Metastable precipitation and ion-extractant transport in liquid-liquid separations of trivalent elements.

The extractant-assisted transport of metal ions from aqueous to organic environments by liquid-liquid extraction has been widely used to separate and recover critical elements on an industrial scale. While current efforts focus on designing better extractants and optimizing process conditions, the mechanism that underlies ionic transport remains poorly understood. Here, we report a nonequilibrium process in the bulk aqueous phase that influences interfacial ion transport: the formation of metastable ion-extractant precipitates away from the liquid-liquid interface, separated from it by a depletion region without precipitates. Although the precipitate is soluble in the organic phase, the depletion region separates the two and ions are sequestered in a long-lived metastable state. Since precipitation removes extractants from the aqueous phase, even extractants that are sparingly soluble in water will continue to be withdrawn from the organic phase to feed the aqueous precipitation process. Solute concentrations in both phases and the aqueous pH influence the temporal evolution of the process and ionic partitioning between the precipitate and organic phase. Aqueous ion-extractant precipitation during liquid-liquid extraction provides a reaction path that can influence the extraction kinetics, which plays an important role in designing advanced processes to separate rare earths and other minerals.

Quantitative Determination of Metal Ion Adsorption on Cellulose Nanocrystals Surfaces.

Nanocellulose is a bio-based material that holds significant potential in the field of water purification. Of particular interest is their potential use as a key sorbent material for the removal of metal ions from solution. However, the structure of metal ions adsorbed onto cellulose surfaces is not well understood. The focus of this work is to determine quantitatively the three-dimensional distribution of metal ions of different valencies surrounding negatively charged carboxylate functionalized cellulose nanocrystals (CNCs) using anomalous small-angle X-ray scattering (ASAXS). These distributions can affect the water and ionic permeability in these materials. The data show that increasing the carboxylate density on the surface of the CNCs from 740 to 1100 mmol/kg changed the nature of the structure of the adsorbed ions from a monolayer into a multilayer structure. The monolayer was modeled as a Stern layer around the CNC nanoparticles, whereas the multilayer structure was modeled as a diffuse layer on top of the Stern layer around the nanoparticles. Within the Stern layer, the maximum ion density increases from 1680 to 4350 mmol of Rb+/(kg of CNC) with the increase in the carboxylate density on the surface of the nanoparticles. Additionally, the data show that CNCs can leverage multiple mechanisms, such as electrostatic attraction and the chaotropic effect, to adsorb ions of different valencies. By understanding the spatial organization of the adsorbed metal ions, the design of cellulose-based sorbents can be further optimized to improve the uptake capacity and selectivity in separation applications.

An Atom-Economic Method for 1,2,3-Triazole Derivatives via Oxidative [3 + 2] Cycloaddition Harnessing the Power of Electrochemical Oxidation and Click Chemistry.

An electrochemical method was developed to accomplish the reagentless synthesis of 4,5-disubstituted triazole derivatives employing secondary propargyl alcohol as C-3 synthon and sodium azide as cycloaddition counterpart. The reaction was conducted at room temperature in an undivided cell with a constant current using a pencil graphite (C) anode and stainless-steel cathode in a MeCN solvent system. The proposed reaction mechanism was convincingly established by carrying out a series of control experiments and further supported by electrochemical and density functional theory (DFT) studies.

Relevance of Surface Adsorption and Aqueous Complexation for the Separation of Co(II), Ni(II), and Fe(III).

