Generation Of Thiyl Radicals Research Articles

Nitric oxide and thiols: Chemical biology, signalling paradigms and vascular therapeutic potential.

Nitric oxide (• NO) interactions with biological thiols play crucial, but incompletely determined, roles in vascular signalling and other biological processes. Here, we highlight two recently proposed signalling paradigms: (1) the formation of a vasodilating labile nitrosyl ferrous haem (NO-ferrohaem) facilitated by thiols via thiyl radical generation and (2) polysulfides/persulfides and their interaction with • NO. We also describe the specific (bio)chemical routes in which • NO and thiols react to form S-nitrosothiols, a broad class of small molecules, and protein post-translational modifications that can influence protein function through catalytic site or allosteric structural changes. S-Nitrosothiol formation depends upon cellular conditions, but critically, an appropriate oxidant for either the thiol (yielding a thiyl radical) or • NO (yielding a nitrosonium [NO+ ]-donating species) is required. We examine the roles of these collective • NO/thiol species in vascular signalling and their cardiovascular therapeutic potential.

Charge Separation in Metal-Organic Framework Enables Heterogeneous Thiol Catalysis.

Photoinduced metal-organic framework (MOF) enabled heterogeneous thiol catalysis has been achieved for the first time. MOF Zr-TPDCS-1, consisting of Zr6-clusters and TPDCS linkers (TPDCS = 3,3'',5,5''-tetramercapto[1,1':4',1''-terphenyl]-4,4''-dicarboxylate), effectively catalyzed the borylation, silylation, phosphorylation, and thiolation of organic molecules. Upon irradiation, the fast electron transfer from TPDCS to Zr6-cluster is believed to facilitate the formation of the thiyl radical, a hydrogen atom transfer catalyst, which competently abstracts the hydrogen from borane, silane, phosphine, or thiol for generating the corresponding element radical to engender the chemical transformations. The elaborate control experiments evidenced the generation of thiyl radicals in MOF and illustrated a radical reaction pathway. The gram-scale reaction worked well, and the product was conveniently separated via centrifugation and vacuum with a turnover number (TON) of ~3880, highlighting the practical application potential of heterogeneous thiyl-radical catalysis.

Charge Separation in Metal‐Organic Framework Enables Heterogeneous Thiol Catalysis

AbstractPhotoinduced metal–organic framework (MOF) enabled heterogeneous thiol catalysis has been achieved for the first time. MOF Zr‐TPDCS‐1, consisting of Zr6‐clusters and TPDCS linkers (TPDCS=3,3′′,5,5′′‐tetramercapto[1,1′:4′,1′′‐terphenyl]‐4,4′′‐dicarboxylate), effectively catalyzed the borylation, silylation, phosphorylation, and thiolation of organic molecules. Upon irradiation, the fast electron transfer from TPDCS to Zr6‐cluster is believed to facilitate the formation of the thiyl radical, a hydrogen atom transfer catalyst, which competently abstracts the hydrogen from borane, silane, phosphine, or thiol for generating the corresponding element radical to engender the chemical transformations. The elaborate control experiments evidenced the generation of thiyl radicals in MOF and illustrated a radical reaction pathway. The gram‐scale reaction worked well, and the product was conveniently separated via centrifugation and vacuum with a turnover number (TON) of ≈3880, highlighting the practical application potential of heterogeneous thiyl‐radical catalysis.

Visible Light-Mediated Thiolation of Substituted 1,4-Naphthoquinones Using Eosin Y as a Photoredox Catalyst.

In the presence of eosin Y, a visible light-induced one-step procedure (isolated yield of ≥75%) for thiolation of substituted 1,4-naphthoquinones using various aromatic and aliphatic thiols at room temperature is described herein. The rate-determining step of the reaction is thiyl radical generation, and the radical was characterized by high-resolution mass spectrometry. Cost effectiveness, operational simplicity, a short reaction time, high atom economy, and a very good yield make this photoredox-mediated process a useful alternative to the transition metal (e.g., Cu, Ag, and Pd)-catalyzed coupling reaction of quinones with thiols or disulfides.

