Coupling Of Thiols Research Articles

Accelerating sulfonyl fluoride synthesis through electrochemical oxidative coupling of thiols and potassium fluoride in flow

Sulfonyl fluorides are valuable synthetic motifs which are currently of high interest due to the popularity of the sulfur (VI) fluoride exchange (SuFEx) click chemistry concept. Herein, we describe a flow chemistry approach to enable their synthesis through an electrochemical oxidative coupling of thiols and potassium fluoride. The reaction can be carried out at room temperature and atmospheric pressure and the yield of the targeted sulfonyl fluoride, by virtue of the short inter-electrode distance between a graphite anode and a stainless-steel cathode, reached up to 92% in only 5 min residence time compared to 6 to 36 h in batch. A diverse set of thiols (7 examples) was subsequently converted in flow. Finally, a fully telescoped process was developed which combines the electrochemical sulfonyl fluoride synthesis with a follow-up SuFEx reaction.

Structure-property relationships of tailored imidazolium- and pyrrolidinium-based poly(ionic liquid)s. Solid-like vs. gel-like systems

In this paper, we present facile synthetic strategies enabling production of well-defined poly(ionic liquids) PILs based on 1-vinyl-4-benzyl-3-methylimidazolium- (VBIm) and 1-vinyl-4-benzyl-3-methylpyrrolidium (VBPy) ionic liquids (IL) possessing different counterions (chloride Cl−vs. bis(trifluoromethanesulfonyl)imide NTf2-) (VBIm/NTf2,VBIm/Cl, VBPy/NTf2,VBPy/Cl). The reaction routes have been selected to design two types of polyelectrolytes i) linear homopolymers showing solid-like behavior and ii) grafted copolymers composing of poly(siloxane) segments extended with analogous ionic domains that shows gel-like behavior. The former one has been produced via controlled radical polymerization methods (CRP) such as atom transfer radical polymerization (ATRP) or reversible addition fragmentation chain-transfer polymerization (RAFT), whereas the second one using thiol-ene coupling photo-polymerization. It was found that the glass transition temperature, Tg, of the synthesized herein linear homopolymer-based systems (both VBIm/NTf2 and VBPy/NTf2- -based) increases with their molecular weight, Mn, similarly as reported for its N-conjugated analogs described in our previous study [Maksym et al.,Polym. Chem., 2017, 8, 5433]. However, they are characterized by markedly lower conductivity, σdc (σdc~10−15 S/cm vs.σdc~10−16S/cm for PVBIm/NTf2vs. PVBPy/NTf2- at Tg determined from calorimetric experiments) when compared to N-conjugated one (σdc~10−9 S/cm for poly(N-vinyl-imidazole)/NTf2). Interestingly, the ionic conductivity value at Tg of grafted is similar to its corresponding linear analogs. Nevertheless, at T = 293K both anhydrous linear and grafted imidazolium-based PILs are characterized by high σdc, reaching values σdc~10−4S/cm and σdc~10−7S/cm, respectively.

Reaction Environment Effect on the Kinetics of Radical Thiol-Ene Polymerizations in the Presence of Amines and Thiolate Anions.

Because of facile implementation, quantitative conversions, and an insensitivity to oxygen, water, and most organic functional groups, radical-mediated thiol-ene coupling (TEC) reactions have emerged as a valuable tool in macromolecule synthesis. It was recently demonstrated that the kinetics and conversions of thiyl radical-mediated reactions are adversely affected in the presence of basic amines by the formation of retardive thiolate anions. Herein, the performance of TEC polymerizations is evaluated under a variety of reaction environments with the intention to aid in the optimal formulation design of TEC reactions in the presence of amines. Results from both bulk and aqueous-phase network photopolymerizations established that sensitivity to amine basicity and pH is dependent on the thiol acidity, although norbornene-type alkenes exhibit a unique ability to achieve high conversions, where allyl ethers, vinyl ether, and vinyl siloxanes are highly inhibited. Additionally, the protic solvents such as alcohols and acetic acid are established as ideal solvents or additives to suppress or eliminate amine-induced retardation.

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge.

Oxidative radical coupling of hydroquinones and thiols using chromic acid: one-pot synthesis of quinonyl alkyl/aryl thioethers.