During the solvent extraction of metal ions from an aqueous to an organic phase, organic-soluble extractants selectively target aqueous-soluble ions for transport into the organic phase. In the case of extractants that are also soluble in the aqueous phase, our recent studies of lanthanide ion-extractant complexes at the surface of aqueous solutions suggested that ion-extractant complexation in the aqueous phase can hinder the solvent extraction process. Here, we investigate a similar phenomenon relevant to the separation of Co(II), Ni(II), and Fe(III). X-ray fluorescence near total reflection and tensiometry are used to characterize ion adsorption behavior at the surface of aqueous solutions containing water-soluble extractants, either bis(2-ethylhexyl) phosphoric acid (HDEHP) or 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (HEHEHP), as well as adsorption to a monolayer of water-insoluble extractant dihexadecyl phosphoric acid (DHDP) at the aqueous-vapor interface. Competitive adsorption of Ni(II) and Fe(III) utilizing either HDEHP or DHDP illustrates the essential feature of the recent lanthanide studies that the ion, which is preferentially extracted in liquid-liquid extraction, Fe(III), is found preferentially adsorbed to the water-vapor interface only in the presence of the water-insoluble extractant DHDP. A more subtle competition produces comparable adsorption behavior of Co(II) and Ni(II) at the surfaces of both HDEHP- and HEHEHP-aqueous solutions in spite of the known preference for Co(II) under solvent extraction conditions. Comparison experiments with a monolayer of DHDP reveal that Co(II) is preferentially adsorbed to the surface. This preference for Co(II) is also supported by molecular dynamics simulations of the potential of mean force of ions interacting with the soluble extractants in water. These results highlight the possibility that complexation of extractants and ions in the aqueous phase can alter selectivity in the solvent extraction of critical elements.

Interrogating Encapsulated Protein Structure within Metal-Organic Frameworks at Elevated Temperature.

Encapsulating biomacromolecules within metal-organic frameworks (MOFs) can confer thermostability to entrapped guests. It has been hypothesized that the confinement of guest molecules within a rigid MOF scaffold results in heightened stability of the guests, but no direct evidence of this mechanism has been shown. Here, we present a novel analytical method using small-angle X-ray scattering (SAXS) to solve the structure of bovine serum albumin (BSA) while encapsulated within two zeolitic imidazolate frameworks (ZIF-67 and ZIF-8). Our approach comprises subtracting the scaled SAXS spectrum of the ZIF from that of the biocomposite BSA@ZIF to determine the radius of gyration of encapsulated BSA through Guinier, Kratky, and pair distance distribution function analyses. While native BSA exposed to 70 °C became denatured, in situ SAXS analysis showed that encapsulated BSA retained its size and folded state at 70 °C when encapsulated within a ZIF scaffold, suggesting that entrapment within MOF cavities inhibited protein unfolding and thus denaturation. This method of SAXS analysis not only provides insight into biomolecular stabilization in MOFs but may also offer a new approach to study the structure of other conformationally labile molecules in rigid matrices.

Extended q-Range X-Ray Scattering Reveals High-Resolution Structural Details of Biomacromolecules in Aqueous Solutions.

We communicate a feasibility study for high-resolution structural characterization of biomacromolecules in aqueous solution from X-ray scattering experiments measured over a range of scattering vectors (q) that is approximately two orders of magnitude wider than used previously for such systems. Scattering data with such an extended q-range enables the recovery of the underlying real-space atomic pair distribution function, which facilitates structure determination. We demonstrate the potential of this method for biomacromolecules using several types of cyclodextrins (CD) as model systems. We successfully identified deviations of the tilting angles for the glycosidic units in CDs in aqueous solutions relative to their values in the crystalline forms of these molecules. Such level of structural detail is inaccessible from standard small angle scattering measurements. Our results call for further exploration of ultra-wide-angle X-ray scattering measurements for biomacromolecules.

Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization.

Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N-myristoyl phenylalanine-N-polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5-2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants.

A direct entry to polycyclic quinoxaline derivatives via I2-DMSO mediated oxidative decarboxylation of α-amino acids and the subsequent Pictet-Spengler cyclization reaction.

A facile and highly efficient iodine-promoted strategy has been delineated for the synthesis of indolo and pyrrolo[1,2-a]quinoxaline derivatives via an oxidative Pictet-Spengler type amino cyclo-annulation reaction using ∝-amino acids as aldehyde surrogates. The concomitant benzylic oxidation and the compatibility of different starting materials under standard conditions made the current method versatile. The salient features of the protocol such as readily available starting materials, inexpensive promoters, environmental benignity, broad substrate scope, scalability, and good to excellent yield make the method more attractive to practitioners of organic synthesis.

Role of Zeolite Structural Properties toward Iodine Capture: A Head-to-head Evaluation of Framework Type and Chemical Composition.