Generation of Thiyl Radicals from Air-Stable, Odorless Thiophenol Surrogates: Application to Visible-Light-Promoted C–S Cross-Coupling

AbstractThe synthetic versatility of thiophenols is offset by their air-sensitivity and foul odor. It is demonstrated that S-aryl isothiouronium salts can be used as precursors to thiyl radicals, extending the practical benefits of these air-stable, odorless salts from ionic to single electron manifolds. The isothiouronium salts are accessed via Ni-catalyzed cross-coupling of (hetero)aryl iodides and thiourea and are isolated as free-flowing solids following anion exchange. Judicious choice of a redox-innocent counteranion enables use of these convenient thiophenol surrogates in radical processes, as is exemplified by the synthesis of non-symmetrical diaryl thioethers via light-promoted S-arylation.

Photogeneration of thiyl radicals using metal‐halide perovskite for highly efficient synthesis of thioethers

AbstractRecently, the use of metal‐halide perovskite (MHP) for photoinduced organics transformation has attracted much attention. We report herein the development of photoinduced thiol‐ene reaction using inorganic MHP of CsPbBr3 nanocrystal that is visible light‐responsive, easy‐to‐prepare, and cost‐effective. Under blue light‐emitting diode (LED), a series of thiol substrates are demonstrated to be highly efficient reaction partners to couple with alkenes tolerated with various functional groups, affording diverse thioethers containing C–S bonds. The CsPbBr3‐mediated thiol‐ene reaction is characterized by high efficiency, broad substrate applicability, excellent yields, and mild conditions. Mechanism investigation shows that the visible light‐excited CsPbBr3 induces the generation of thiyl radicals via hole oxidation to initiate the reaction, followed by redox neutral pathway and/or chain transfer pathway to accomplish thiol–olefin coupling. It is notable that CsPbBr3 exhibits advanced thiol‐ene performance than that using MHP analogs and others. The work presents a new exploration of MHP‐mediated transformation and shows great potential of MHPs for radical chemistry.

Photoactive Metal-Organic Frameworks for the Selective Synthesis of Thioethers: Coupled with Phosphine to Modulate Thiyl Radical Generation.

Metal-organic framework (MOF) materials are intriguing photocatalysts to trigger radical-mediated chemical transformations. We report herein the synthesis and characterization of a series of isomorphic MOFs which show a novel structure, wide visible-light absorption, high chemical stability, and specific redox potential. The prepared MOFs were explored for the photoinduced single-electron oxidation of thiol compounds, generating reactive thiyl radicals to afford thioethers via a convenient thiol-olefin reaction. Importantly, we provide a widely applicable strategy by combing a photoactive MOF with phosphine to modulate the generation of thiyl radical in the reaction, thereby producing a single product of the thioether without the formation of a disulfide byproduct due to the dimerization of thiyl radicals. The photocatalytic reaction takes advantage of this strategy, showing great generality where tens of thiols and olefins have been examined as coupling partners. In addition, the strategy has also been demonstrated to be effective for the reactions catalyzed by other MOFs. Mechanism studies reveal that the selective synthesis of C-S products relies on a synergy between the photoinduced generation of a thiyl radical over the MOF and the in situ cleavage of S-S bond into a S-H bond by phosphine. It is notable that the synthesized MOFs show advanced performance in comparison with classical MOFs. The work not only provides a series of novel MOF photocatalysts that are capable of photoinduced thiol-olefin coupling but also indicates the great potential of MOFs for photochemical transformations mediated by reactive radicals.

Ultrasonic Generation of Thiyl Radicals: A General Method of Rapidly Connecting Molecules to a Range of Electrodes for Electrochemical and Molecular Electronics Applications.