An efficient, simple and practical protocol for one-pot sequential oxidative radical C–H/S–H cross-coupling of thiols with hydroquinones (HQs) and oxidation leading to the formation of quinonyl alkyl/aryl thioethers using H2CrO4 was developed. This cross-coupling of thiyl and aryl radicals offers mono thioethers in good to moderate yield and works well with a wide variety of thiols. Similarly, this method works well for coupling of 2-amino thiophenol and HQs to form phenothiazine-3-ones 5a–c. C–S bond formation via thioether synthesis was observed using a chromium reagent for the first time. Theoretical studies on the pharmacokinetic properties of compounds 5a–c revealed that due to drug-like properties, compound 5b strongly binds with Alzheimer's disease (AD) associated AChE target sites.

Metal-free C-S coupling of thiols and disulfides.

In organic synthesis, transition-metal and photoredox-catalysis-based reaction systems are emerging trends for the construction of C-S bonds. Many review articles have recently appeared in this field; however, we present herein an overview of metal-free C-S coupling reactions using thiols or disulfides as sulfur surrogates. The oxidants we have considered include peroxides, tert-butyl nitrite (TBN), DDQ, iodine reagents, and molecular oxygen. In addition, selective electrochemical oxidative transformations are also covered with mechanistic details.

Metal-free synthesis of imino-disaccharides and calix-iminosugars by photoinduced radical thiol-ene coupling (TEC).

Radical thiol-ene coupling was exploited for the first time to prepare imino-disaccharides and multivalent iminosugars starting from sugar thiols and iminosugar alkenes or iminosugar thiols and tetra-allylated calixarene, respectively.

Polyesters with main and side chain phosphoesters as structural motives for biocompatible electrospun fibres

The functionalisation of polymacrolactones with phosphoesters was achieved by thiol–ene coupling resulting in copolymers with modulated properties.

Thiol-ene coupling reaction achievement and monitoring by "in situ" UV irradiation NMR spectroscopy.

In this study, the possibilities of a new “in situ” LED UV illumination NMR spectroscopic technique for performing an initiator-free thiol–ene “click” coupling reaction of an allyl-functionalized poly(allyl glycidyl ether) (PAGE) prepolymer with a number of mono- and di-oligo polyethylene glycol (PEG) thiols is demonstrated. The state-of-the-art setup constructed with LEDs as UV light sources that illuminate through optical fibers directly into an NMR testing tube at a fixed wavelength of 365 nm is appropriate for various polymeric materials and biologically active substances. The selected experimental protocol uses a series of periods of irradiation and dark periods, thus providing opportunities to conduct an effective thiol–ene “click” reaction and simultaneously study the kinetics of the photochemical reaction with the exposure time, as well as macromolecular association directly in a solution applying the whole types of NMR methods: from conventional 1H or 13C NMR to diffusion NMR spectroscopy (DOSY). In addition, the molecular mass characteristics of the prepared copolymers were studied by gel-permeation chromatography (GPC). The observed differences in the reaction rates as well as in the size of species formed (the corresponding hydrodynamic radiuses Rh of aggregates) as a result of the coupling process of parent PAGE prepolymers and model PEG thiols were thoroughly discussed and the reaction pathway proposed.

Highly ordered mesoporous La(III)‐substituted 5‐oxopyrrolidine‐2‐carboxylic acid (Glp) immobilized on SBA‐15 as a very efficient nanocatalyst for green aerobic oxidative coupling of thiols to disulfides

Selective aerobic oxidative coupling of thiols that are catalyzed by La(III)‐substituted 5‐oxopyrrolidine‐2‐carboxylic acid (Glp) immobilized on SBA‐15 (SBA‐15@Glp–La; SBA = Santa Barbara amorphous) was studied. Using SBA‐15@Glp–La, the complete conversion was achieved at room temperature in the presence of air without producing any over‐oxidized yields. SBA‐15@Glp–La was prepared by post‐grafting technique. 5‐Oxopyrrolidine‐2‐carboxylic acid (Glp) condensation followed by La(III) impregnation caused this La(III)‐grafted 5‐oxopyrrolidine‐2‐carboxylic acid (Glp) to immobilize on SBA‐15. This SBA‐15@Glp–La catalyst shows excellent catalytic activity in the selective aerobic oxidative coupling of thiols. Effects of amount of the catalyst, polarity of the solvent, effects of substrate, and catalyst reusability were investigated. It has been observed that seven repetitive reaction cycles did not cause any appreciable loss in the catalytic activity of this catalyst. The catalyst characterization by scanning electron microscopy, energy‐dispersive X‐ray spectroscopy, X‐ray diffraction, Fourier‐transform infrared spectroscopy, thermal gravimetric analysis, transmission electron microscopy, inductively coupled plasma, elemental mapping, and N2 adsorption–desorption is reported. The procedure developed is heterogeneous and environmentally benign.

