Hydrothiolation Reaction Research Articles

Post-metallation functionalization of the [(C^C)Au(P^P)]+ scaffold through a hydrothiolation reaction.

Complex 1 [(C^C)Au(dppv)]PF6 (dppv = cis-1,2-diphenylphosphinoethylene) is reported to react efficiently and selectively with aliphatic and aromatic thiols in the presence of a base. This methodology enables the smooth introduction of various functional groups on the [(C^C)Au(P^P)]+ scaffold.

Photocatalyst-free hydrothiolation of gem-difluoroalkenes with thiols

A photocatalyst-free hydrothiolation reaction of aromatic gem-difluoroalkenes was developed under the irradiation of blue light in dimethyl carbonate as a green solvent.

Thiol-ene click reaction as an effective tool for the synthesis of PEG-functionalized alkoxysilanes-precursors of anti-fog coatings

The article presents a very simple method of glass modification to obtain the anti-fog effect. Silanes containing two types of functional groups, namely a hydrophilic and polar polyether group and an alkoxysilyl group (to bond with the surface of the modified material) were synthesized in thiol-ene reactions. The hydrothiolation reactions of polyethers containing a C=C terminal bond with mercaptoalkoxysilane proceeded efficiently, yielding quantitatively appropriate products under mild reaction conditions. This method enabled the synthesis of a series of alkoxysilanes functionalized with polyethers, differing in structure. The group of obtained derivatives was characterized by 1H, 13C, 29Si NMR, and FT-IR analyses, and then used to prepare coatings on glass using the sol–gel method. The coated glass surfaces exhibited transparency, superhydrophilic or hydrophilic properties, anti-fog and anti-frost performance.

Evaluation of a trinuclear heteroleptic bis-cyclometalated iridium(III) complex as a photoredox catalyst for visible light-mediated hydrothiolation reactions

A trinuclear bis-cyclometalated iridium(III) polypyridyl complex was synthesised and evaluated as a photoredox catalyst for visible light- mediated thiol-ene coupling reactions. Electronic absorption and emission studies revealed that the complex shows a blue-shifted emission spectrum, with a wavelength at 578 nm, relative to the canonical iridium complex, [Ir(ppy)3] (598 nm). The emissions are attributed to the transition from the triplet MLCT excited state (3MLCT) to the ground state. Cyclic voltammetry studies demonstrated that this complex is a promising candidate for the photoredox catalysed reactions, with the trinuclear iridium complex increasing the oxidation potential without sacrificing the reduction ability. The iridium(III) complex was evaluated as a photoredox catalyst in the model hydrothiolation coupling reaction and benchmarked against a trinuclear ruthenium congener. Reactions conducted with the trinuclear iridium polypyridyl complex resulted in the highest NMR yields.

Expanding the Role of Dimeric Species: On-Cycle Involvement, Improved Stability, and Control of Stereo-Specificity. A Case Study of Atom-Economic Catalytic Hydrothiolation

A common assumption that dimeric metal complexes in many catalytic systems represent a resting state and are not directly involved in catalytic processes was revised in a combined experimental and theoretical study. On-cycle participation of dimeric metal complexes, rather than typically assumed off-cycle involvement, was revealed, and advantageous performance in terms of improved selectivity was observed. The conceptual rationalization for the participation of dimeric species in the catalytic cycle was developed. The Pd-catalyzed hydrothiolation process (where strong Pd–S binding is well established and a persistent opinion for the inactive/poisoning role of dimeric species is presumed) was evaluated as a challenging system to test the concept. Activation of an (NHC)Pd(Cl)(acac) precatalyst (NHC─N-heterocyclic carbene and acac─acetylacetonate) under the reaction conditions produced monomeric (NHC)Pd(SPh)2 or dimeric (NHC)2Pd2(SPh)4 species depending on the steric bulkiness of the NHC ligand. Dimeric complexes possessed higher selectivity and tolerated disulfide impurities in contrast to monomeric complexes. Quantum chemical modeling suggested that dimeric catalysis proceeds through the opening of only one (μ-SPh)–Pd bridging bond with retention of the dimeric structure. The second bridging bond is maintained, which prevents the monomerization of the complex. Catalytically active species were detected in a hydrothiolation reaction by high-resolution mass spectrometry and NMR spectroscopy. Proving the opportunity for productive homogeneous catalysis via strongly coordinated dimeric metal species opens new opportunities for catalyst design in the increased nuclearity dimension.

