Sulfonyl Research Articles

A New Method for the Introduction of an Acylsulfonamide Moiety Applied to a 3-Substituted Functionalized Indole Framework ­Related to the Welwitindolinone Alkaloids

AbstractThe one-pot reaction between an α-formylcyclohexanone derivative and tosyl azide in the presence of rhodium trifluoroacetate dimer afforded an acylsulfonamide derivative. This transformation is proposed to arise from a domino mechanism involving the in situ generation, through the Regitz method, of an α-diazoketone, followed by its transformation into a rhodium carbenoid and its combination with N-tosylformamide, generated as a side product of the first step of the mechanism. Overall, this transformation leads to the generation of a C–N bond between the formyl carbon and the azide nitrogen adjacent to the sulfonyl group.

Catalyst-Controlled Direct Oxysulfonylation of Alkenes by Using Sulfonylazides as the Sulfonyl Radical.

A copper/cobalt-catalyzed difunctionalization of alkenes with sulfonylazides and tert-butyl hydroperoxide has been achieved. This protocol provides an efficient and direct oxysulfonylation approach to β-ketosulfones and β-sulfonyl peroxides in moderate to good yields under mild conditions. This methodology applies sulfonylazides as a new sulfonyl radical source and features a wide substrate scope and good functional group tolerance.

Radical Cascade Cyclization of Unactivated Alkene-Tethered Indoles with Aryldiazonium Salt and Sodium Metabisulfite to Access Azo- and Sulfonylated-2,3-Dihyro-1H-pyrrolo[1,2-a]indoles.

A method for the construction of heterocyclic scaffold 2,3-dihyro-1H-pyrrolo[1,2-a]indoles via arylsulfonyl radical-triggered cascade cyclization of unactivated alkene-tethered indoles in the absence of any external photocatalyst has been developed. This protocol features easily accessible starting materials such as sodium metabisulfite and aryldiazonium tetrafluoroborates at room temperature and offers good functional group compatibility, enabling the introduction of various functionalized sulfonyl and azo groups into pyrrolo[1,2-a]indoles.

EnT-Mediated Amino-Sulfonylation of Alkenes with Bifunctional Sulfonamides: Access to β-Amino Sulfone Derivatives.

β-Amino sulfones are commonly found structural motifs in biologically active compounds. Herein, we report a direct photocatalyzed amino-sulfonylation reaction of alkenes for the efficicient production of important compounds by simple hydrolysis without the need for additional oxidants and reductants. In this transformation, the sulfonamides worked as bifunctional reagents, simultaneously generating sulfonyl radicals and N-centered radicals which were added to alkene in a highly atom-economical fashion with high regioselectivity and diastereoselectivity. This approach showed high functional group tolerance and compatibility, facilitating the late-stage modification of some bioactive alkenes and sulfonamide molecules, thereby expanding the biologically relevant chemical space. Scaling up this reaction led to an efficient green synthesis of apremilast, one of the best-selling pharmceuticals, demonstrating the synthetic utility of the applied method. Moreover, mechanistic investigations suggest that an energy transfer (EnT) process was in operation.

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses.

Spirocyclic compounds containing heterocyclic moieties represent promising 3D scaffolds for modern drug design. In the search for novel anti-flaviviral agents, we have obtained a series of 3-[N,N-bis(sulfonyl)amino]isoxazolines containing spiro-annulated cyclooctane rings and assessed their antiviral activity against tick-borne encephalitis (TBEV), yellow fever (YFV), and West Nile (WNV) viruses. The structural analogs of spirocyclic compounds with a single sulfonyl group or 1,2-annulated cyclooctane ring were also investigated. Almost all the studied 3-[N,N-bis(sulfonyl)amino]isoxazolines revealed antiviral activity against TBEV and WNV. The most active against TBEV was spiro-isoxazoline derivative containing p-nitrophenyl groups in the sulfonyl part (EC50 2.0 ± 0.5 μM), while the highest potency against WNV was found for the compounds with lipophilic substituents in sulfonyl moiety, naphtyl being the most favorable one (EC50 1.3 ± 0.5 μM). In summary, two novel scaffolds of anti-flaviviral agents based on N,N-bis(sulfonyl)amino]isoxazoline were proposed, and the compounds of this type demonstrated activity against TBEV and WNV.

