Benchtop Conditions Research Articles

Hydrothiolation of Triisopropylsilyl Acetylene Sulfur Pentafluoride - Charting the Chemical Space of β-SF5 Vinyl Sulfides.

Recently, we suggested liquid and high-boiling TIPS-CC-SF5 (TASP) as a versatile reagent to access so far elusive SF5-containing building blocks by less specialized laboratories under bench-top conditions. The synthesis of non-aromatic SF5 building blocks generally requires on-site fluorination or pentafluorosulfanylation steps employing toxic and/or gaseous reagents. Herein, we underline the versatility of this reagent by reporting a benign bench-top protocol for the synthesis of Z-configured β-pentafluorosulfanylated vinyl sulfides in good to excellent yields (up to 99 %) with exclusive (Z)-diasteroselectivity and broad functional group tolerance. This method exploits an in-situ protodesilylation-hydrothiolation sequence. This so far uncharted class of compounds was characterized by means of NMR-spectroscopy as well as SC-XRD. Furthermore, we suggest the reaction to proceed via a kinetically controlled closed-shell reaction pathway, corroborated by in-silico experiments.

Outlook and opportunities for engineered environments of breast cancer dormancy.

Dormant, disseminated breast cancer cells resist treatment and may relapse into malignant metastases after decades of quiescence. Identifying how and why these dormant breast cancer cells are triggered into outgrowth is a key unsolved step in treating latent, metastatic breast cancer. However, our understanding of breast cancer dormancy in vivo is limited by technical challenges and ethical concerns with triggering the activation of dormant breast cancer. In vitro models avoid many of these challenges by simulating breast cancer dormancy and activation in well-controlled, bench-top conditions, creating opportunities for fundamental insights into breast cancer biology that complement what can be achieved through animal and clinical studies. In this review, we address clinical and preclinical approaches to treating breast cancer dormancy, how precisely controlled artificial environments reveal key interactions that regulate breast cancer dormancy, and how future generations of biomaterials could answer further questions about breast cancer dormancy.

Full optimization of dynamic nuclear polarization on a 1 tesla benchtop polarizer with hyperpolarizing solids.

Hyperpolarization by dissolution dynamic nuclear polarization (dDNP) provides the opportunity to dramatically increase the weak nuclear magnetic resonance (NMR) signal of liquid molecular targets using the high polarization of electron radicals. Unfortunately, the solution-state hyperpolarization can only be accessed once since freezing and melting of the hyperpolarized sample happen in an irreversible fashion. A way to expand the application horizon of dDNP can therefore be to find a recyclable DNP alternative. To pursue this ambitious goal, we recently introduced the concept of recyclable hyperpolarized flow (HypFlow) DNP where hyperpolarization happens in porous hyperpolarizing solids placed in a compact benchtop DNP polarizer at a magnetic field of 1 T and a temperature of 77 K. Here we aim to optimize the radical concentrations immobilized in hyperpolarizing solids with the objective of generating as much polarization as possible in a timeframe (<1 s) compatible with future recyclable DNP applications. To do so, the solid-state DNP enhancement factors, build-up rates and DNP spectra of different hyperpolarizing solids containing various nitroxide radical loadings (20-74 μmol cm-3) are compared against the DNP performance of varying nitroxide concentrations (10-100 mM) solvated in a glassy frozen solution. We demonstrate that in <1 s, polarization enhancement goes up to 56 and 102 with surface-bound and solvated radicals, respectively, under the optimized conditions. For the range of nitroxide concentrations used cross effect DNP seems to be the dominant mechanism under benchtop conditions. This was deduced from the electron paramagnetic resonance (EPR) lineshape of TEMPOL investigated using Q-band EPR measurements.