Synthesis and Anticancer and Antiviral Activities of C-2'-Branched Arabinonucleosides.

d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2’ position were prepared from the corresponding 3’,5’-O-silylene acetal-protected nucleoside 2’-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2’-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl β-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2’ substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2’-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.

Sequential Heck Cross-Coupling and Hydrothiolation Reactions Taking Place in the Ligand Sphere of a Chiral Dehydroalanine Ni(II) Complex: Asymmetric Route to β-Aryl Substituted Cysteines.

A practically useful protocol for the asymmetric synthesis of artificial β-aryl-substituted cysteine derivatives was developed through sequential Pd(II)-catalyzed Heck cross-coupling with aryl iodides and hydrothiolation reaction with various alkyl thiols in the presence of triethylamine taking place in the ligand sphere of a robust and bench-stable chiral dehydroalanine Ni(II) complex. The subsequent acidic decomposition of the single diastereomeric Ni(II) complexes led to the target enantiopure cysteine derivatives.

Thermal Mapping of Self-Promoted Calcium Carbide Reactions for Performing Energy-Economic Processes.

The syntheses of various chemical compounds require heating. The intrinsic release of heat in exothermic processes is a valuable heat source that is not effectively used in many reactions. In this work, we assessed the released heat during the hydrolysis of an energy-rich compound, calcium carbide, and explored the possibility of its usage. Temperature profiles of carbide hydrolysis were recorded, and it was found that the heat release depended on the cosolvent and water/solvent ratio. Thus, the release of heat can be controlled and adjusted. To monitor the released heat, a special tube-in-tube reactor was assembled using joining part 3D-printed with nylon. The thermal effect of the reaction was estimated using a thermoimaging IR monitor. It was found that the kinetics of heat release are different when using mixtures of water with different solvents, and the maximum achievable temperature depends on the type of solvent and the amount of water and carbide. The possibility of using the heat released during carbide hydrolysis to initiate a chemical reaction was tested using a hydrothiolation reaction—the nucleophilic addition of thiols to acetylene. In a model experiment, the yield of the desired product with the use of heat from carbide hydrolysis was 89%, compared to 30% in this intrinsic heating, which was neglected.

Green Catalytic Method for Hydrothiolation of Allylamines: An External Electric Field.

Based on the idea of environmental friendliness, we first studied the hydrothiolation reactions of thiophenol with allylamine using a green catalyst—an external electric field (EEF). The hydrothiolation reactions could occur through Markovnikov addition (path M) and anti-Markovnikov addition (path AM) pathways. The calculation results demonstrated that when the EEF was oriented along F–X, F–Y, and F+Z directions, path M was accelerated. However, it is favorable for path AM only when the EEF is oriented along the +X and −Y-axes. In addition, the introduction of the EEF further increased and lowered the differences of the reaction barrier as the EEF was oriented along F–X, F–Y, and F+X directions. The solvent effects were also considered in this work. Hopefully, this unprecedented and green catalytic method for the hydrothiolation reactions of allylamine may provide guidance in the lab.

Radical-mediated thiol–ene ‘click’ reactions in deep eutectic solvents for bioconjugation

Herein, we report the first application of deep eutectic solvents (DESs) in radical-mediated hydrothiolation reactions.