Pillar-layered metal-organic frameworks with benchmark C2H2/C2H4 and C2H6/C2H4 selectivity for one-step C2H4 production

Energy-efficient adsorptive separation shows great potential for the one-step production of high-purity ethylene (C2H4) from ternary C2 hydrocarbons. However, it remains a formidable challenge to fabricate high-performance adsorbents that exhibit simultaneous high selectivity (>2) towards acetylene/ethylene (C2H2/C2H4) and ethane/ethylene (C2H6/C2H4). Herein, we report a pillar-layered metal–organic framework, Ni(sdba)(dabco)0.5 (H2sdba = 4,4′-sulfonyldibenzoic acid; dabco = 1,4-diazabicyclo [2.2.2] octane), for preferential trapping of C2H6 and C2H2 over C2H4. The abundant accessible binding sites endow Ni(sdba)(dabco)0.5 with outstanding C2H2/C2H4 (2.28) and C2H6/C2H4 (2.47) selectivity with high C2H6 (3.15 mmol g−1) and C2H2 (4.41 mmol g−1) uptake among porous materials reported for one-step C2H4 purification. Dynamic breakthrough experiments demonstrated the feasibility of producing high-purity C2H4 (>99.9%) from C2H2/C2H6/C2H4 gas-mixtures (1/1/1 and 1/9/90, v/v/v) in a single step. Computational simulations reveal that the aromatic-rich pore spaces, which decorated with accessible interlayer uncoordinated oxygen atoms of sulfonyl groups and alkyl functionalities, can provide multiple C-H···O, C-H···π, and C-H···H interactions for selectively recognizing C2H6 and C2H2 over C2H4.

Unlocking the Potential of β-Fragmentation of Aminophosphoranyl Radicals for Sulfonyl Radical Reactions.

Exploiting β-scission in aminophosphoranyl radicals for radical-mediated transformations has been a longstanding challenge. In this study, we investigated the untapped potential of β-fragmentation in aminophosphoranyl radicals by leveraging the unique properties of the P-N bond and the substituents of P(III) reagents. Our approach carefully considers factors such as cone angle and electronic properties of phosphine and employs density functional theory (DFT) calculations to probe structural and molecular orbital influence. We successfully induced β-fragmentation through N-S bond cleavage of aminophosphoranyl radicals under visible light and mild conditions, generating a range of sulfonyl radicals derived from pyridinium salts via the photochemical activity of electron donor-acceptor (EDA) complexes. This innovative synthetic strategy exhibits broad applicability, including late-stage functionalization, and paves the way for valuable sulfonyl radical-mediated reactions, such as alkene hydrosulfonylation, difunctionalization, and pyridylic C-H sulfonylation.

An evaluation of spectral and statistical parameters of ion pair complexation of Zafirlukast using chromogenic dyes in solid dispersion-based formulations

The purpose of present work was to develop a novel analytical method for orally given leukotriene antagonist Zafirlukast (ZST), present in Meglumine and Eudragit EEPO based solid dispersion formulation. Four simple, extraction-free, fast, and economical methods based on charge transfer complexation among nitrogen of ZST with sulfonyl group comprising chromogenic mediator bromophenol blue (BPB-Method B), bromothymol blue (BTB-Method C) and bromocresol green (BCG-Method D). The first method (A) is based on the analysis using 0.1 M HCl as a solvent at λmax 242 nm while chromogenic methods yield color complex at λmax 415 nm (BPB-Method B), λmax 420 nm (BTB-Method C) and λmax 435 nm (BCG-Method D). The Beer’s Law stayed linear in the concentration ranges of 1–10, 10–75, 5–40 and 15–100 μg/ml for methods A, B, C and D, respectively. The spectral and thermodynamic characterization of each method was carried out by the application of Molar Absorptivity, LOD, LOQ, Association Constant and Gibbs free energy (ΔGo). The methods were statistically optimized and evaluated by F-Distribution Value, P-Value, Shapiro-Wilk P-Value, regression analysis, Q-Q plot, prediction interval, residual histogram and plots. Various experimental conditions affecting the complexation and stability of chromogenic complexes are cautiously studied including optimal temperature, chromogenic agent volume, color stability, recovery, precision and accuracy. All the measurements were executed under ICH guidelines. It can be established that proposed would be an appropriate prospective analytical approach for estimation of ZST in pure bulk, solid dispersions and dosage forms.