(Ph3P)AuCl-catalyzed homocoupling of arylboronic acids under benchtop conditions: Synthesis of biphenyls

(Ph3P)AuCl was discovered to be a powerful catalyst in the homocoupling of arylboronic acids and potassium aryltrifluoroborates for the synthesis of symmetrical biaryls. The reactions take place under benchtop reaction conditions in 96% EtOH at temperatures between rt and 50 °C with no exclusion of air or humidity, in the presence of F-TEDA (Selectfluor™) as an oxidant. The procedure is very functional group tolerant, and affords the corresponding biaryls in high yields with large substrate scope (26 examples).

Development of a novel UPLC-MS/MS method for the simultaneous quantification of mycophenolic mofetil, mycophenolic acid, and its major metabolites: Application to pharmacokinetic and tissue distribution study in rats

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) used to prevent rejection in organ transplant patients. The purpose of this study is to develop a sensitive LC-MS/MS method to simultaneously quantify MMF, MPA, and two major metabolites, mycophenolic acid-glucuronide (MPAG) and Acyl-mycophenolic acid-glucuronide (AcMPAG) and applied this method in a pharmacokinetic (PK) and tissue distribution study. A Shimadzu UHPLC system coupled to an AB Sciex QTrap 4000 mass spectrometer was used for the analysis. Protein precipitation with a mixture of methanol: acetonitrile (2:1, v:v) was used to process the plasma samples and tissue samples. Separation was achieved using an Ultra Biphenyl 5 µm column (100 × 2.1 mm) with 0.1% formic acid in water (A) and acetonitrile (B) as the mobile phases. Quantification analysis was performed under positive ionization mode using the multiple reaction monitoring (MRM) approach. The method was linear in the range of 1.22 – 1250.00 nM for all four analytes with correlation coefficient values > 0.99. The method was reproducible, with intra- and inter-day accuracy ranging from 85.0 ± 11.2–108.3 ± 6.50 for all analytes in both plasma, liver and intestine homogenates. The extraction recovery and matrix effect of plasma sample using a mixture methanol/acetonitrile (2:1, V:V) can achieve an acceptable range (<20%), but extraction recovery and matrix effect of AcMPAG decreased to 64.10 ± 15.42 in the liver and intestine homogenates. The analytes in plasma were found to be stable under bench-top, freeze-thaw, and storage conditions. The validated method was successfully applied to quantify MMF, MPA, MPAG, and AcMPAG in a rat PK study. The PK results showed MPA was the major form exposed in the plasma in rats after oral administration of MMF, but the major metabolites in the rat’s tissue disposition were MPAG.

Green Chromatographic Method for Determination of Active Pharmaceutical Ingredient, Preservative, and Antioxidant in an Injectable Formulation: Robustness by Design Expert.

We report an efficient HPLC method for simultaneous qualitative and quantitative analysis of lincosamide antibiotic injectable formulations containing Clindamycin phosphate (CMN), benzyl alcohol (BA), and ethylenediaminetetraacetic acid (EDTA) as major ingredients. The three components were separated by Phenomenex prodigy C8 (250 mm × 4.6 mm, 5 μm) HPLC column, flow rate 1.1 mL/min, injection volume 30 μL, and column temperature 35 °C, using 0.05 M sodium acetate buffer (pH 4.5) with acetonitrile (ACN) in the ratio of 80:20 (v/v). The detection wavelength was set as 240 nm. The method was validated as per International Conference on Harmonization (ICH) guidelines and was confirmed to be specific, precise, accurate, and linear. Method robustness was executed by utilizing quality in the design of the experiment. Accuracy results were found to be 99.3–100.5% for CMN, 99.3–100.8% for BA, and 99.1–100.3% for EDTA. Precision results were obtained as % relative standard deviation (RSD): 0.6% for CMN, 0.4% for BA, and 0.4% for EDTA. Correlation coefficient (r2) values were obtained as >0.999 for the three components. Analytical solutions are stable for 48 h at benchtop and refrigerator conditions. The greenness of the analytical method was evaluated by the Green Analytical Procedure Index (GAPI), National Environmental Method Index (NEMI), analytical eco-scale, and Analytical Greenness (AGREE) tools to confirm that the method is eco-friendly.