High Refractive Index Polymers (n > 1.7), Based on Thiol–Ene Cross-Linking of Polarizable P═S and P═Se Organic/Inorganic Monomers

A new class of high refractive index polymers was developed through the thiol–ene coupling reaction of trivinylphosphine chalcogenides, [(CH2═CH−)3P═X (X = S, Se)], with 1,2-ethane dithiol and 1,3-...

Metal‐Free Cercosporin‐Photocatalyzed C‐S Coupling for the Selective Synthesis of Aryl Sulfides under Mild Conditions

Aryl sulfides are important motifs of bioactive molecules, which are generally synthesized by transition metal‐based coupling reactions under harsh conditions. Herein, we developed a new method that visible light along with cercosporin, produced by liquid fermentation and functioned as a cost‐effective and environmentally friendly photocatalyst, prompted the selective synthesis of aryl sulfides through C–S coupling of thiols and diazonium salts under mild conditions. Furthermore, this method can also be performed with a great conversion by the direct use of cercosporin‐containing fermentation supernatant as catalytic system without organic solvent extraction.

Curing behavior and properties of high biosourced epoxy resin blends based on a triepoxy monomer and a tricarboxylic acid hardener from 10-undecenoic acid

Renewable propane-1,2,3-triyl tris(9-(oxiran-2-yl) nonanoate) (EGU, 100 wt% biogenic) and a tricarboxylic acid triglyceride (CGTU) hardener (85.7 wt% biogenic) were synthesized from 10-undecenoic acid (10-UDA) and used to produce epoxy resins with 52–92 wt% biobased carbon. CGTU was prepared by thermally activated thiol-ene coupling of thioglycolic acid onto propane-1,2,3-triyl tris(undec-10-enoate), (GUD) in the absence of solvent. The characterized CGTU was used as a green hardener of blends based on EGU and a conventional bisphenol A-based epoxy pre-polymer (DGEBA) at various mass percentages (0–100 wt%) with an stoichiometric epoxy/acid equivalent ratio. Calorimetric studies revealed higher peak temperature, lower reaction heats, and longer gelation times in resins with high EGU proportion, evidencing the lower reactivity of aliphatic EGU compared with aromatic DGEBA. Cured resins were yellowish transparent rubber-like materials with glass transition temperatures (Tg) varying from −14 °C to −42 °C and tensile strength in the range of 1750 kPa–790 kPa, for 0 and 100 wt % EGU, respectively. The soluble fraction of all resins was less than 4.3%, reflecting a high level of crosslinking. Thermosets with high biobased content showed both UV-light protection and visible light transparency.

Building organosilica hybrid nanohemispheres via thiol-ene click reaction on alumina thin films deposited by atomic layer deposition (ALD)

The present work shows a surface-induced preparation of sub-100 nm organosilica nanohemispheres on atomic layer deposited (ALD) Al2O3 thin films, which was achieved by cooperative condensation/hydrolysis and thiol-ene click chemical reactions. The two-step synthetic approach consists of an initial silanization of the Al2O3 film with vinyltrimethoxysilane (VTMS), followed by a photo-promoted growth of surface-bound nanoparticles in the presence of (3-mercaptopropyl)trimethoxysilane (MPTMS). Characterization by means of FE-SEM, XPS and EDS points towards the growth of the nanohemispherical structures being governed by an initial nucleation of thiolated organosilica seeds in solution as a result of self-condensation of MPTMS and oxidation of thiols to disulfides. Once bound to the vinyl terminated Al2O3via photo-assisted thiol-ene coupling, these seeds promote area-selective growth of the nanoparticles through binding of further MPTMS from the solution. After an additional ALD deposition of ZnO, the resulting thin hybrid film exhibits enhanced hydrophobicity when compared to ZnO films deposited directly on Al2O3 under the same processing conditions.

Stereoselective Thioconjugation by Photoinduced Thiol-ene Coupling Reactions of Hexo- and Pentopyranosyl d- and l-Glycals at Low-Temperature-Reactivity and Stereoselectivity Study.

A comprehensive optimization and mechanistic study on the photoinduced hydrothiolation of different d‐ and l‐ hexo‐ and pentoglycals with various thiols was performed, at the temperature range of RT to −120 °C. Addition of thiols onto 2‐substituted hexoglycals proceeded with complete 1,2‐cis‐α‐stereoselectivity in all cases. Hydrothiolation of 2‐substituted pentoglycals resulted in mixtures of 1,2‐cis‐α‐ and ‐β‐thioglycosides of varying ratio depending on the configuration of the reactants. Hydrothiolation of unsubstituted glycals at −80 °C proceeded with excellent yields and, except for galactal, provided the axially C2‐S‐linked isomers with high selectivity. Cooling was always beneficial to the efficacy, increased the yields and in most cases significantly raised the stereoselectivity. The suggested mechanism explains the different conformational preferences of the intermediate carbon‐centered radicals, which is a crucial factor in the stereoselectivity of the reactions.