Bi‐affinity Electrolyte Optimizing High‐Voltage Lithium‐Rich Manganese Oxide Battery via Interface Modulation Strategy

AbstractThe practical implementation of high‐voltage lithium‐rich manganese oxide (LRMO) cathode is limited by the unanticipated electrolyte decomposition and dissolution of transition metal ions. The present study proposes a bi‐affinity electrolyte formulation, wherein the sulfonyl group of ethyl vinyl sulfone (EVS) imparts a highly adsorptive nature to LRMO, while fluoroethylene carbonate (FEC) exhibits a reductive nature towards Li metal. This interface modulation strategy involves the synergistic use of EVS and FEC as additives to form robust interphase layers on the electrode. As‐formed S‐endorsed but LiF‐assisted configuration cathode electrolyte interphase with a more dominant −SO2− component may promote the interface transport kinetics and prevent the dissolution of transition metal ions. Furthermore, the incorporation of S component into the solid electrolyte interphase and the reduction of its poorly conducting component can effectively inhibit the growth of lithium dendrites. Therefore, a 4.8 V LRMO/Li cell with optimized electrolyte may demonstrate a remarkable retention capacity of 97 % even after undergoing 300 cycles at 1 C.

Bi-affinity Electrolyte Optimizing High-Voltage Lithium-Rich Manganese Oxide Battery via Interface Modulation Strategy.

The practical implementation of high-voltage lithium-rich manganese oxide (LRMO) cathode is limited by the unanticipated electrolyte decomposition and dissolution of transition metal ions. The present study proposes a bi-affinity electrolyte formulation, wherein the sulfonyl group of ethyl vinyl sulfone (EVS) imparts a highly adsorptive nature to LRMO, while fluoroethylene carbonate (FEC) exhibits a reductive nature towards Li metal. This interface modulation strategy involves the synergistic use of EVS and FEC as additives to form robust interphase layers on the electrode. As-formed S-endorsed but LiF-assisted configuration cathode electrolyte interphase with a more dominant -SO2 - component may promote the interface transport kinetics and prevent the dissolution of transition metal ions. Furthermore, the incorporation of S component into the solid electrolyte interphase and the reduction of its poorly conducting component can effectively inhibit the growth of lithium dendrites. Therefore, a 4.8 V LRMO/Li cell with optimized electrolyte may demonstrate a remarkable retention capacity of 97 % even after undergoing 300 cycles at 1 C.

Degradation of bisphenol A, bisphenol S, and bisphenol AF in the UV-LED/chlorine reaction: Effect of pH on the kinetics, transformation products, and degradation pathway

We investigated the UV-LED/chlorine reaction for the degradation of bisphenol A (BPA) and its alternatives, bisphenol S (BPS) and bisphenol AF (BPAF) in water. Three bisphenols (BPs) were removed by the pseudo-first-order kinetics. BPA showed the highest removal compared to BPS and BPAF at pH 7 due to the electron-donating isopropyl group in BPA compared to electron-withdrawing sulfonyl and hexafluoro-isopropyl groups in BPS and BPAF, respectively. While the degradation of BPs during the UV-LED/chlorine reaction was contributed mainly by reactive chlorine species (RCS) at pH 6 to 8, and mainly by chlorination reaction at pH 9 due to the different functional groups and pKa values of BPs, and the status of chlorine depending on pHs. While humic acid suppressed the degradation of BPs, HCO3− ions generally increased the removal of BPs. Chlorinated BPs (ClxBPs) were identified as major transformation products (TPs) in the UV-LED/chlorine reaction using LC-QTOF/MS analysis, and these ClxBPs were effectively removed by further reaction. In addition, >15 minor TPs and three mineralization products (acetate, formate, and chloroform) were identified for each BP degradation. Defluorination (37% in 4 hr) was observed an as the mineralization pathway for BPAF, indicating that UV-LED/chlorine reaction can break the strong C-F bond on BPAF. We proposed the degradation pathways of three BPs based on the identified TPs and theoretical reactive sites calculated using the condensed Fukui function. The major pathways were sequential chlorine substitution, coupling reaction, and hydroxylation reaction. The ECOSAR assessment showed that the UV-LED/chlorine process is effective in lowering the ecotoxicities of BPs and their TPs.

A serendipity of nanofiltration membrane modification using a simple approach: Limited sulfonamidation, remarkable improvements

Surface modification via secondary interfacial polymerization (IP) is a promising technology for the enhancement of nanofiltration (NF) membrane performance such as rejection selectivity. In this study, sulfuryl chloride (SC), containing sulfur element, was employed to introduce sulfonic groups into the active layer of membranes, with a main purpose of investigating the secondary IP mechanisms as well as the variation of membrane structural and physicochemical properties. Moreover, the SC-modified membranes would be endowed with favorable performance. Results showed that SC in a hexane environment behaved similarly with small and reactive diacyl dichloride in enhancing membrane surface negative charge density and contracting membrane pores. Membrane surface characterization showed that the sulfur element had a low concentration with an S/N ratio less than 0.04. This indicated that, on the one hand, the residual amine groups in the nascent active layer for secondary IP were quite limited, and on the other hand, the improvement of membrane performance was remarkably affected by the introduced sulfonyl groups. Consequently, SC in the hexane environment could further enhance the crosslinking degree of the active layer. In addition, SC modification could increase the membrane surface hydrophilicity and narrow the pore size distribution. The SC-modified membranes would be suitable for advanced treatment of drinking water. An optimized membrane with SC modification had a molecular weight cutoff of ∼350 Da and a surface zeta potential of ∼−55.8 mV, and could effectively reject five negatively charged per- and polyfluoroalkyl substances (with molecular weight ranging from 214 to 414 Da) by over 80% while with a low rejection of MgCl2 below 30%..