Green Liquid Chromatography Method for the Determination of Related Substances Present in Olopatadine HCl Nasal Spray Formulation, Robustness by Design Expert.

Dual therapeutic nature drug mast cell stabilizer and histamine receptor antagonist olopatadine hydrochloride (OPT) nasal spray does not have an official monograph, and no literature is available. Eye drops formulation had the official monograph for impurities, but the determination was done in two methods. A simple and effective green liquid chromatography method to develop and validate for the related substances of OPT nasal spray formulation. A 25 min gradient method was employed to separate impurities and OPT with a 1.0 mL/min flow rate using a Boston green C8 (150 mm × 4.6 mm, 5 µm) HPLC column. The set wavelength and column oven temperatures were 299 nm and 30°C, respectively. pH 3.5 phosphate buffer-acetonitrile in the ratio of (70:30, v/v) as mobile phase A and (50:50, v/v) ratio as mobile phase B. A Quality by Design (QbD) based Design of Experiments (DoE) was employed to evaluate the robustness characteristics of the analytical method validation. The obtained RSD from the precision and intermediate precision was 0.4 to 4.1%. The % recovery of the impurities from LOQ to 150% of specification level was 87.5 to 110.3%. The linear regression curves for the impurities with a correlation coefficient of >0.999 indicate that all peak responses are linear with the concentration. The sample and standard solutions were stable for 24 h at benchtop and refrigerator conditions. All the critical peaks were well separated from the forced degradation studies' diluent, placebo, and generated degradation peaks. The method validation data and QbD based robustness study results indicate that the developed impurities method fits the routine quality control laboratory use. National Environmental Index (NMEI), Green Analytical Procedure Index (GAPI), Analytical Eco-scale and Analytical Greenness (AGREE) tools expressed the method's greenness. The proposed method is QbD utilized and green chemistry assessed impurities determination method for OPT in nasal spray formulation.

Unique green chromatography method for the determination of serotonin receptor antagonist (Ondansetron hydrochloride) related substances in a liquid formulation, robustness by quality by design-based design of experiments approach.

Serotonin receptor antagonist drug Ondansetron hydrochloride injectable formulation containing all related substances was identified and quantified by a single, simple, sensitive, eco-friendly, and green high-performance liquid chromatography method. The disseverment of all impurities was achieved with the Discovery Cyano (250 × 4.6) mm, 5μm column. The gradient program was composed of pH 5.7 phosphate buffer as mobile phase A and acetonitrile as mobile phase B. The flow rate, column compartment temperature, and detection wavelengths were 0.9 mL/min, 30°C, and 216 nm, respectively. The method was validated as per current regulatory guidelines. The obtained %relative standard deviation for the precision results was between 0.55 and 2.72% for all impurities. The correlation coefficient values from the linearity experiment for impurities and analyte were more than 0.995. The accuracy results were obtained between 88.4 and 113.0% for all impurities. Both sample and standard solutions showed 24 h stability at benchtop and refrigerator conditions. All impurities and analytes met the specificity and mass balance for all forced degradation conditions. Quality-by-design-based design of experiments was utilized to establish the method's robustness. Method greenness was assessed by using the current advanced tool green analytical procedure index, National Environmental Methods Index, and analytical eco-scale.

Development of a novel UPLC-MS/MS method for the simultaneously quantification of polydatin and resveratrol in plasma: Application to a pharmacokinetic study in rats

