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1. Novel perfluorinated nanofiltration membranes for isolation of pharmaceutical compounds

   https://doi.org/10.1016/j.seppur.2020.117944  

   Chau, John ; Sirkar, Kamalesh K ; Pennisi, Kenneth J ; Vaseghi, Gazelle ; Derdour, Lotfi ; Cohen, Benjamin ( January 2021 , Separation and purification technology)

   null (Ed.)

   Polymeric membranes for separation of pharmaceutical intermediates/products by organic solvent nanofiltration (OSN) have to be highly resistant to many organic solvents including high-boiling polar aprotic ones, e.g., N- methyl-2-pyrollidone (NMP), dimethylsulfoxide (DMSO), dimethylformamide (DMF). Unless cross-linked, few polymers resist swelling or dissolution in such solvents; however particular perfluoropolymers are resistant to almost all solvents except perfluorosolvents. One such polymer, designated AHP1, a glassy amorphous hydrophobic perfluorinated polymer, has been studied here. Additional perfluoropolymers studied here are hydrophilically modified (HMP2 and HMP3) versions to enhance the flux of polar aprotic solvents. OSN performances of three types of membranes including the hydrophilically modified ones were studied via solvent flux and solute rejection at pressures up to 5000 kPa. The solutes were four active pharmaceutical ingredients (APIs) or pharmaceutical intermediates having molecular weights (MWs) between 432 and 809 Da and three dyes, Oil Blue N (378 Da), Sudan Black B (456 Da), Brilliant Blue R (826 Da). Solvents used were: ethyl acetate, toluene, n- heptane, iso-octane, DMSO, tetrahydrofuran (THF), DMF, acetone, NMP, methanol. Test cells included stirred cells and tangential flow cells. Pure solvent fluxes through three membrane types were characterized using a particular parameter employing various solvent properties. All three membranes achieved high solute rejections around 91–98% at ambient temperatures. HMP2 membrane achieved 95% solute rejection for an API (809 Da) in DMSO at a high temperature, 75 ◦C. A two-stage simulated nanofiltration process achieved 99%+ rejection of a pharmaceutical intermediate (MW, 432 Da) in 75v% NMP-25v% ethyl acetate solution. 

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2. Microfluidic Synthesis of Elastomeric Microparticles: A Case Study in Catalysis of Palladium-Mediated Cross-Coupling

   Bennett, Jeffrey A ; Genzer, Jan ; Abolhasani, Milad ( October 2018 , 2018 AIChE Annual Meeting)

