Alternative Synthetic Approach Research Articles

Exploring the Impact of Ring Mobility on the Macroscopic Properties of Doubly Threaded Slide-Ring Gel Networks.

The integration of mechanically interlocked molecules (MIMs) into polymeric materials has led to the development of mechanically interlocked polymers (MIPs). One class of MIPs that have gained attention in recent years are slide-ring gels (SRGs), which are generally accessed by crosslinking rings on a main-chain polyrotaxane. The mobility of the interlocked crosslinking moieties along the polymer backbone imparts enhanced properties onto these networks. An alternative synthetic approach to SRGs is to use a doubly threaded ring as the crosslinking moiety, yielding doubly threaded slide-ring gel networks (dt-SRGs). In this study, a photo-curable ligand-containing thread was used to assemble a series of metal-templated pseudo[3]rotaxane crosslinkers that allow access to polymer networks that contain doubly threaded interlocked rings. The physicochemical and mechanical properties of these dt-SRGs with varying size of the ring crosslinking moieties were investigated and compared to an entangled gel (EG) prepared by polymerizing the metal complex of the photo-curable ligand-containing thread, and a corresponding covalent gel (CG). Relative to the EG and CG, the dt-SRGs exhibit enhanced swelling behavior, viscoelastic properties, and stress relaxation characteristics. In addition, the macroscopic properties of dt-SRGs could be altered by "locking" ring mobility in the structure through remetalation, highlighting the impact of the mobility of the crosslinks.

Exploring the Impact of Ring Mobility on the Macroscopic Properties of Doubly Threaded Slide‐Ring Gel Networks

AbstractThe integration of mechanically interlocked molecules (MIMs) into polymeric materials has led to the development of mechanically interlocked polymers (MIPs). One class of MIPs that have gained attention in recent years are slide‐ring gels (SRGs), which are generally accessed by crosslinking rings on a main‐chain polyrotaxane. The mobility of the interlocked crosslinking moieties along the polymer backbone imparts enhanced properties onto these networks. An alternative synthetic approach to SRGs is to use a doubly threaded ring as the crosslinking moiety, yielding doubly threaded slide‐ring gel networks (dt‐SRGs). In this study, a photo‐curable ligand‐containing thread was used to assemble a series of metal‐templated pseudo[3]rotaxane crosslinkers that allow access to polymer networks that contain doubly threaded interlocked rings. The physicochemical and mechanical properties of these dt‐SRGs with varying size of the ring crosslinking moieties were investigated and compared to an entangled gel (EG) prepared by polymerizing the metal complex of the photo‐curable ligand‐containing thread, and a corresponding covalent gel (CG). Relative to the EG and CG, the dt‐SRGs exhibit enhanced swelling behavior, viscoelastic properties, and stress relaxation characteristics. In addition, the macroscopic properties of dt‐SRGs could be altered by “locking” ring mobility in the structure through remetalation, highlighting the impact of the mobility of the crosslinks.

Frustrated Alternative Approaches towards the Synthesis of a Thermally Stable 1,2-Diazacyclobutene.

We have previously demonstrated that an appropriately substituted four-membered-ring 1,2-diazacyclobutene is a useful compound in organic synthesis for the introduction of strained 1,2-diazetidine rings. In order to further explore the reactivity of this interesting heterocycle, we sought a method to improve upon the poor synthetic yield reported earlier. A novel route involving the synthesis of a similarly substituted 1,2-diazetidine compound followed by free-radical bromination and base-catalyzed debromination appeared promising. While there are some studies on the synthesis of the desired 1,2-diazetidine precursor, when we attempted its synthesis, we instead observed the exclusive formation of an eight-membered "dimer"-like compound. The structure of this compound was confirmed via single-crystal X-ray analysis. Fortunately, an alternative synthetic approach for the formation of the desired 1,2-diazetidine precursor proved successful, and the structure of the precursor has been confirmed via X-ray analysis. However, unfortunately, the required bromination step proved to be more challenging than expected, and ultimately, this route had to be abandoned since the anticipated improvement upon the original yield did not seem promising. Single-crystal X-ray analysis proved pivotal in properly identifying the structures of the synthesized compounds.