The purpose of this study is to develop a sensitive LC-MS-MS method to simultaneously quantify polydatin and its metabolite, resveratrol, for its application in a pharmacokinetic (PK) study and to determine polydatin hydrolysis by microflora. A Shimadzu UHPLC system coupled to an AB Sciex QTrap 4000 mass spectrometer was used for the analysis. Separation was achieved using an Acquity BEH C18 column (2.1 × 50 mm) with acetonitrile and 0.1% formic acid as the mobile phases. Analysis was performed under negative ionization mode using the multiple reaction monitoring (MRM) approach. The method was linear in the range of 9.77–1250 nM for both resveratrol and polydatin with correlation coefficient values >0.99. Themethodhas been shown to be reproducible, with intra- and inter-day accuracy and precision ±10.4% of nominal values, for both analytes. The average extraction recovery rates were 81.78–98.3% for polydatin and 86.4–103.2% for resveratrol, respectively. Matrix effect was in the acceptable range (<15%). The analytes in plasma were found to be stable under bench-top, freeze-thaw, and storage (−4 °C) conditions. The metabolic studies showed that polydatin can be rapidly hydrolyzed by rat fecal S9 fractions and PK studies showed that both polydatin and resveratrol were exposed in the plasma and variable tissues. This novel UPLC-MS-MS method can quantify the levels of both polydatin and its major metabolite resveratrol in biological samples.

Unfolding Textile-Based Pneumatic Actuators for Wearable Applications.

Textile based pneumatic actuators have recently seen increased development for use in wearable applications thanks to their high strength to weight ratio and range of achievable actuation modalities. However, the design of these textile-based actuators is typically an iterative process due to the complexity of predicting the soft and compliant behavior of the textiles. In this work we investigate the actuation mechanics of a range of physical prototypes of unfolding textile-based actuators to understand and develop an intuition for how the geometric parameters of the actuator affect the moment it generates, enabling more deterministic designs in the future. Under benchtop conditions the actuators were characterized at a range of actuator angles and pressures (0 - 136 kPa), and three distinct performance regimes were observed, which we define as Shearing, Creasing, and Flattening. During Flattening, the effects of both the length and radius of the actuator dominate with maximum moments in excess of 80 Nm being generated, while during Creasing the radius dominates with generated moments scaling with the cube of the radius. Low stiffness spring like behavior is observed in the Shearing regime, which occurs as the actuator approaches its unfolded angle. A piecewise analytical model was also developed and compared to the experimental results within each regime. Finally, a prototype actuator was also integrated into a shoulder assisting wearable robot, and on-body characterization of this robot was performed on five healthy individuals to observe the behavior of the actuators in a wearable application. Results from this characterization highlight that these actuators can generate useful on-body moments (10.74 Nm at 90° actuator angle) but that there are significant reductions compared to bench-top performance, in particular when mostly folded and at higher pressures.

Fast Detection of Beta Galactosidase and Enzyme Kinetics with 4-Aminophenyl-β-D-Galactopyranoside as Substrate

Beta-galactosidase (β-Gal) is an important enzyme utilized to determine cell senescence and understand disease pathology, among being utilized for several biosensing applications. This key biomarker can be measured indirectly using electrochemical methods by detecting the electroactive p-aminophenol (PAP) produced from the enzymatic conversion of a substrate. Here, we present a quick electrochemical method based on cyclic voltammograms (CVs) to quantify the amount of β-Gal in aqueous solution in under 5 minutes. Using timed CVs, the enzyme kinetics of β-Gal versus 4-aminophenyl-β-D-galactopyranoside (PAPG) was estimated. The detection limit for β-Gal was 40 ng ml−1 using the timed quick CV method. KM was found to be 18.7 ± 0.7 µM, and Vmax 10.1 ± 0.6 µmol min−1 mg−1, for β-Gal with PAPG as a substrate. By adding divalent salts Mg2+ and Ca2+, KM was lowered to nearly half, and Vmax increased by 20%. The electrochemical protocol utilized neutral pH and ambient room temperature benchtop conditions, making it amenable to scanning electrochemical microscopy and lab-on-chip detection platforms. In addition to cell senescence, this quick and simple electrochemical method can be used in broad biosensing applications, including the detection of water and foodborne pathogens and the identification of toxic contaminants.

A Robust Pd-Catalyzed C-S Cross-Coupling Process Enabled by Ball-Milling.