   Metal-mediated cross-coupling reactions offer organic chemists a wide array of stereo- and chemically-selective reactions with broad applications in fine chemical and pharmaceutical synthesis.1 Current batch-based synthesis methods are beginning to be replaced with flow chemistry strategies to take advantage of the improved consistency and process control methods offered by continuous flow systems.2,3 Most cross-coupling chemistries still encounter several issues in flow using homogeneous catalysis, including expensive catalyst recovery and air sensitivity due to the chemical nature of the catalyst ligands.1 To mitigate some of these issues, a ligand-free heterogeneous catalysis reaction was developed using palladium (Pd) loaded into a polymeric network of a silicone elastomer, poly(hydromethylsiloxane) (PHMS), that is not air sensitive and can be used with mild reaction solvents (ethanol and water).4 In this work we present a novel method of producing soft catalytic microparticles using a multiphase flow-focusing microreactor and demonstrate their application for continuous Suzuki-Miyaura cross-coupling reactions. The catalytic microparticles are produced in a coaxial glass capillary-based 3D flow-focusing microreactor. The microreactor consists of two precursors, a cross-linking catalyst in toluene and a mixture of the PHMS polymer and a divinyl cross-linker. The dispersed phase containing the polymer, cross-linker, and cross-linking catalyst is continuously mixed and then formed into microdroplets by the continuous phase of water and surfactant (sodium dodecyl sulfate) introduced in a counter-flow configuration. Elastomeric microdroplets with a diameter ranging between 50 to 300 micron are produced at 25 to 250 Hz with a size polydispersity less than 3% in single stream production. The physicochemical properties of the elastomeric microparticles such as particle swelling/softness can be tuned using the ratio of cross-linker to polymer as well as the ratio of polymer mixture to solvent during the particle formation. Swelling in toluene can be tuned up to 400% of the initial particle volume by reducing the concentration of cross-linker in the mixture and increasing the ratio of polymer to solvent during production.5 After the particles are produced and collected, they are transferred into toluene containing palladium acetate, allowing the particles to incorporate the palladium into the polymer network and then reduce the palladium to Pd0 with the Si-H functionality present on the PHMS backbones. After the reduction, the Pd-loaded particles can be washed and dried for storage or switched into an ethanol/water solution for loading into a micro-packed bed reactor (µ-PBR) for continuous organic synthesis. The in-situ reduction of Pd within the PHMS microparticles was confirmed using energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS) and focused ion beam-SEM, and TEM techniques. In the next step, we used the developed µ-PBR to conduct continuous organic synthesis of 4-phenyltoluene by Suzuki-Miyaura cross-coupling of 4-iodotoluene and phenylboronic acid using potassium carbonate as the base. Catalyst leaching was determined to only occur at sub ppm concentrations even at high solvent flow rates after 24 h of continuous run using inductively coupled plasma mass spectrometry (ICP-MS). The developed µ-PBR using the elastomeric microparticles is an important initial step towards the development of highly-efficient and green continuous manufacturing technologies in the pharma industry. In addition, the developed elastomeric microparticle synthesis technique can be utilized for the development of a library of other chemically cross-linkable polymer/cross-linker pairs for applications in organic synthesis, targeted drug delivery, cell encapsulation, or biomedical imaging. References 1. Ruiz-Castillo P, Buchwald SL. Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem Rev. 2016;116(19):12564-12649. 2. Adamo A, Beingessner RL, Behnam M, et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science. 2016;352(6281):61 LP-67. 3. Jensen KF. Flow Chemistry — Microreaction Technology Comes of Age. 2017;63(3). 4. Stibingerova I, Voltrova S, Kocova S, Lindale M, Srogl J. Modular Approach to Heterogenous Catalysis. Manipulation of Cross-Coupling Catalyst Activity. Org Lett. 2016;18(2):312-315. 5. Bennett JA, Kristof AJ, Vasudevan V, Genzer J, Srogl J, Abolhasani M. Microfluidic synthesis of elastomeric microparticles: A case study in catalysis of palladium-mediated cross-coupling. AIChE J. 2018;0(0):1-10. 

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3. Synthesis and conformational preferences of peptides and proteins with cysteine sulfonic acid

   https://doi.org/10.1039/D3OB00179B  

   Bhatt, Megh R. ; Zondlo, Neal J. ( March 2023 , Organic & Biomolecular Chemistry)

   Cysteine sulfonic acid (Cys-SO3H; cysteic acid) is an oxidative post-translational modification of cysteine, resulting from further oxidation from cysteine sulfinic acid (Cys- SO2H). Cysteine sulfonic acid is considered an irreversible post-translational modification, which serves as a biomarker of oxidative stress that has resulted in oxidative damage to proteins. Cysteine sulfonic acid is anionic, as a sulfonate (Cys-SO –; cysteate), in the ionization state that 3 is almost exclusively present at physiological pH (pKa ~ –2). In order to understand protein structural changes that can occur upon oxidation to cysteine sulfonic acid, we analyzed its conformational preferences, using experimental methods, bioinformatics, and DFT-based computational analysis. Cysteine sulfonic acid was incorporated into model peptides for α-helix and polyproline II helix (PPII). Within peptides, oxidation of cysteine to the sulfonic acid proceeds rapidly and efficiently at room temperature in solution with methyltrioxorhenium (MeReO3) and H2O2. Peptides containing cysteine sulfonic acid were also generated on solid phase using trityl-protected cysteine and oxidation with MeReO3 and H2O2. Using methoxybenzyl (Mob)-protected cysteine, solid-phase oxidation with MeReO3 and H2O2 generated the Mob sulfone precursor to Cys-SO – within fully synthesized peptides. These two solid-phase methods allow the synthesis of peptides containing either Cys-SO – or Cys-SO – in a 32 practical manner, with no solution-phase synthesis required. Cys-SO – had low PPII propensity 3 for PPII propagation, despite promoting a relatively compact conformation in φ. In contrast, in a PPII initiation model system, Cys-SO – promoted PPII relative to neutral Cys, with PPII initiation similar to Cys thiolate but less than Cys-SO – or Ala. In an α-helix model system, Cys- 2 SO – promoted α-helix near the N-terminus, due to favorable helix dipole interactions and 3 favorable α-helix capping via a sulfonate-amide side chain-main chain hydrogen bond. Across all peptides, the sulfonate side chain was significantly less ordered than that of the sulfinate. Analysis of Cys-SO – in the PDB revealed a very strong propensity for local (i/i or i/i+1) side 3 chain-main chain sulfonate-amide hydrogen bonds for Cys-SO –, with > 80% of Cys-SO – 33 residues exhibiting these interactions. DFT calculations conducted to explore these conformational preferences indicated that side chain-main chain hydrogen bonds of the sulfonate with the intraresidue amide and/or with the i+1 amide were favorable. However, hydrogen bonds to water or to amides, as well as interactions with oxophilic metals, were weaker for the sulfonate than the sulfinate, due to lower charge density on the oxygens in the sulfonate. 