Herein, we report ultrasonic generation of thiyl radicals as a general method for functionalizing a range of surfaces with organic molecules. The method is simple, rapid, can be utilized at ambient conditions and involves sonicating a solution of disulfide molecules, homolytically cleaving S-S bonds and generating thiyl radicals that react with the surfaces by forming covalently bound monolayers. Full molecular coverages on conducting oxides (ITO), semiconductors (Si-H), and carbon (GC) electrode surfaces can be achieved within a time scale of 15-90 min. The suitability of this method to connect the same molecule to different electrodes enabled comparing the conductivity of single molecules and the electrochemical electron transfer kinetics of redox active monolayers as a function of the molecule-electrode contact. We demonstrate, using STM break-junction technique, single-molecule heterojunction comprising Au-molecule-ITO and Au-molecule-carbon circuits. We found that despite using the same molecule, the single-molecule conductivity of Au-molecule-carbon circuits is about an order of magnitude higher than that of Au-molecule-ITO circuits. The same trend was observed for electron transfer kinetics, measured using electrochemical impedance spectroscopy for ferrocene-terminated monolayers on carbon and ITO. This suggests that the interfacial bond between different electrodes and the same molecule can be used to tune the conductivity of single-molecule devices and to control the rate of charge transport in redox active monolayers, opening prospects for relating various types of interfacial charge-transfer rate processes.

Visible-light-induced intramolecular charge transfer in the radical spirocyclisation of indole-tethered ynones.

Indole-tethered ynones form an intramolecular electron donor–acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols. This initiates a novel radical chain sequence, based on dearomatising spirocyclisation with concomitant C–S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor–acceptor complex in synthesis.

Visible-Light-Promoted Thiyl Radical Generation from Sodium Sulfinates: A Radical-Radical Coupling to Thioesters.

A convenient visible-light photoredox catalysis has been developed for the synthesis of thioesters from two readily available starting materials: acid chlorides and sodium sulfinates. The facile generation of acyl radical species under the visible light photoredox conditions allows the formation of thiyl radical species from sodium sulfinates via multiple single electron transfer reactions, where the final acyl radical-thiyl radical coupling has been accomplished. The direct radical-radical coupling strategy offers a mild and controlled photochemical approach to important synthetic building blocks such as thioesters.

Sulfides and Disulfides of s-Triazine: Potential Thermal Thiyl Radical Generators.

A series of aliphatic and aromatic thioethers and dithioethers of s-triazine were synthesised to study their thermal properties, in particular the thermally induced thiyl radical generation ability. Four symmetric s-triazine sulfides of the type (RS)3 C3 N3 , namely 2,4,6-tris(phenylthio)- (1), 2,4,6-tris(para-tolylthio)- (3), 2,4,6-tris(ethylthio)- (5) and 2,4,6-tris(tert-butylthio)-1,3,5-triazine (7), as well as four symmetric s-triazine disulfides of the type (RSS)3 C3 N3 , namely 2,4,6-tris(phenyldithio)- (2), 2,4,6-tris(para-tolyldithio)- (4), 2,4,6-tris(ethyldithio)- (6) and 2,4,6-tris(tert-butyldithio)-1,3,5-triazine (8) were synthesised. All compounds were comprehensively characterised by 1 H and 13 C NMR, infrared and Raman spectroscopy as well as elemental analyses. Single-crystal X-ray diffraction analyses of 1, 2 and 5 are discussed. The thermal behaviour was studied by thermogravimetric analyses coupled with mass spectrometry (TGA-MS) and quantum chemical calculations. Limiting oxygen index (LOI) flammability tests showed that the disulfides are the most promising radical generators, and are most likely suitable flame retardants for selected polymers.

Generation of thiyl radicals in a zinc(ii) porous coordination polymer by light-induced post-synthetic deprotection.

Kinetic stabilisation of unstable chemical species in nanospace is of potential importance in the field of materials and synthetic chemistry, and porous coordination polymers (PCPs) represent a facile platform to provide such reaction fields. Thiyl radicals are important reactive substances that often play a leading role in organic and bioorganic chemistry. However, their generation in nanospace has been barely investigated due to synthetic difficulties. Here, we report a facile methodology for the functionalisation of active thiyl substituents on PCP pore surfaces using a post-synthetic protection and deprotection technique. The thiyl radicals were generated inside a zinc(ii)-based PCP upon the deprotection of asymmetric disulfides, which were used as the protecting groups by ultraviolet light irradiation.