A remarkable change in inhibition potency and selectivity of isofagomine by simple N-modification

AbstractHerein, we present an alternative and elegant synthetic approach toward powerful β-glucosidase inhibitor isofagomine. Derivatizations of the ring nitrogen provided a selected set of N-modified isofagomine analogues. Biological evaluation of these compounds showed a remarkable change in potency as well as α/β-preference for various glycosidases from different sources when compared to the parent compound isofagomine. Overall, the conducted N-modification improved the potency against α-glucosidase from Saccharomyces cerevisiae (GH13). Coming along, significant diminished activities toward GH1 family β-glucosidases from three different sources have been observed for all tested derivatives. Moreover, and contrary to isofagomine, deactivations of β-galactosidase from Escherichia coli (GH2) as well as α-mannosidase from Canavalia ensiformis (GH38) have not been verified for this series of compounds. Graphical abstract

Cation exchange synthesis of AgBiS2 quantum dots for highly efficient solar cells.

Silver bismuth sulfide (AgBiS2) nanocrystals have emerged as a promising eco-friendly, low-cost solar cell absorber material. Their direct synthesis often relies on the hot-injection method, requiring the application of high temperatures and vacuum for prolonged times. Here, we demonstrate an alternative synthetic approach via a cation exchange reaction. In the first-step, bis(stearoyl)sulfide is used as an air-stable sulfur precursor for the synthesis of small, monodisperse Ag2S nanocrystals at room-temperature. In a second step, bismuth cations are incorporated into the nanocrystal lattice to form ternary AgBiS2 nanocrystals, without altering their size and shape. When implemented into photovoltaic devices, AgBiS2 nanocrystals obtained by cation exchange reach power conversion efficiencies of up to 7.35%, demonstrating the efficacy of the new synthetic approach for the formation of high-quality, ternary semiconducting nanocrystals.

Towards Conformal and Fluorine-Free Coatings on Carbon Fiber Substrates for Polymer Electrolyte Fuel Cells

Decarbonizing the automotive sector has become a priority in the last decades. Polymer electrolyte fuel cells (PEFCs) are a promising technology for this purpose, thanks to their high power, high efficiency, fast refilling and potentially zero emissions. In particular, PEFCs are well-suited for heavy-duty applications, as they show unique scalability in terms of power and efficiency, and require a limited amount of infrastructure, as fewer refuelling stations are needed due to dedicated and more predictable routes1. However, to achieve reliable and cost-effective systems, existing challenges related to performance and durability need to be overcome. A powerful approach to improve the competitiveness of the system is to optimize the water management, as it is a complex but performance-defining issue2. Although the water generated during operation is beneficial to the membrane and the ionomer for proton conduction, it causes mass transport losses in the gas diffusion media by blocking the transport pathways for the reactant gases, limiting the overall performance of the system. State-of-the-art gas diffusion media are made by dip-coating carbon fiber-based substrates in a polytetrafluoroethylene (PTFE) dispersion. The treatment provides the material with the required hydrophobicity, but suffers from two major drawbacks. First, the PTFE coverage is heterogenous, which results in uneven distribution of the wetting properties3. Second, the weak physical interactions between the substrate and the coating cause PTFE loss under operating conditions, negatively impacting the overall system performance and durability4. In addition, efforts are being made to replace fluorine-containing materials, which are very prominent in PEFCs, because of the fluorine toxicity that might result in a ban of per- and polyfluoroalkyl substances in 20245.Our goal is to overcome the existing challenges through an alternative coating approach leveraging principles of liquid phase electrochemistry, electrografting. The proposed technique enables the formation of tunable and conformal hydrophobic layers covalently bonded to the substrate6,7, which we hypothesize would result in more stable and homogeneous coatings. Furthermore, given the large variety of molecules that can be grafted using this method, we foresee a pathway for the development of fluorine-free coatings. In this talk, I will first discuss our alternative synthetic approach to hydrophobize fibrous substrates using fluorine-free molecules, such as silanes or siloxanes. Secondly, I will present our efforts to elucidate the relationship between the fibrous substrate composition and their properties. To assess the chemical nature and the morphology of the surfaces, we perform X-ray photoelectron spectroscopy and scanning electron microscopy with energy dispersive X-ray spectroscopy, confirming the presence of Si element on the surfaces. To evaluate the wetting properties, we measure external contact angles of water and lower surface tension mixtures on diffusion media surfaces, solid surface energies, and electrochemical double layer capacitance as an indirect metric of the wetted area. Thanks to these techniques, we find comparable water repellency between the new coating materials and the traditional PTFE-based ones. Finally, I will discuss the performance of the novel gas diffusion layers in single-cell polymer electrolyte fuel cells. The ultimate goal of our research is to synthesize advanced fluorine-free gas diffusion media with improved performance and durability. Acknowledgments This project has received funding from the Fuel Cells and Hydrogen 2 Joint Undertaking (JU) under grant agreement No 101007170. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and Hydrogen Europe and Hydrogen Europe Research. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 899987 and the Eindhoven Institute for Renewable Energy Systems. References (1) Cullen, D. A.; Neyerlin, K. C.; Ahluwalia, R. K.; Mukundan, R.; More, K. L.; Borup, R. L.; Weber, A. Z.; Myers, D. J.; Kusoglu, A. Nat Energy 2021, 6 (5), 462–474.(2) Yue, L.; Wang, S.; Araki, T.; Utaka, Y.; Wang, Y. Int J Hydrogen Energy 2021, 46 (3), 2969–2977.(3) Rofaiel, A.; Ellis, J. S.; Challa, P. R.; Bazylak, A. J Power Sources 2012, 201, 219–225.(4) Pan, Y.; Wang, H.; Brandon, N. P. J Power Sources 2021, 230560.(5) ECHA (European Chemical Agency), Restriction on the manufacture, placing on the market and use of PFASs , 2023, https://echa.europa.eu/-/echa-publishes-pfas-restriction-proposal.(6) Bélanger, D.; Pinson, J. Chem Soc Rev 2011, 40 (7), 3995–4048.(7) Thomas, Y. R. J.; Benayad, A.; Schroder, M.; Morin, A.; Pauchet, J. ACS Appl Mater Interfaces 2015, 7 (27), 15068–15077.

Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (Kiσ1R = 38 ± 3.7; Kiσ2R = 2917 ± 769 and HDACs IC50 = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ1R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.

Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures.

Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [127I]PSMA-m-IB and [127I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [123I]PSMA-p-IB was higher than that of [123I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [123I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [123I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [123I]PSMA-p-IB showed less accumulation than [177Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.

Iron(III) Sulfate-Mediated Synthesis of 2,5-Furandicarboxylic Acid Dimethyl Ester from Galactaric Acid

2,5-furandicarboxylic acid (FDCA) is one of the most studied bio-based monomers, being considered the best substitute for fossil-derived terephthalic acid in plastic production. FDCA is employed in the preparation of polyethylene furanoate (PEF), demonstrating superior mechanical and thermal proprieties compared to the widely used polyethylene terephthalate (PET). Nevertheless, FDCA synthesis mostly relies on the oxidation of the bio-based platform chemical hydroxymethyl furfural (HMF), whose notoriously instable nature renders FDCA yield and industrial scale-up production complicated. On the contrary, FDCA esters are less studied, even though they have greater solubility in organic media, which would favor their isolation and potential application as monomers for PEF. On these premises, we report herein an alternative green synthetic approach to FDCA methyl ester (FDME) using galactaric acid as the substrate, dimethyl carbonate (DMC) as the green media, and Fe2(SO4)3 as the heterogeneous Lewis acid. Optimization of the reaction conditions allowed the selective production of FDME in a 70% isolated yield; product purification was achieved via flash column chromatography over silica. Furthermore, it was possible to employ up to 5.0 g of galactaric acid in a single reaction, leading to a good isolated yield of FDME.

Synthetic Improvements and an Alternative Synthetic Approach to exo‐Dicyclopentadiene‐1‐one: A Useful Building Block for Cyclopentanoids

AbstractHere, we describe the synthetic improvements to the known compound exo‐dicyclopentadiene‐1‐one (exo‐DCPD‐1‐one). Also, an alternative and efficient synthetic approach to exo‐DCPD‐1‐one was developed in a non‐hazardous manner. All the synthesized compounds here are well‐characterized by NMR analysis. The structure and relative stereochemistry of some key intermediates were confirmed by single‐crystal X‐ray diffraction (XRD) studies. Overall, the synthetic studies described here are useful to prepare exo‐DCPD‐1‐one on a multi‐gram scale in a safe manner. The exo‐DCPD‐1‐one is found to be a useful building block to prepare a wide variety of cyclopentanoids.