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4. In Situ Tracking of Composition and Morphology of a Diblock Copolymer Film with GISAXS during Exchange of Solvent Vapors at Elevated Temperatures

   https://doi.org/10.1002/adfm.201706226  

   Berezkin, Anatoly V. ; Jung, Florian ; Posselt, Dorthe ; Smilgies, Detlef‐M. ; Papadakis, Christine M. ( March 2018 , Advanced Functional Materials)

   Solvothermal vapor annealing at elevated temperature is applied to a thin film from a cylinder‐forming polystyrene‐block‐poly(dimethyl siloxane) (PS‐b‐PDMS) diblock copolymer. At this, the film is swollen in the vapor ofn‐heptane (highly selective for PDMS). This vapor is stepwise replaced by the vapor of toluene (weakly selective for PS). The morphologies are investigated using in situ, real‐time grazing‐incidence small‐angle X‐ray scattering (GISAXS). The initial cylindrical morphology is transformed into, among others, the lamellar one. This novel type of experiments allows probing a trajectory in the state diagram of the PS‐b‐PDMS/n‐heptane/toluene mixture. To corroborate the morphologies, they are generated by molecular simulations, and the 2D GISAXS maps are calculated using the distorted‐wave Born approximation. To relate the morphologies to the solvent distribution in the two types of nanodomains, the latter is estimated from the intensities of the Bragg reflections in the 2D GISAXS maps along with the swelling ratio of the film. Comparison with the results from a similar experiment carried out at room temperature results in the same sequence of morphologies; however, at elevated temperature, more well‐ordered structures are obtained. This new approach proves to be efficient to achieve a block copolymer thin film having a desired morphology and orientation.

    

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5. Two-dimensional d-π conjugated metal-organic framework based on hexahydroxytrinaphthylene

   https://doi.org/10.1007/s12274-020-2874-x  

   Meng, Zheng ; Mirica, Katherine A. ( July 2020 , Nano Research)

   The development of new two-dimensional (2D) d-π conjugated metal-organic frameworks (MOFs) holds great promise for the construction of a new generation of porous and semiconductive materials. This paper describes the synthesis, structural characterization, and electronic properties of a new d-π conjugated 2D MOF based on the use of a new ligand 2,3,8,9,14,15-hexahydroxytrinaphthylene. The reticular self-assembly of this large π-conjugated organic building block with Cu(II) ions in a mixed solvent system of 1,3-dimethyl-2-imidazolidinone (DMI) and H2O with the addition of ammonia water or ethylenediamine leads to a highly crystalline MOF Cu3(HHTN)2, which possesses pore aperture of 2.5 nm. Cu3(HHTN)2 MOF shows moderate electrical conductivity of 9.01 × 10−8 S·cm−1 at 385 K and temperature-dependent band gap ranging from 0.75 to 1.65 eV. After chemical oxidation by I2, the conductivity of Cu3(HHTN)2 can be increased by 360 times. This access to HHTN based MOF adds an important member to previously reported MOF systems with hexagonal lattice, paving the way towards systematic studies of structure-property relationships of semiconductive MOFs. 

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