Combining Click Reactions for the One-Pot Synthesis of Modular Biomolecule Mimetics.

Here, we report on the first combined one-pot use of the two so-called "click reactions": the thiol-ene coupling and the copper-catalyzed alkyne-azide cycloaddition. These reactions were employed in an alternating and one-pot fashion to combine appropriately functionalized monomeric carbohydrate building blocks to create mimics of trisaccharides and tetrasaccharides as single anomers, with only minimal purification necessary. The deprotected oligosaccharide mimics were found to bind both plant lectins and human galectin-3.

Acid-sensitive auxiliary assisted atypical diubiquitin synthesis exploiting thiol-ene coupling

Atypical ubiquitin (Ub) chains are generally involved in intracellular physiological processes, while the molecular mechanisms underlying their regulation remain unclear. In this work, we report an acid-sensitive auxiliary group based bifunctional handle that can prepare Lys27-, Lys29- and Lys33-diUb analogs by thiol-ene coupling (TEC) in combination with native chemical ligation (NCL). A prominent advantage of this method is the rapid and effective removal of acid-sensitive auxiliary groups after the formation of the isopeptide bond mimic. Collectively, this work illustrates the utility of the new strategy in the simple and efficient production of homogeneous atypical diUb analogs for biochemical and biophysical studies.

Depolymerization of Bottlebrush Polypentenamers and Their Macromolecular Metamorphosis.

The depolymerization of bottlebrush (BB) polymers with varying lengths of polycyclopentene (PCP) backbone and polystyrene (PS) grafts is investigated. In all cases, ring closing metathesis (RCM) depolymerization of the PCP BB backbone appears to occur through an end-to-end depolymerization mechanism as evidenced by size exclusion chromatography. Investigation on the RCM depolymerization of linear PCP reveals a more random chain degradation process. Quantitative depolymerization occurs under thermodynamic conditions (higher temperature and dilution) that drives RCM into cyclopentenes (CPs), each bearing one of the original PS grafts from the BB. Catalyst screening reveals Grubbs' third (G3) and second (G2) generation catalyst depolymerize BBs significantly faster than Grubbs' first generation (G1) and Hoveyda-Grubbs' second generation (HG2) catalyst under identical conditions while solvent (toluene versus CHCl3) plays a less significant role. The length of the BB backbone and PS side chains also play a minor role in depolymerization kinetics, which is discussed. The ability to completely deconstruct these BB architectures into linear grafts provides definitive insights toward the ATRP "grafting-from" mechanism originally used to construct the BBs. Core-shell BB block copolymers (BBCPs) are shown to quantitatively depolymerize into linear diblock polymer grafts. Finally, the complete depolymerization of BBs into α-cyclopentenyl-PS allows further transformation to other architectures, such as 3-arm stars, through thiol-ene coupling onto the CP end group. These unique materials open the door to stimuli-responsive reassembly of BBs and BBCPs into new morphologies driven by macromolecular metamorphosis.

Green Synthesis of Aryl Thioethers through Cu-catalysed C-S Coupling of Thiols and Aryl Boronic Acids in Water

An efficient, practical, highly selective and environmentally benign method is reported for the synthesis of aryl thioethers via the coupling of thiols with aryl boronic acids in the presence of NaOH and a catalytic amount of CuSO4 at 130 °C using water as a green solvent. The products were obtained in moderate to excellent yields; more importantly, the use of toxic ligands and solvents was avoided. A broad range of aryl boronic acids and scalable processes make this methodology valuable and versatile for the synthesis of a broad range of aryl sulfides.

Sulfonyl Fluoride Synthesis through Electrochemical Oxidative Coupling of Thiols and Potassium Fluoride.

Sulfonyl fluorides are valuable synthetic motifs for a variety of applications, among which sulfur(VI) fluoride exchange-based “click chemistry” is currently the most prominent. Consequently, the development of novel and efficient synthetic methods to access these functional groups is of great interest. Herein, we report a mild and environmentally benign electrochemical approach to prepare sulfonyl fluorides using thiols or disulfides, as widely available starting materials, in combination with KF, as an inexpensive, abundant and safe fluoride source. No additional oxidants nor additional catalysts are required and, due to mild reaction conditions, the reaction displays a broad substrate scope, including a variety of alkyl, benzyl, aryl and heteroaryl thiols or disulfides.