Regional Classification of Serbian Railway Transport System Through Efficient Synthetic Indicator

The railway transport system is one of the most important elements in the development of the economy and the social space of any area. The main objective of the study is to analyse the regional differentiation in railway development in Serbia with causal interference. The research has been conducted based on secondary data collected from multiple sources, and the existing synthetic Indicator was applied to classify eight states based on their railway infrastructural status. An alternative synthetic indicator approach has been proposed and found to be more efficient than the existing synthetic Indicator. The causality of such unequal development has been analysed through a correlation test by defining the composite infrastructure index. The analysis revealed that railway infrastructure significantly influences Serbia's economic and social development. The service area of railway infrastructure indicates the potential zone for future growth.

KOH-promoted cascade C-Cl bond activation and amidation of trichloromethyl aromatic compounds with formamides in water.

A KOH-promoted cascade C-Cl bond activation and amidation of trichloromethyl aromatic compounds with formamides using water as a solvent has been developed. This methodology suggested an alternative synthetic approach for the synthesis of aryl amide compounds in the absence of catalysts, additives and organic solvents. In addition, the yields of gram-scale reactions are good and provide a basis for synthetic application.

Cover Feature: Mannich Reaction: An Alternative Synthetic Approach for Various Pyrrole‐Based Anion Receptors and Chelating Ligands (Eur. J. Org. Chem. 34/2022)

The Cover Feature illustrates the Mannich reaction as an alternative approach for the synthetic development of structurally diverse pyrrole-based acyclic, tripodal, macrocyclic, and macrobicyclic molecules, which are useful as anion receptors, chelating ligands, and as precursors for further reactions. Background image is the main arena of the C. V. Raman Global University where the corresponding author is currently working at. More information can be found in the Review by T. Guchhait, Satabdi Roy et al.

Mannich Reaction: An Alternative Synthetic Approach for Various Pyrrole‐Based Anion Receptors and Chelating Ligands

AbstractThis review article highlights the synthetic design of various pyrrole‐based acyclic, tripodal, macrocyclic, and macrobicyclic Mannich bases and their applications, mainly as anion receptors. By varying the amine‐types and molar proportions of reagents, a range of value‐added Mannich bases are obtained. Herein, the synthesis and properties of several azacalixpyrroles, azacalixdipyrrolylmethanes, and azacryptands are discussed. Emphasis is also given to the applications of pyrrole‐based Mannich bases in the construction of some chelating ligands as one of the steps in multistep organic syntheses. In addition, the use of Mannich products as ligands for synthesizing metal complexes is also described. More importantly, the establishment of Mannich reactions as an alternative approach for traditionally used Schiff's base or aldehyde/ketone‐condensation reactions is delineated.

Highly Conductive Garnet-Type Electrolytes: Access to Li6.5La3Zr1.5Ta0.5O12 Prepared by Molten Salt and Solid-State Methods.

Tantalum-doped garnet (Li6.5La3Zr1.5Ta0.5O12, LLZTO) is a promising candidate to act as a solid electrolyte in all-solid-state batteries owing to both its high Li+ conductivity and its relatively high robustness against the Li metal. Synthesizing LLZTO using conventional solid-state reaction (SSR) requires, however, high calcination temperature (>1000 °C) and long milling steps, thereby increasing the processing time. Here, we report on a facile synthesis route to prepare LLZTO using a molten salt method (MSS) at lower reaction temperatures and shorter durations (900 °C, 5 h). Additionally, a thorough analysis on the properties, i.e., morphology, phase purity, and particle size distribution of the LLZTO powders, is presented. LLZTO pellets, either prepared by the MSS or the SSR method, that were sintered in a Pt crucible showed Li+ ion conductivities of up to 0.6 and 0.5 mS cm-1, respectively. The corresponding activation energy values are 0.37 and 0.38 eV, respectively. The relative densities of the samples reached values of approximately 96%. For comparison, LLZTO pellets sintered in alumina crucibles or with γ-Al2O3 as sintering aid revealed lower ionic conductivities and relative densities with abnormal grain growth. We attribute these observations to the formation of Al-rich phases near the grain boundary regions and to a lower Li content in the final garnet phase. The MSS method seems to be a highly attractive and an alternative synthetic approach to SSR route for the preparation of highly conducting LLZTO-type ceramics.

Photoswitchable gRNAs for Spatiotemporally Controlled CRISPR-Cas-Based Genomic Regulation.