This study evaluated zeolite-based sorbents for iodine gas [I2(g)] capture. Based on the framework structures and porosities, five zeolites, including two faujasite (FAU), one ZSM-5 (MFI), one mesoMFI, one ZSM-22 (TON), as well as two mesoporous materials, were evaluated for I2(g) capture at room temperature and 150 °C in an iodine-saturated environment. From these preliminary studies, the three best-performing zeolites were ion-exchanged with Ag+ and evaluated for I2(g) capture under similar conditions. Energy-dispersive X-ray spectroscopy data suggest that Ag-FAU frameworks were the materials with the highest capacity for I2(g) in this study, showing ∼3× higher adsorption compared to Ag-mordenite (Ag-MOR) at room temperature, but X-ray diffraction measurements show that the faujasite structure collapsed during the adsorption studies because of dealumination. The Ag-MFI zeolites are decent sorbents in real-life applications, showing both good sorption capacities and higher stability. In-depth analyses and characterizations, including synchrotron X-ray absorption spectroscopy, revealed the influence of structural and chemical properties of zeolites on the performance for iodine adsorption from the gas phase.

Antagonistic Role of Aqueous Complexation in the Solvent Extraction and Separation of Rare Earth Ions.

Solvent extraction is used widely for chemical separations and environmental remediation. Although the kinetics and efficiency of this process rely upon the formation of ion-extractant complexes, it has proven challenging to identify the location of ion-extractant complexation within the solution and its impact on the separation. Here, we use tensiometry and X-ray scattering to characterize the surface of aqueous solutions of lanthanide chlorides and the water-soluble extractant bis(2-ethylhexyl) phosphoric acid (HDEHP), in the absence of a coexisting organic solvent. These studies restrict ion-extractant interactions to the aqueous phase and its liquid-vapor interface, allowing us to explore the consequences that one or the other is the location of ion-extractant complexation. Unexpectedly, we find that light lanthanides preferentially occupy the liquid-vapor interface. This contradicts our expectation that heavy lanthanides should have a higher interfacial density since they are preferentially extracted by HDEHP in solvent extraction processes. These results reveal the antagonistic role played by ion-extractant complexation within the aqueous phase and clarify the advantages of complexation at the interface. Extractants in common use are often soluble in water, in addition to their organic phase solubility, and similar effects to those described here are expected to be relevant to a variety of separations processes.

No ordinary proteins: Adsorption and molecular orientation of monoclonal antibodies.

The interaction of monoclonal antibodies (mAbs) with air/water interfaces plays a crucial role in their overall stability in solution. We aim to understand this behavior using pendant bubble measurements to track the dynamic tension reduction and x-ray reflectivity to obtain the electron density profiles (EDPs) at the surface. Native immunoglobulin G mAb is a rigid molecule with a flat, "Y" shape, and simulated EDPs are obtained by rotating a homology construct at the surface. Comparing simulations with experimental EDPs, we obtain surface orientation probability maps showing mAbs transition from flat-on Y-shape configurations to side-on or end-on configurations with increasing concentration. The modeling also shows the presence of ß sheets at the surface. Overall, the experiments and the homology modeling elucidate the orientational phase space during different stages of adsorption of mAbs at the air/water interface. These finding will help define new strategies for the manufacture and storage of antibody-based therapeutics.

Free Thiols Regulate the Interactions and Self-Assembly of Thiol-Passivated Metal Nanoparticles.

Thiol ligands bound to the metallic core of nanoparticles determine their interactions with the environment and self-assembly. Recent studies suggest that equilibrium between bound and free thiols alters the ligand coverage of the core. Here, X-ray scattering and MD simulations investigate water-supported monolayers of gold-core nanoparticles as a function of the core-ligand coverage that is varied in experiments by adjusting the concentration of total thiols (sum of free and bound thiols). Simulations demonstrate that the presence of free thiols produces a nearly symmetrical coating of ligands on the core. X-ray measurements show that above a critical value of core-ligand coverage the nanoparticle core rises above the water surface, the edge-to-edge distance between neighboring nanoparticles increases, and the nanoparticle coverage of the surface decreases. These results demonstrate the important role of free thiols: they regulate the organization of bound thiols on the core and the interactions of nanoparticles with their surroundings.

Accurate Determination of the Quantity and Spatial Distribution of Counterions around a Spherical Macroion.

