techniques have allowed for the observation, characterization, and isolation of reaction intermediates in mechanochemical transformations. In this Minireview, we present a series of examples in which reactive intermediates have been detected in mechanochemical reactions spanning organic, organometallic, inorganic, and materials chemistry. Many of these intermediates were stabilized by non-covalent interactions, which played a pivotal role in guiding the chemical transformations. We believe that by uncovering and understanding such instances, the growing mechanochemistry community could find novel opportunities in catalysis and discover new mechanochemical reactions while achieving simplification in chemical reaction design.

The Role of Crystalline Intermediates in Mechanochemical Cyclorhodation Reactions Elucidated by in-Situ X-ray Powder Diffraction and Computation.

The occurrence of crystalline intermediates in mechanochemical reactions might be more widespread than previously assumed. For example, a recent study involving the acetate-assisted C-H activation of N-Heterocycles with [Cp*RhCl2 ]2 by ball milling revealed the formation of transient cocrystals between the reagents prior to the C-H activation step. However, such crystalline intermediates were only observed through stepwise intervallic ex-situ analysis, and their exact role in the C-H activation process remained unclear. In this study, we monitored the formation of discrete, stoichiometric cocrystals between benzo[h]quinoline and [Cp*RhCl2 ]2 by ball milling using in-situ synchrotron X-ray powder diffraction. This continuous analysis revealed an initial cocrystal that transformed into a second crystalline form. Computational studies showed that differences in noncovalent interactions made the [Cp*RhCl2 ]2 unit in the later-appearing cocrystal more reactive towards NaOAc. This demonstrated the advantage of cocrystal formation before the acetate-assisted metalation-deprotonation step, and how the net cooperative action of weak interactions between the reagents in mechanochemical experiments can lead to stable supramolecular assemblies, which can enhance substrate activation under ball-milling conditions. This could explain the superiority of some mechanochemical reactions, such as acetate-assisted C-H activation, compared to their solution-based counterparts.

Simultaneous recognition of dopamine and uric acid in real samples through highly sensitive new electrode fabricated using ZnO/carbon quantum dots: bio-imaging and theoretical studies.

Dopamine (DA) and uric acid (UA), which are vital components in human metabolism, cause several health problems if they are present in altered concentrations; thus, the determination of DA and UA is essential in real samples using selective sensors. In the present study, graphite carbon paste electrodes (CPE) were fabricated using ZnO/carbon quantum dots (ZnO/CQDs) and employed as electrochemical sensors for the detection of DA and UA. These electrodes were fully characterized via different analytical techniques (XRD, SEM, TEM, XPS, and EDS). The electrochemical responses from the modified electrodes were evaluated using cyclic voltammetry, square wave voltammetry, and electrochemical impedance spectroscopy. The results showed that the present electrode has exhibited high sensitivity towards DA, recognizing even at low concentrations (0.12 µM), and no inference was observed in the presence of UA. The ZnO/CQD electrode was applied for the simultaneous detection of co-existing DA and UA in real human urine samples and the peak potential separation between DA and UA was found to be greatly associated with the synergistic effect originated from ZnO and CQDs. The limit of detection (LOD) of the electrode was analyzed, and compared with other commercially available electrodes. Thus, the ZnO/CQD electrode was used to detect DA and UA in real samples, such as Saccharomyces cerevisiae cells.

Microstructure, Phase Evolution, and Chemical Behavior of CrCuFeNiTiAlx High Entropy Alloys Processed by Mechanical Alloying.

High entropy alloys (HEAs) of the type CrCuFeNiTi-Alx were processed through mechanical alloying. The aluminum concentration was varied in the alloy, to determine its effect on the HEAs' microstructure, phase formation, and chemical behavior. X-ray diffraction studies performed on the pressureless sintered samples revealed the presence of structures composed of face centered cubic (FCC) and body centered cubic (BCC) solid-solution phases. Since the valences of the elements that form the alloy are different, a nearly stoichiometric compound was obtained, increasing the final entropy of the alloy. The aluminum was partly responsible for this situation, which also favored transforming part of the FCC phase into BCC phase on the sintered bodies. X-ray diffraction also indicated the formation of different compounds with the alloy's metals. Bulk samples exhibited microstructures with different phases. The presence of these phases and the results of the chemical analyses revealed the formation of alloying elements that, in turn, formed a solid solution and, consequently, had a high entropy. From the corrosion tests, it could be concluded that the samples with a lower aluminum content were the most resistant to corrosion.

Cocrystal Formation Precedes the Mechanochemically Acetate-Assisted C-H Activation with [Cp*RhCl2 ]2.

This work reports the experimentally studied mechanochemical formation of rhodacycles by ball milling pyridine- and quinoline-derived substrates and [Cp*RhCl2 ]2 in the presence of NaOAc. Ex-situ analysis of the mechanochemical reactions using powder X-ray diffraction (PXRD), solid-state UV-vis spectroscopy and ATR-FTIR spectroscopy revealed the formation of unexpected cocrystals between the substrates and the rhodium dimer prior to the C-H activation step. This sequence of events differs from the generally accepted steps in solution in which cleavage of [Cp*RhCl2 ]2 is initiated by acetate ions. Additionally, the mechanochemical approach enabled the synthesis of the six-membered rhodacycle [Cp*Rh(2-benzilpyridine)Cl], a metal complex repeatedly reported as inaccessible in solution. Altogether, the results of this investigation clarify some of the fundamental aspects of mechanochemical cyclometallations.

Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine.

In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin. This work contributes to the elucidation of a reaction mechanism that has been subjected to a number of interpretations over time and paints a clear picture of how mechanosynthesis can be applied and optimized for the preparation of added-value molecules.

Polymer and small molecule mechanochemistry: closer than ever.

The formation and scission of chemical bonds facilitated by mechanical force (mechanochemistry) can be accomplished through various experimental strategies. Among them, ultrasonication of polymeric matrices and ball milling of reaction partners have become the two leading approaches to carry out polymer and small molecule mechanochemistry, respectively. Often, the methodological differences between these practical strategies seem to have created two seemingly distinct lines of thought within the field of mechanochemistry. However, in this Perspective article, the reader will encounter a series of studies in which some aspects believed to be inherently related to either polymer or small molecule mechanochemistry sometimes overlap, evidencing the connection between both approaches.

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions.

In the search for versatile reagents compatible with mechanochemical techniques, in this work we studied the reactivity of N-fluorobenzenesulfonimide (NFSI) by ball milling. We corroborated that, by mechanochemistry, NFSI can engage in a variety of reactions such as fluorinations, fluorodemethylations, sulfonylations, and amidations. In comparison to the protocols reported in solution, the mechanochemical reactions were accomplished in the absence of solvents, in short reaction times, and in yields comparable to or higher than their solvent-based counterparts.

Mechanochemical Prebiotic Peptide Bond Formation*.

The presence of amino acids on the prebiotic Earth, either stemming from endogenous chemical routes or delivered by meteorites, is consensually accepted. Prebiotically plausible pathways to peptides from inactivated amino acids are still unclear as most oligomerization approaches rely on thermodynamically disfavored reactions in solution. Now, a combination of prebiotically plausible minerals and mechanochemical activation enables the oligomerization of glycine at ambient temperature in the absence of water. Raising the reaction temperature increases the degree of oligomerization concomitantly with the formation of a commonly unwanted cyclic glycine dimer (DKP). However, DKP is a productive intermediate in the mechanochemical oligomerization of glycine. The findings of this research show that mechanochemical peptide bond formation is a dynamic process that provides alternative routes towards oligopeptides and establishes new synthetic approaches for prebiotic chemistry.

Mechanochemical Palladium-Catalyzed Carbonylative Reactions Using Mo(CO)6.

Esters and amides were mechanochemically prepared by palladium-catalyzed carbonylative reactions of aryl iodides by using molybdenum hexacarbonyl as a convenient solid carbonyl source and avoiding a direct handling of gaseous carbon monoxide. Real-time monitoring of the mechanochemical reaction by in situ pressure sensing revealed that CO is rapidly transferred from Mo(CO)6 to the active catalytic system without significant release of molecular carbon monoxide.

Genetic Predictors of Long-term Response to Antitumor Necrosis Factor Agents in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P value < 0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value  < 0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P value < 0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.

Radiation oncologists' attitudes and beliefs about intensity-modulated radiation therapy and stereotactic body radiation therapy for prostate cancer.

BACKGROUND: To better understand how radiation oncologists perceive intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) for prostate cancer and how these perceptions may influence treatment decisions. METHODS: We conducted semi-structured interviews of radiation oncologists between January-May, 2016. We used a purposeful sampling technique to select participants across a wide range of experience, regions, and practice types. Two trained qualitative researchers used an inductive, iterative approach to code transcripts and identify themes. We then used content analysis and thematic analysis of the coded transcripts to understand radiation oncologists' attitudes and beliefs about IMRT and SBRT. RESULTS: Thematic saturation was achieved after 20 interviews. Participants were affiliated with academic (n = 13; 65%), private (n = 5; 25%), and mixed (n = 2; 10%) practices and had a wide range of clinical experience (median 19 years; range 4-49 years). Analysis of interview transcripts revealed four general themes: 1) most radiation oncologists offered surgery, brachytherapy, IMRT, and active surveillance for low-risk patients; 2) there was no consensus on the comparative effectiveness of IMRT and SBRT; 3) key barriers to adopting SBRT included issues related to insurance, reimbursement, and practice inertia; and 4) despite these barriers, most participants envisioned SBRT use increasing over the next 5-10 years. CONCLUSIONS: In the absence of strong opinions about effectiveness, nonclinical factors influence the choice of radiation treatment. Despite a lack of consensus, most participants agreed SBRT may become a standard of care in the future.

Electro-Mechanochemical Atom Transfer Radical Cyclizations using Piezoelectric BaTiO3.