The recently discovered CRISPR-Cas gene editing system and its derivatives have found numerous applications in fundamental biology research and pharmaceutical sciences. The need for precise external control over the gene editing and regulatory events has driven the development of inducible CRISPR-Cas systems. While most of the light-controllable CRISPR-Cas systems are based on protein engineering, we developed an alternative synthetic approach based on modification of crRNA/tracrRNA duplex (guide RNA or gRNA) with photocaging groups, preventing the gRNA from recognizing its genome target sequence until its deprotection is induced within seconds of illumination. This approach relies on a straightforward solid-phase synthesis of the photocaged gRNAs, with simpler purification and characterization processes in comparison to engineering a light-responsive protein. We have demonstrated the feasibility of photocaging of gRNAs and light-mediated DNA cleavage upon brief exposure to light in vitro. We have achieved light-mediated spatiotemporally resolved gene editing as well as gene activation in cells, whereas photocaged gRNAs showed virtually no detectable gene editing or activation in the absence of light irradiation. Finally, we have applied this system to spatiotemporally control gene editing in zebrafish embryos in vivo, enabling the use of this strategy for developmental biology and tissue engineering applications.

An Alternative and Facile Synthetic Approach for the Precursors of 3- and 6-Aminosugar Donors and Study of One-pot Glycosyltrasferation

3- and 6-aminosugars are common motifs in bioactive compounds playing pivotal roles in the bioactivity of the core molecules to which they are attached. However, de novo synthesis of 3- and 6-amino...

Revisiting indeno[2,1-c]fluorene synthesis while exploring the fully conjugated s-indaceno[2,1-c:6,5-c']difluorene.

Described herein is an alternative synthetic approach for conjugated indeno[2,1-c]fluorene, including the experimental and theoretical investigations of a tetraradicaloid s-indaceno[2,1-c:6,5-c']difluorene that belongs to the rarely explored indacenodifluorene family containing 4n + 2 monocyclic conjugated π-electrons. Expedient synthesis, broad absorption reaching 1150 nm, and small HOMO-LUMO energy gap make [2,1-c:6,5-c']s-IDF a promising candidate for optoelectronic applications.

Valorization of C5 polyols by direct carboxylation to FDCA: Synthesis and characterization of a key intermediate and role of carbon dioxide

Replacing fossil-C based plastics with those derived from renewable-C is one of the goals of the modern polymer industry. 2,5-Furan dicarboxylic acid (2,5-FDCA) is a candidate to substitute terephthalic acid as comonomer for polyesters. 2,5-FDCA is usually produced from C6 sugars. Carboxylation of 2-furancarboxylic acid (2-FCA) to 2,5-FDCA is an alternative synthetic approach to such monomer for polyethene furoate (PEF) preparation. In this work, several inorganic carbonates have been tested in the 2-FCA carboxylation in presence and absence of CO2. A key copper intermediate has been synthesized and fully characterized that is able to increase the acidity and, thus, the reactivity of 5-H towards a carbonate species. Carboxylation occurs at 93% yield in absence of CO2. The role of metal salts and CO2 were investigated. The conversion yield of 2-FCA into the dicarboxylic acid is related to the charge density on the metal cation, increasing with lower charge-density.

Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock.

Ozanimod represents a recently developed, promising active pharmaceutical ingredient (API) molecule in combating multiple sclerosis. Addressing the goal of a scalable, economically attractive, and technically feasible process for the manufacture of this drug, a novel alternative synthetic approach toward ( S)-4-cyano-1-aminoindane as a chiral key intermediate for ozanimod has been developed. The total synthesis of this intermediate is based on the utilization of naphthalene as a readily accessible, economically attractive, and thus favorable petrochemical starting material. At first, naphthalene is transformed into 4-carboxy-indanone within a four-step process by means of an initial Birch reduction, followed by an isomerization of the C═C double bond, oxidative C═C cleavage, and intramolecular Friedel-Crafts acylation. The transformation of the 4-carboxy-indanone into ( S)-4-cyano-1-aminoindane then represents the key step for introducing the chirality and the desired absolute S configuration. When evaluating complementary biocatalytic approaches based on the use of a lipase and transaminase, respectively, the combination of a chemical reductive amination of the 4-carboxyindanone followed by a subsequent lipase-catalyzed resolution turned out to be the most efficient route, leading to the desired key intermediate ( S)-4-cyano-1-aminoindane in satisfactory yield and with excellent enantiomeric excess of 99%.