The accurate distribution of countercations (Rb+ and Sr2+ ) around a rigid, spherical, 2.9-nm size polyoxometalate cluster, {Mo132 }42- , is determined by anomalous small-angle X-ray scattering. Both Rb+ and Sr2+ ions lead to shorter diffuse lengths for {Mo132 } than prediction. Most Rb+ ions are closely associated with {Mo132 } by staying near the skeleton of {Mo132 } or in the Stern layer, whereas more Sr2+ ions loosely associate with {Mo132 } in the diffuse layer. The stronger affinity of Rb+ ions towards {Mo132 } than that of Sr2+ ions explains the anomalous lower critical coagulation concentration of {Mo132 } with Rb+ compared to Sr2+ . The anomalous behavior of {Mo132 } can be attributed to majority of negative charges being located at the inner surface of its cavity. The longer anion-cation distance weakens the Coulomb interaction, making the enthalpy change owing to the breakage of hydration layers of cations more important in regulating the counterion-{Mo132 } interaction.

Highly Z-selective synthesis of 1,3-oxathiol-2-ylidenes and 4-methylene-oxazolidine-2-thiones via atom-specific 5-exo-dig cyclization of propargyl alcohol with isothiocyanate.

DBU mediated 5-exo-dig cyclization of isothiocyanate and propargyl alcohol leading to valuable heterocyclic compounds has been accomplished. The different modes of nucleophilicity (either S-selective or N-selective) of isothiocyanates were found to depend on the substitution pattern of propargyl alcohol. The terminal propargyl alcohol and isothiocyanate underwent an N-nucleophilic attack to afford 3-substituted 4-methylene oxazolidine-2-thiones. In contrast, exclusive S-nucleophilic cyclization was observed with internal propargyl alcohol to produce (Z)-1,3-oxathiol-2-ylidenes and (Z)-N-(Z)-4-ethylidene-1,3-oxathiolan-2-ylidenes from secondary and primary propargyl alcohols, respectively. The formation of high Z-selectivity in the imine motif and alkene is the highlight of this new method as multiple selectivities over C[double bond, length as m-dash]N and C[double bond, length as m-dash]C in a single system are synthetically highly challenging. The Z-selectivity in imine and alkene may be attributed to electronic and steric factors respectively.

Armoring the Interface with Surfactants to Prevent the Adsorption of Monoclonal Antibodies.

The pharmaceutical industry uses surface-active agents (excipients) in protein drug formulations to prevent the aggregation, denaturation, and unwanted immunological response of therapeutic drugs in solution as well as at the air/water interface. However, the mechanism of adsorption, desorption, and aggregation of proteins at the interface in the presence of excipients remains poorly understood. The objective of this work is to explore the molecular-scale competitive adsorption process between surfactant-based excipients and two monoclonal antibody (mAb) proteins, mAb-1 and mAb-2. We use pendant bubble tensiometry to measure the ensemble average adsorption dynamics of mAbs with and without the excipient. The surface tension measurements allow us to quantify the rate at which the molecules "race" to the interface in single-component and mixed systems. These results define the phase space, where coadsorption of both mAbs and excipients occurs onto the air/water interface. In parallel, we use X-ray reflectivity (XR) measurements to understand the molecular-scale dynamics of competitive adsorption, revealing the surface-adsorbed amounts of the antibody and excipient. XR has revealed that at a sufficiently high surface concentration of the excipient, mAb adsorption to the surface and subsurface domains was inhibited. In addition, despite the fact that both mAbs adsorb via a similar mechanistic pathway and with similar dynamics, a key finding is that the competition for the interface directly correlates with the surface activity of the two mAbs, resulting in a fivefold difference in the concentration of the excipient needed to displace the antibody.

Continuous Curvature Change into Controllable and Responsive Onion-like Vesicles by Rigid Sphere-Rod Amphiphiles.

We observe the formation of highly controllable and responsive onion-like vesicles by using rigid sphere-rod amphiphilic hybrid macromolecules, composed of charged, hydrophilic Keggin-type clusters (spheres) and hydrophobic rod-like oligofluorenes (OFs). Unlike the commonly used approach, which mainly relies on chain bending of flexible molecules to satisfy different curvatures in onion-like vesicles, the rigid hybrids form flexible interdigitations by tuning the angles between OFs, leading to the formation of bilayers with different sizes. The self-assembled vesicles possess complete onion-like structures from most inner to outer layers, and their size (layer number) can be accurately manipulated by different solution conditions including solvent polarity, ionic strength, temperature, and hybrid concentration, with fixed interbilayer distance under all conditions. Moreover, the vesicle size (layer number) shows excellent reversibility to the change of temperature. The charged feature of spheres, rod length, and overall hybrid architecture shows significant effects on the formation of such onion-like vesicles.