Visible light-induced crosslinking enables highly permeable and chlorine-resistant polyamide membranes for water purification

Nanofiltration (NF) based purification technology plays a growing role in water softening, wastewater reuse, and drinking water production, whose core component is the thin-film composite (TFC) polyamide (PA) surface separating layer with high water permeation and significant antifouling and chemical resistance. Strengthening water transport with simultaneously improving chemical tolerance and fouling resistance accords with the demands for sustainable water treatment. In this work, a photo-assisted crosslinked NF membrane with a regulated interlaced stripe surface morphology was fabricated through grafting 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) into the PA network during visible light irradiation. Surface structures and chemical features were characterized, and the NF performance, antifouling and chlorine resistance were systematically evaluated. The optimal membrane with AMPS molecules carrying sulfonyl groups crosslinked in the PA network was rendered electronegative charge, uniformly narrowed pore size, improved hydrophilicity, and higher crosslinking degree. The water permeation was augmented to 30.5 L m−2 h−1·bar−1 for the optimal membrane, four times more advanced than the pristine membrane with a water permeability of 5.9 L m−2 h−1·bar−1, and the divalent salt retention was improved to 99.7%. In addition, the optimal membrane also exhibited outstanding chlorine tolerance, fouling removal, and antifouling capacity. The flux recovery ratio (FRR) of the best membrane outperformed that of the pristine membrane and the flux declined more slowly in the whole fouling cycle testing. This work provides a novel avenue for fabricating high-efficiency TFC membranes with great water permeation and fouling resistance.

Oxidative Cascade Sulfonylation/Cyclisation of N‐Propargylindoles with Hantzsch Esters via Sulfur Dioxide Insertion

AbstractAn oxidative sulfonylation/cyclisation of N‐propargylindoles with Hantzsch esters through sulfur dioxide insertion has been developed. The method uses Na2S2O5 as sulfur dioxide source along with 4‐alkyl‐substituted Hantzsch esters as radical precursors for accessing sulfonyl radicals, and allows for the synthesis of 2‐sulfonated 9H‐pyrrolo[1,2‐a]indoles.

Sulfur-Containing Persistent Free Radicals and Reactive Species on Photoaged Microplastics: Identification and the Formation Mechanism.

The elemental composition may affect the persistent free radical (PFR) and reactive species (RS) formation associated with photoaging microplastics; however, a relevant study is still lacking. This study systematically investigated the formation, evolution, and types of PFRs and RS on sulfur-containing microplastics (S-MPs) under simulated sunlight. Electron paramagnetic resonance detection and power saturation curve analysis isolated three different PFRs on each photoaging poly(phenylene sulfide) (PPS) and polysulfone (PSF). Combining the results of characterization and density functional theory calculation, these observed PFRs on the irradiated S-MPs were classified as oxygen-centered radicals with an adjacent S atom (namely, thio-oxygen radicals), oxygen-centered and sulfur-centered radicals, where the thio-oxygen radicals on PPS were benzenethiol-like radicals, and oxygen-centered radicals and sulfur-centered radicals on PSF that were identified as benzenesulfonic-like radicals and phenyl sulfonyl-like radicals, respectively. Moreover, potential precursor molecule fragments of PFRs on the photoaging S-MPs, including p-toluenesulfinic acid and benzenesulfonic acid, were detected by pyrolysis-gas chromatography/mass spectrometry and liquid chromatography-mass spectrometry. Interestingly, reactive sulfur species (SO3•-) was also observed on irradiated S-MPs in addition to reactive oxygen species, which was mainly derived from the reaction of •OH and sulfonyl radicals. These results have implications for assessing the potential risks of atmospheric S-MPs.