Polynuclear heteroleptic ruthenium(II) photoredox catalysts: Evaluation in blue-light-mediated, regioselective thiol-ene reactions

Polynuclear heteroleptic ruthenium(II) photosensitisers combining either imine or amine-functionalised bipyridyl ligands were synthesised (via Schiff-base condensation/reductive amination reactions), characterised and investigated for their photoreactivity in the hydrothiolation reaction. Furthermore, electrochemical, electronic absorption and emission studies of the complexes were conducted. All the ligand-modified, heteroleptic complexes show red-shifted emission spectra (614–633 nm) relative to the canonical [Ru(bpy)3](PF6)2 complex (609 nm), attributed to the transition from the triplet MLCT excited state (3MLCT) to the ground state. The complexes were evaluated as visible-light photoredox catalysts in the radical hydrothiolation reaction of olefins (thiol-ene coupling) to afford thioethers. Control reactions performed in the absence of the photocatalyst resulted in either significantly lower yields (6%) or no product formation, demonstrating the role of the complexes as photoredox catalysts. The reactions carried out using trinuclear complexes (Ered (Ru2+*/+) = +0.300 V vs Ag/Ag+) resulted in increased yields in comparison with their respective mononuclear congeners and greater than those reported for [Ru(bpy)3](PF6)2, demonstrating the benefits of using polynuclear photocatalysts for photoinitiated redox catalysis reactions.

Water Extract of Rice Straw Ash: Experimental Design and Evaluation of Their Activity in the Hydrothiolation Reaction

Water Extract of Rice Straw Ash (WERSA) has attracted special attention in several areas of chemistry since they have been considered an alternative tool for green processes. Hence, the characterization of ashes and extract of this biomass are fundamental to figure out their particular applicability in a wide range of transformations. In this regard, herein we have characterized the ashes of rice straw (RSA) and its respective aqueous extract using Inductively Coupled Plasma Optical Emission Spectrometry and x-ray fluorescence. Noteworthy, we have investigated the effect of the metals from WERSA on the hydrothiolation of phenylacetylene employing ANOVA response, coefficient of determination, linear regression model as well as Fischer Test. Based on all these studies, it was found that calcium is the most important metal for the hydrothiolation reaction when compared to other metals present in the WERSA. Thus, it was also possible to propose a plausible reaction mechanism for the hydrothiolation of alkynes. In addition, the chemistry described herein might represent a new eco-friendly tendency for the organochalcogen field.

Synthesis of 4-thiol-furanosidic uronate via hydrothiolation reaction.

Uronic acids are not only important building blocks of polysaccharides and oligosaccharides but also are widely used in the food and pharmaceutical industries. Inspired by the structure of natural products, here, we disclosed base-mediated and radical-mediated hydrothiolation reactions for the preparation of thiol-contained uronates. In comparison with base-mediated reaction, radical-mediated hydrothiolation is inefficient due to the electron-withdrawing group on the ethylene group; nevertheless, the adduct had excellent stereoselectivity at both C-4 and C-5 positions. For the alkaline approach, thiols as nucleophiles can regioselectively and stereoselectively attach to the C-4 position of Δ-4,5-unsaturated uronate with moderate to good yields. However, poor stereoselectivity at the C-5 position was observed due to retro thiol-Michael addition. After removing the protecting group of the thiol, the thiol adduct was isomerized to the furanosidic form and the 4-thiol-furanosidic uronate derivative was synthesized for the first time.

Synthesis of vinyl sulfides and thioethers via a hydrothiolation reaction of 4-hydroxydithiocoumarins and arylacetylenes/styrenes.

The synthesis of vinyl sulfides (3a-m) and thioethers (7a-k), exclusive Markovnikov products, is reported by a copper(I) iodide catalyzed regioselective hydrothiolation reaction of terminal alkynes/alkenes and 4-hydroxydithiocoumarins. However, anti-Markovnikov hydrothiolation products (5a-f) were obtained in the case of 2-ethynylpyridine, with exclusive Z selectivity in good yields. The important aspects of this protocol are the absence of expensive metal complexes and additives to act as ligands, mild reaction conditions, high regioselectivity, good yields, and shorter reaction times.

In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design

AbstractThe potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T‐cells, and B‐cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A‐dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target‐catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity.