Correction: Iodine mediated oxidative cross coupling of 2-aminopyridine and aromatic terminal alkyne: a practical route to imidazo[1,2-a]pyridine derivatives.

Correction for 'Iodine mediated oxidative cross coupling of 2-aminopyridine and aromatic terminal alkyne: a practical route to imidazo[1,2-a]pyridine' by Surya Kanta Samanta et al., Org. Biomol. Chem., 2019, 17, 6441-6449.

Iodine mediated oxidative cross coupling of 2-aminopyridine and aromatic terminal alkyne: a practical route to imidazo[1,2-a]pyridine derivatives.

A novel, transition-metal free route leading to imidazo[1,2-a]pyridine derivatives via iodine mediated oxidative coupling between 2-aminopyridine and aromatic terminal alkyne has been demonstrated. This newly developed method discloses an operationally simple way for the construction of imidazoheterocycles. Commercially available antiulcer drug zolimidine may readily be synthesized employing this method.

The LANCA three-component reaction to highly substituted ß-ketoenamides - versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives.

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to ß-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-ß-ketoenamides. ß-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of ß-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of ß-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile ß-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key ß-ketoenamides show a unique substitution pattern - not easily accomplishable by alternative methods - and therefore many subsequent reactions are possible.

Structural insights into the multinuclear speciation of tetravalent cerium in the tri-n-butyl phosphate-n-dodecane solvent extraction system.

X-ray and electrochemical studies of organic phases obtained by the extraction of tetravalent cerium, Ce(iv), from aqueous nitric acid (3 M) with tri-n-butyl phosphate (TBP) in n-dodecane reveal a tetranuclear Ce(iv) structural motif. This finding is consistent with the results of previous liquid-liquid extraction (LLE) studies that implicate the aggregation of (Ce-O-Ce)6+ dimers into multinuclear Ce(iv)·TBP solvates. The organic solution structures elaborated here for the Ce(iv)-HNO3-20% TBP-n-C12H26 system are correlated with multiscale phenomena-from the atomic level of the cerium coordination environment to the supramolecular scale of solute aggregates-in the organic phases, which are of relevance to the PUREX (Plutonium Uranium Reduction EXtraction) process. The combination of XANES, EXAFS, and SAXS results indicate the presence of tetranuclear cerium(iv)-oxo core structures in each of the organic phases investigated. In addition to the use of X-ray spectroscopy and scattering for direct metrical details about the organic phase solute speciation, three-phase-electrode differential pulse voltammetry (DPV) of the third phase reveals a wave attributable to Ce(iv) reduction. The electrode potential is consistent with values for the reduction of Ce(iv) in (Ce-O-Ce)6+ dimers in aqueous electrolytes. The Ce(iv) coordination chemistry of the organic solvates is independent of the bulk phenomenon of phase splitting, namely third phase formation. The local, molecular environment of Ce in the organic phase before splitting is identical to those in the two organic phases (the dense third phase and the light phase) after splitting. SAXS data are consistent with the formation of small spherical reverse micelles with core diameters (approx. 6 Å) that can accommodate a tetranuclear Ce(iv) oxo-cluster solvate of TBP. Sticky sphere modeling of the SAXS data for the organic phases with low cerium concentrations (<0.14 M) is consistent with the presence of randomly- and homogenously-dispersed micelles in combination with short-range percolated, associated micelles. At high cerium concentrations (approx. 1.5 M) in the third phase, the SAXS modeling is consistent with correlated, long-range percolated micellar aggregates. The presence of strong inter-micellar interactions (-3 to -5kBT) in all organic phases of the Ce(iv)-HNO3-TBP-n-C12H26 LLE system suggests that the phenomena of phase splitting and third phase inversion are due to liquid precipitation that is dependent solely on the concentration of the tetranuclear Ce solvate.