Production of nanocellulose using controlled acid hydrolysis from large-scale production of micro-fibrillated cellulose derived from oil palm empty fruit bunches

Nanocellulose is generally known as a versatile material, which is suitable for various applications due to its unique physicochemical properties, including light weight, ease of tunable surface functionalization, and excellent mechanical properties. This research aims to characterize and synthesize nanocellulose produced from acid hydrolysis of large-scaled micro-fibrillated cellulose (MFC) derived from oil palm empty fruit bunches by varying concentrations of H2SO4 from 20 to 35 v/v %. The obtained large-scaled MFC had a density of 1.01 kg/m3 and was dominantly composed of 71% cellulose. After acid hydrolysis of MFC, there were gradual changes in the colour of the obtained cellulose nanocrystals (CNC) dispersion from light white to a darker color with the increase of acid concentration, in which the over hydrolysis occurs at 35% of acid concentration. The use of 25-30% H2SO4 showed the optimum condition to avoid over-hydrolysis and resulted in bright white color of CNC dispersion with excellent stability at zeta potential value of -74.2±0.1 to -88.4±0.2 mV. It was supported by Fourier transform infrared (FTIR) due to the presence of negatively charged sulfonyl and hydroxyl groups upon CNC formation to offer excellent dispersion stability. Based on transmission electron microscope (TEM), rod-like shape CNC with a low aspect ratio of 11.8 at the dimension of 12.8 ± 6.7 nm in width and 151.9 ± 38.3 nm in length was successfully produced. Based on X-ray diffraction (XRD) analysis, the crystallinity of the sample was 76%.

Dual Nickel/Photoredox-Catalyzed Asymmetric Carbosulfonylation of Alkenes.

An asymmetric three-component carbosulfonylation of alkenes is presented here. The reaction, involving the simultaneous formation of a C-C and a C-S bond across the π-system, uses a dual nickel/photoredox catalytic system to produce both β-aryl and β-alkenyl sulfones in high yields and with excellent levels of stereocontrol (up to 99:1 er). This protocol exhibits a broad substrate scope and excellent functional group tolerance and its synthetic potential has been demonstrated by successful applications toward pharmacologically relevant molecules. A broad array of control experiments supports the involvement of a secondary alkyl radical intermediate generated through radical addition of a sulfonyl radical to the double bond. Moreover, stoichiometric and cross-over experiments further suggest an underlying Ni(0)/Ni(I)/Ni(III) pathway operative in these transformations.

Visible-Light-Promoted Selective Sulfonylation and Selenylation of Dienes to Access Sulfonyl-/Seleno-benzazepine Derivatives.

A novel visible-light-promoted selective sulfonylation and selenylation of dienes with selenosulfonates has been developed. This technology provides mild access to a wide range of sulfonyl benzo[b]azepinones and seleno-benzo[b]azepines. Preliminary mechanistic studies suggest that the sulfonylation involves a sulfonyl radical engaged cascade process, and the selenylation is accomplished through a sequential oxidation/electrophilic cyclization process. The large-scale operation and late-stage modification experiment reveal the promising utility of this protocol.

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors.

The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9-13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC50 values of ca. 0.6-10.2 nM) compared to the known drug erlotinib (IC50 of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.

Design and Synthesis of Benzenesulfonamides Coupled with Piperidine, Morpholine, and N,N‐Dimethylethanamine Moieties as Apoptotic Inducers through VEGFR2 and Topoisomerase II Inhibition

AbstractNovel hybrid series of benzenesulfonamide coupled with piperidine, morpholine, and N,N‐dimethylethanamine moieties at sulfonyl group were designed through pharmacophore hybridization, synthesized, and evaluated for cancer treatment. Benzenesulfonamide‐based derivatives had been synthesized, structurally elucidated, and biologically evaluated as potent VEGFR2 kinase and topoisomerase II inhibitors with cytotoxicity against MCF‐7 and HepG2 cells. Interestingly, the most cytotoxic compound against MCF‐7 and HepG2 cells exhibited promising IC50 values of 0.08 and 0.186 μM, respectively, compared to Doxorubicin as the reference drug with IC50 values of 7.67 and 8.28 μM. It exhibited promising dual enzyme inhibition VEGFR2 and Topoisomerase II with IC50 values of 13.24 nM and 8.3 μM compared to Sorafenib and Doxorubicin as standard drugs. It significantly stimulated total apoptotic breast cancer cell death by 55.25‐fold (34.26 % compared to 0.62 for the control), arresting the cell cycle at S‐phase, which affected the apoptosis‐mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the anti‐apoptotic gene Bcl‐2. A molecular docking study was conducted to confirm the binding affinity of the designed compounds towards VEGFR2 and Topoisomerase II proteins with good binding energy and interactive modes as their co‐crystallized ligands.