In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design.

The potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T-cells, and B-cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A-dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target-catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity.

Atmospheric Oxygen Mediated Radical Hydrothiolation of Alkenes.

A mild, metal-free, atmospheric oxygen-mediated radical hydrothiolation of alkenes (and alkyne) is reported. A variety of sulfur containing motifs including alkanethiols, thiophenols and thioacids undergo an atmospheric oxygen-mediated radical hydrothiolation reaction with a plethora of alkenes in good yield with excellent functional group compatibility, typically with short reaction times to furnish a range of functionalized products. Biomolecules proved tolerant to the conditions and the procedure is robust and easily executable requiring no specialized equipment. Concise mechanistic studies confirm the process proceeds through radical intermediates in a thiol-ene reaction manifold. The methodology offers an efficient "green" approach for thiol-ene mediated "click" ligation and a milder alternative to thermally initiated hydrothiolation processes.

Efficient visible light initiated hydrothiolations of alkenes/alkynes over Ir2S3/ZnIn2S4: Role of Ir2S3

The hydrothiolations of alkynes/alkenes with thiols is an atom-economic and thus attractive method for the constructions of C-S bonds. Here Ir2S3/ZnIn2S4 nanocomposites with varied Ir2S3 loadings were obtained by one-pot solvothermal method from ZnCl2, InCl3 and thioacetamide with IrCl3. The loading of Ir2S3 on the surface of ZnIn2S4 promoted the hydrothiolations of alkenes and alkynes, with an optimum performance observed over 0.5 mol% Ir2S3/ZnIn2S4 nanocomposite. Based on the studies on the performance of several other cocatalysts (MoS2, NiS and Pd) loaded ZnIn2S4 and the EIS analyses, it was proposed that the superior performance over Ir2S3/ZnIn2S4 nanocomposite can be ascribed to an improved efficiency on the photogeneration of the thiyl radicals by loading Ir2S3 as well as its inactivity for photocatalytic hydrogen evolution, a side reaction in the light initiated hydrothiolation reaction over ZnIn2S4. This study not only demonstrates an efficient and green strategy to synthesize thiolated products under visible light based on semiconductor photocatalysis, but also provides some guidances for the design and development of photocatalytic systems for light induced organic syntheses.

Durable, highly hydrophobic modification of cotton fabric with fluorine-free polysiloxanes obtained via hydrosilylation and hydrothiolation reactions

Cotton fabrics were subjected to modification with fluorine-free polysiloxanes. In the first stage a series of polysiloxanes substituted with alkoxysilyl groups and/or alkyl chains were synthesized. Two methods of functionalization of vinyl group-containing polysiloxanes were used, i.e. hydrosilylation and hydrothiolation. Cotton fabrics were modified via dip-coating technique in solutions of the prepared compounds or by thiol–ene click reaction directly on the surface of cotton. In the first stage of the latter method cotton fabrics were modified by sol–gel technique with 3-mercaptopropyltrimethoxysilane in order to obtain mercapto-functionalized samples. After grafting SH groups on the surface, the fabrics were easily functionalized using the photoclick thiol–ene reaction with vinyl groups containing polysiloxane or vinyl- and alkyl-groups containing polysiloxane. The hydrophobicity was determined by measuring the water contact angle. Changes in the surface morphology were examined by FTIR spectroscopy and scanning electron microscopy (SEM). The coatings of the modified fabrics were subjected to elemental analysis using SEM–EDS techniques. All modified cotton fabrics showed highly hydrophobic properties. All obtained hydrophobic fabrics were fully resistant to the washing process, which proves the durability of the developed modifications.

Visible light photoredox-catalyzed hydrothiolation of enamides and enecarbamates

An efficient visible light photoredox-catalyzed, Markovnikov selective, hydrothiolation reaction of enamides and enecarbamates is presented. This protocol is mild and operationally simple. This process provides access to N,S-acetal products from available thiols and a variety of enamides and enecarbamates.