The formation and regeneration of active CuI species is a fundamental mechanistic step in copper-catalyzed atom transfer radical cyclizations (ATRC). Typically, the presence of the catalytically active CuI species in the reaction mixture is secured by using high CuI catalyst loadings or the addition of complementary reducing agents. In this study it is demonstrated how the piezoelectric properties of barium titanate (BaTiO3 ) can be harnessed by mechanical ball milling to induce electrical polarization in the strained piezomaterial. This strategy enables the conversion of mechanical energy into electrical energy, leading to the reduction of a CuII precatalyst into the active CuI species in copper-catalyzed mechanochemical solvent-free ATRC reactions.

Direct Visualization of a Mechanochemically Induced Molecular Rearrangement.

Recent progress in the field of mechanochemistry has expanded the discovery of mechanically induced chemical transformations to several areas of science. However, a general fundamental understanding of how mechanochemical reactions by ball milling occur has remained unreached. For this, we have now implemented in situ monitoring of a mechanochemically induced molecular rearrangement by synchrotron X-ray powder diffraction, Raman spectroscopy, and real-time temperature sensing. The results of this study demonstrate that molecular rearrangements can be accomplished in the solid state by ball milling and how in situ monitoring techniques enable the visualization of changes occurring at the exact instant of a molecular migration. The mechanochemical benzil-benzilic acid rearrangement is the focal point of the study.

Mechanochemical Copper-Catalyzed Asymmetric Michael-Type Friedel-Crafts Alkylation of Indoles with Arylidene Malonates.

A mechanochemical version of the asymmetric Michael-type Friedel-Crafts alkylation of indoles with arylidene malonates was developed. The reaction proceeds under ambient atmosphere using a chiral bis(oxazoline)copper catalyst in a mixer mill. Under these reaction conditions nineteen 3-substituted indole derivatives were synthesized in good to excellent yields (up to 98 %), and with good enantioselectivities (up to 91:9 e.r.) after short milling times.

Mechanochemistry of Gaseous Reactants.

In recent years, the application of mechanical energy to chemical systems has repeatedly proven beneficial to facilitate chemical transformations in various areas in chemistry. Today, a systematic body of evidence indicates that mechanochemistry holds great promise to become a game-changer in chemical synthesis. Not only does mechanochemistry permit access to products that are inaccessible by established means (e.g. purely thermal activation), mechanochemical reactions often outperform their solution-based counterparts in terms of sustainability. Most mechanochemical reactions carried out by ball milling techniques involve transformations of solids and liquids, but the number of mechanochemical reactions with gaseous reactants is increasing. The aim of this Minireview is to provide an overview of recent chemical reactions involving gaseous samples by ball milling techniques and to highlight advances in ball milling technology for the safe handling of gaseous reagents. Examples of reactions proceeding at the interface of solid-/liquid-/gas-gas systems that led to significant improvements in reactivity or selectivity will also be highlighted.

Mechanosynthesis of Odd-Numbered Tetraaryl[n]cumulenes.

A mechanochemical synthesis of one-dimensional carbon allotrope carbyne model compounds, namely tetraaryl[n]cumulenes (n=3, 5) was realized. Central for the mechanosynthesis of the cumulenic carbon nanostructures were the development of a mechanochemical Favorskii alkynylation-type reaction and the implementation of a solvent-free, acid-free reductive elimination with tin(II) chloride by ball milling.

Synthesis of acylglycerol derivatives by mechanochemistry.

In recent times, many biologically relevant building blocks such as amino acids, peptides, saccharides, nucleotides and nucleosides, etc. have been prepared by mechanochemical synthesis. However, mechanosynthesis of lipids by ball milling techniques has remained essentially unexplored. In this work, a multistep synthetic route to access mono- and diacylglycerol derivatives by mechanochemistry has been realized, including the synthesis of diacylglycerol-coumarin conjugates.

Mindfulness for Chronic Low Back Pain: A Qualitative Analysis.

Objective: Mindfulness is a nonpharmacologic mind-body therapy that has been shown to be effective in older adults with chronic low back pain (cLBP). There are few first-person accounts in the literature that describe the older adult experience and perspective while learning mindfulness and meditation to treat pain. The objective of this study was to investigate dominant themes present in the experiences of older adults applying mindfulness and meditation to cope with cLBP. Design: Qualitative analysis of four focus groups. Subject: Twenty-five adults age 65 years or older who had completed an eight-week mindfulness program. Methods: The focus groups met for a comprehensive discussion session about their experience with mindfulness and meditation. The audio for each session was recorded, and the discussions were transcribed. Codebook development, qualitative coding, and thematic analysis were performed. The coders each coded all four transcripts, following which they met to adjudicate all coding differences until they were in complete agreement on coding. Results: Several key themes were brought up by older adults utilizing mindfulness as a means of coping with pain, which included overcoming fear of pain ("Before [learning mindfulness], I used to dread pain"), pain awareness ("You're focusing more on being aware than the pain; now that's what helps me"), and pain significance ("It becomes insignificant"). Conclusions: The themes identify several ways mindfulness impacts older adults with cLBP, including decreased negative emotions related to chronic pain such as fear of pain, a different perspective or change in awareness about pain, and reducing the significance of pain.