Biomimetic Thiyl Radical Chemistry by γ‐Irradiation of Micelles and Vesicles Containing Unsaturated Fatty Acids

AbstractDifferent types of lipid aggregations, such as micelles and liposomes, can be used as biomimetic models. The uses of γ‐irradiation as a valid methodology for simulating the biological generation of thiyl radicals in these models are summarized and, in particular, thiyl radical catalyzed cistrans isomerization of unsaturated lipids is underlined. The efficiency of antioxidants against lipid isomerization assayed by biomimetic models and the importance of trans lipids as novel biomarkers of radical stress are also described.

Suicidal Inactivation of Methemoglobin by Generation of Thiyl Radical: Insight into NAC Mediated Protection in RBC

N-acetyl-L-cysteine (NAC) improves antioxidant potentials of RBCs to provide protection against oxidative stress induced hemolysis. The antioxidant mechanism of NAC to reduce oxidative stress in RBC, studied through inactivation of pro-oxidant MetHb. NAC causes irreversible inactivation of the MetHb in an H2O2 dependent manner, and the inactivation follows the pseudo- first- order kinetics. The kinetic constants are ki = 8.5μM, kinact = 0.706 min(-1) and t1/2 = 0.9 min. Spectroscopic studies indicate that MetHb accepts NAC as a substrate and oxidizes through a single electron transfer mechanism to the NACox. The single e- oxidation product of NAC has been identified as the 5, 5'- dimethyl-1- pyrroline N- oxide (DMPO) adduct of the sulfur centered radical (a(N) = 15.2 G and a(H)=16.78 G). Binding studies indicate that NACox interacts at the heme moiety and NAC oxidation through MetHb is essential for NAC binding. Heme-NAC adduct dissociated from MetHb and identified (m/z 1011.19) as 2:1 ratio of NAC/heme in the adduct. TEMPO and PBN treatment reduces NAC binding to MetHb and protects against inactivation confirms the role of thiyl radical in the inactivation process. Furthermore, scavenging thiyl radicals by TEMPO abolish the protective effect of NAC in hemolysis. Current work highlights antioxidant mechanism of NAC through NAC thiyl radical generation, and MetHb inactivation to exhibit protection in RBC against oxidative stress induced hemolysis.

Reactivity of Thiyl Radicals Generated from Thiomethoxide and Dimethyldisulfide in Microheterogeneous Media

Abstract: Sodium thiomethoxide and dimethyldisulfide will be shown to be convenient sources of methyl thiyl radicals for effecting the cis-trans double bond isomerization of oleic acid to elaidic acid residues arranged in phospholipid bilayers of the microheterogeneous aqueous environment of liposomes. The methods used for methyl thiyl radical generation encompass radiolytic and photochemical meth-ods. The convenience of these methyl thiyl radical sources will be interpreted in terms of the turn-over numbers in the radical chain cis-trans isomerization reaction of unsaturated lipids. Keywords: Methyl thiyl radicals, Sodium thiomethoxide, Dimethyldisulfide, cis-trans isomerization. INTRODUCTION Thiyl radicals have been extensively studied in the context of free radical double bond isomerization. Fig. ( 1 ) shows the reaction mechanism of free thiyl radical RS• double bond isomerization that consists of a reversible addition of radical RS• to the double bond. The regeneration of the double bond is obtained by
-elimination of RS• and the result is in favor of the

Initiation of Radical Chain Reactions of Thiol Compounds and Alkenes without any Added Initiator: Thiol‐Catalyzed cis/trans Isomerization of Methyl Oleate