An operationally simple mechanochemical C-S coupling of aryl halides with thiols has been developed. The reaction process operates under benchtop conditions without the requirement for a (dry) solvent, an inert atmosphere, or catalyst preactivation. The reaction is finished within 3 h. The reaction is demonstrated across a broad range of substrates; the inclusion of zinc metal has been found to be critical in some instances, especially for coupling of alkyl thiols.

The bench-top accuracy of the VerteTrack spinal stiffness assessment device

BackgroundThe assessment of spinal stiffness by manual palpation in clinical settings has demonstrated both poor accuracy and reliability. More recently, mechanical methods for assessment of spinal stiffness have demonstrated superior accuracy and reliability. However, mechanical methods of spinal stiffness assessment can be expensive, time consuming and/or unsuited to clinical practice. While a new device has been designed to address these issues (VerteTrack), its benchtop performance remains unknown.AimTo measure the bench-top performance of VerteTrack.MethodsA series of laboratory-based experiments were conducted in February 2018 to investigate the accuracy (precision and bias) of load and displacement measurements obtained by VerteTrack and then were compared against an appropriate reference standard. Measurements of both multiple-level continuous assessment (multiple spinal levels measured), and single-level assessment (single spinal level measured) were performed on a viscoelastic foam medium (AIREX® balance beam, Switzerland) and the resulting stiffness calculated.ResultsVerteTrack demonstrated high precision at all loads and displacements. There was minimal systematic measurement bias identified for applied versus reference load (mean bias = − 0.123 N; 95%CI − 0.182 to 0.428 N, p < .001), and no systematic measurement bias for measured versus reference displacement (mean difference = 0.02 mm; 95%CI − 0.09 to 0.14 mm, p < .001). The magnitude of stiffness obtained during multiple-level continuous assessment was on average 0.25 N/mm (2.79%) less than that for single-level assessment (95%CI − 0.67 to 0.17 N/mm, p < .001).ConclusionsVerteTrack demonstrated high accuracy (high precision, low bias) under bench-top conditions. The difference in stiffness found between multiple versus single spinal levels should be considered in the research context, but is unlikely to be clinically relevant. The results of this study demonstrate that VerteTrack may be suitable for both single and multi-level spinal stiffness measurements in-vivo.

Thermoresponsive Poly(ß-hydroxyl amine)s: Synthesis of a New Stimuli Responsive Amphiphilic Homopolymer Family through Amine-Epoxy 'Click' Polymerization.

A new synthesis of amphiphilic homopolymers is described. In this synthesis, commercially available and inexpensive primary amines and di-epoxide molecules are utilized as AA- and BB-types of monomers in an amine-epoxy ‘click’ polymerization process. This process can be carried out in water and at room temperature. It does not require a catalyst or inert conditions and forms no byproducts. Therefore, the polymer synthesis can be carried out in open-air and bench-top conditions and a post-synthesis purification step is not required. The modularity of the synthesis, on the other hand, allows for facile structural modulation and tuning of the thermally triggered aggregation process in the temperature range of 7 to 91 °C. Finally, the underlying principles can be translated from linear architectures to polymer networks (hydrogels).

Photolytic, radical-mediated hydrophosphination: a convenient post-polymerisation modification route to P-di(organosubstituted) polyphosphinoboranes [RR'PBH2] n.

Polymers with a phosphorus-boron main chain have attracted interest as novel inorganic materials with potentially useful properties since the 1950s. Although examples have recently been shown to be accessible via several routes, the materials reported so far have been limited to P-mono(organosubstituted) materials, [RHPBH2] n , containing P-H groups. Here we report a general route for the post-polymerisation modification of such polyphosphinoboranes giving access to a large range of previously unknown examples featuring P-disubstituted units. Insertion of alkenes, R'CH[double bond, length as m-dash]CH2 into the P-H bonds of poly(phenylphosphinoborane), [PhHPBH2] n was facilitated by irradiation under UV light in the presence of the photoinitiator 2,2-dimethoxy-2-phenylacetophenone (DMPAP) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) under benchtop conditions giving high molar mass, air-stable polymers [PhR'PBH2] n with controlled functionalisation and tunable material properties. The mechanistic explanation for the favourable effect of the addition of TEMPO was also investigated and was proposed to be a consequence of reversible binding to radical species formed from the photolysis of DMPAP. This new methodology was also extended to the formation of crosslinked gels and to water-soluble bottlebrush copolymers showcasing applicability to form a wide range of polyphosphinoborane-based soft materials with tunable properties.

Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrazolo[1,5- a]pyrimidines.

An efficient, three-component strategy for Rh(III)-catalyzed annulation of readily available 3-aminopyrazoles, aldehydes, and sulfoxonium ylides to give diverse pyrazolo[1,5- a]pyrimidines is disclosed. The reactions were performed under straightforward benchtop conditions using microwave heating with short reaction times. Good yields were obtained for many substituted aminopyrazoles and a very large variety of aromatic and heteroaromatic aldehydes, including those incorporating electron-withdrawing, electron-donating, basic nitrogen, halide and acidic functionality. Ester and methoxy functionalities could also be directly installed on the pyrimidine ring by employing ethyl glyoxylate and trimethyl orthoformate in place of the aldehyde, respectively. In addition, a range of sulfoxonium ylides provided products in good yields to establish that aryl, heteroaryl, and branched and unbranched alkyl substituents can be introduced with this reagent. Finally, the first use of a formyl sulfoxonium ylide in a chemical transformation enabled the preparation of products with only a single substituent on the pyrimidine ring as introduced by the aldehyde coupling partner. For the formyl ylide, a one-pot, stepwise reaction sequence was used to prevent competitive condensation of the formyl group with the aminopyrazole.

Phosphorus Coordination Chemistry in Catalysis: Air Stable P(III)-Dications as Lewis Acid Catalysts for the Allylation of C–F Bonds

Modification of C–F bonds with main-group catalysts has typically employed electron-deficient Lewis superacids in high oxidation states, and the challenges of preparing and handling such species have prevented broader adoption of metal-free reduction protocols. Here, we show that a hemilabile ligand coordinated to an easily accessed P(III) center imparts air stability without sacrificing the ability to activate C–F bonds. Catalytic C–C coupling of benzyl fluorides with allylsilanes was achieved using a P(III) complex under benchtop conditions. This application of coordination chemistry principles to main-group Lewis acids reveals a new strategy for controlling catalysis.

Room-Temperature C–H Functionalization Sequence under Benchtop Conditions for the Undergraduate Chemistry Laboratory

An iridium(III)-mediated C–H functionalization sequence involving a concerted cyclometalation–deprotonation/migratory insertion pathway is reported for the undergraduate chemistry laboratory. The air- and water-stable iridacycle intermediates are readily isolated and characterized by NMR spectroscopy. Both steps of the experiment are performed at room temperature under benchtop conditions, rendering the protocol suitable for a wide range of student skill levels.

Rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles

The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions.

Redox Exfoliation of Layered Transition Metal Dichalcogenides.

Transition metal dichalcogenides (TMDs) have attracted considerable attention in a diverse array of applications due to the breadth of possible property suites relative to other low-dimensional nanomaterials (e.g., graphene, aluminosilicates). Here, we demonstrate an alternative methodology for the exfoliation of bulk crystallites of group V-VII layered TMDs under quiescent, benchtop conditions using mild redox chemistry. Anionic polyoxometalate species generated from edge sites adsorb to the TMD surface and create Coulombic repulsion that drives layer separation without the use of shear forces. This method is generalizable (MS2, MSe2, and MTe2) and effective in preparing high-concentration (>1 mg/mL) dispersions with narrow layer thickness distributions more rapidly and with safer reagents than alternative solution-based approaches. Finally, exfoliation of these TMDs is demonstrated in a range of solvent systems that were previously inaccessible due to large surface energy differences. These characteristics could be beneficial in the preparation of high-quality films and monoliths.