A kinetic study of the dodecanethiol-catalyzed cis/trans isomerization of methyl oleate (cis-2) without added initiator was performed by focusing on the initiation of the radical chain reaction. The reaction orders of the rate of isomerization were 2 and 0.5 for 1 and cis-2, respectively, and an overall kinetic isotope effect k(H)/k(D) of 2.8 was found. The initiation was shown to be a complex reaction. The electron-donor/-acceptor (EDA) complex of dodecanethiol (1) and cis-2 formed in a pre-equilibrium reacts with thiol 1 to give a stearyl and a sulfuranyl radical through molecule-assisted homolysis (MAH) of the sulfur-hydrogen bond. Fragmentation of the latter gives the thiyl radical, which catalyzes the cis/trans isomerization. A computational study of the EDA complex, MAH reaction, and the sulfuranyl radical calculated that the activation energy of the isomerization was in good agreement with the experimental result of E(A)=82 kJ M(-1). Overall, the results may explain that the thermal generation of thiyl radicals without any initiator is responsible for many well-known thermally initiated addition reactions of thiol compounds to alkenes and their respective polymerizations and for the low shelf-life stability of cis-unsaturated thiol compounds and of mixtures of alkenes and thiol compounds.

Thiyl Radical Generation in Thiol or Disulfide Containing Photosensitive Systems

AbstractThe generation of thiyl radicals in various multicomponent photosensitive systems based on a ketone, a coumarin or a ketocoumarin and containing a thiol or a disulfide and eventually chloro bis‐imidazole has been studied through laser flash photolysis. A set of more than 70 new interaction rate constants is provided. The measurements of the quantum yields in sulfur radicals and the rate constants of the different processes in many combinations as well as the molecular orbital calculations allow to discuss the driving factors of the involved reactions. This approach should shed some light on the possible explanations of the high performance of some of these combinations when used as photoinitiating systems for radical photopolymerization reactions.magnified image

The Use of Ascorbic Acid to Promote the Polymerization of 11S Globulin

We investigated the effects of L-ascorbic acid (AsA) on 11S globulin, which was reduced by 2-mercaptoethanol. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis verified that AsA promoted the polymerization of 11S globulin via the formation of disulfide bridges. The generation of thiyl radicals (S·) in 11S globulin was examined by electron spin resonance spectroscopy coupled with spin trapping. The superoxide anion radical (O-2 ) was produced by the photoactivation of riboflavin. A typical line shape was observed for S·. Staining with nitroblue tetrazolium dye confirmed that O-2 was produced in the 11S globulin solution due to the autooxidation of AsA. Although the 11S globulin lacking AsA did not yield a rigid gel, the sample containing AsA successfully yielded a rigid gel. Thus, it is clear that O-2 generated during AsA oxidation exerts beneficial effects on 11S globulin in its reduced form.

Ascorbate peroxidase-thioredoxin interaction.

Proteomics data have suggested ascorbate peroxidase (APX) to be a potential thioredoxin-interacting protein. Using recombinant enzymes, we observed that incubation of pea cytosolic APX with reduced poplar thioredoxins h drastically inactivated the peroxidase. A similar inactivation is induced by reduced glutathione and dithiothreitol, whereas diamide and oxidized glutathione have no effect. Oxygen consumption measurements, modifications of the APX visible spectrum and protection by hydrogen peroxide scavenging enzymes suggest that APX oxidizes thiols leading to the generation of thiyl radicals. These radicals can in turn react with thiyl anions to produce the disulfide radical anions, which are responsible for oxygen reduction and subsequent hydrogen peroxide production. The APX inactivation is not due solely to hydrogen peroxide since fluorimetry indicates that the environment of the APX tryptophan residues is dramatically modified only in the presence of thiol groups. The physiological implications of this interaction are discussed.

Trans-Fatty acids and radical stress: What are the real culprits?

Free radical-catalysed cis– trans isomerization of unsaturated lipids in biomimetic models and their significance in eukaryotic cells have been explored in the last few years, an integrating hypothesis being that trans-fatty acids have their origins in both dietary sources and from isomerization of natural isomers by an endogenous radical stress. In this perspective, a summary of the achievements and a discussion of the possible biological sources of isomerizing radical species are given, indicating a need for further research on thiyl radical generation in biological systems. In this context, crucial questions remain to be answered by free radical research involving membrane lipids, thus contributing to lipidomics and embracing biology and medicine.