Sulfur-based Radical Research Articles

N-Heterocyclic Carbene-Derived Carbon Disulfide Radical Ligands for Palladium Diradicals.

N-heterocyclic carbenes (NHCs) are recognized for their ability to stabilize various main group radicals; however, NHC-derived, sulfur-based radicals remain rare. In this study, we successfully synthesized and characterized a series of palladium diradical complexes that featured new sulfur-based radical ligands from NHC-carbon disulfide adducts. Spectroscopic and computational characterizations of the palladium complexes confirmed the open-shell singlet ground state, which resulted from the antiferromagnetic coupling of two unpaired electrons on each ligand. Proton nuclear magnetic resonance relaxometry was used to experimentally confirm the presence of these unpaired electrons. Moreover, the redox behavior of the complexes was localized on the ligand center, confirming the redox activity of the ligands. The discovery of this sulfur-based, redox-active radical ligand underscores the versatility and significance of NHC-derived radicals, thereby expanding the repertoire of radical ligands and opening new avenues for advanced material and catalytic systems.

Chemoselective Proteomics, Zinc Fingers, and a Zinc(II) Model for H2S Mediated Persulfidation.

The gasotransmitter hydrogen sulfide (H2S) is thought to be involved in the post-translational modification of cysteine residues to produce reactive persulfides. A persulfide-specific chemoselective proteomics approach with mammalian cells has identified a broad range of zinc finger (ZF) proteins as targets of persulfidation. Parallel studies with isolated ZFs show that persulfidation is mediated by ZnII, O2, and H2S, with intermediates involving oxygen- and sulfur-based radicals detected by mass spectrometry and optical spectroscopies. A small molecule ZnII complex exhibits analogous reactivity with H2S and O2, giving a persulfidated product. These data show that ZnII is not just a biological structural element, but also plays a critical role in mediating H2S-dependent persulfidation. ZF persulfidation appears to be a general post-translational modification and a possible conduit for H2S signaling. This work has implications for our understanding of H2S-mediated signaling and the regulation of ZFs in cellular physiology and development.

Photocatalytic aerobic thiocyanation/sulfonylation of alkynes by D-A type COFs: Enhanced generation of superoxide and sulfur-based radicals via building units adjusted band structures

Photocatalytic radical-mediated aerobic thiocyanation/sulfonylation of alkynes represents the most straightforward and atom-economic method to synthesize α-thiocyanate/sulfonyl ketones. The core issue is the generation of desired thiocyanate/sulfonyl radicals and their subsequent conversion into target products. In this work, three polyimide-based donor–acceptor COFs, named TAPB-PMDA, TTA-PMDA, and TTA-NDA, respectively, have been prepared for the photosynthesis of α-thiocyanate/sulfonyl ketones. Based on efficient adjusting electron donor-accept capacity of building units, TTA-NDA possesses broader visible absorption, richer redox properties, faster carrier separation efficiency and shows higher photocatalytic activity in thiocyanation/sulfonylation of alkynes under blue LED light illumination. Control experiments and EPR tests provide insight into the tandem radical addition/cross-coupling mechanism, in which the thiocyanate/sulfonyl radicals generation via h+ oxidation and the reactive oxygen species (ROS, e.g. •OH, H2O2, 1O2, O2•−) production by e− reduction carry out simultaneously, avoiding the employing of electron sacrificial agents or extra additives as precursors of singe electron transfer reagents. This operable strategy opens up a door for the difunctionalization of alkynes in photosynthetic manner.

Production of a Surface-Localized Oxidant during Oxygenation of Mackinawite (FeS).

The oxygenation of mackinawite (FeS) frequently occurs at anoxic-oxic interfaces in both natural and engineered systems such as intertidal sediment, in activated sludge in water treatment processes, and during sulfidized zero-valent iron particle corrosion. During reoxygenation events, FeS may drive a Fenton-like process leading to the production of strong oxidants though the details of this process are poorly understood. In this study, benzoic acid (BA) has been used to probe both the magnitude and identity of these strong oxidants under circumneutral pH conditions. The major product of BA oxidation during FeS oxygenation was found to be 2,5-dihydroxybenzoic acid (2,5-DHBA) rather than monohydroxybenzoic acids identified to be the major products in a range of hydroxyl radical (HO·)-dominated systems. Based upon relative reactivity with other competitive probes and nature of the hydroxybenzoate product distribution, it is hypothesized that the strong oxidant must be a surface-localized entity such as high-valent iron or surface-associated hydroxyl or sulfur-based radicals with reactivity differing from those formed in free solution. The importance of both the reactivity of the oxidant and adsorption of the substrate to the surface is demonstrated.

Diversity-Oriented Desulfonylative Functionalization of Alkyl Allyl Sulfones.

The diversity-oriented desulfonylative functionalization of alkyl allyl sulfones with various sulfone-type reagents by radical chemistry has been developed. The readily installed allylsulfonyl moiety acts as a C-radical precursor, which is substituted by various functionalities using sulfur-based radical trapping reagents. The generality of this approach is documented by the successful desulfonylative alkynylation, azidation, trifluoromethylthiolation, sulfenylation, trifluoromethylselenylation, halogenation, and deuteration. The method is compatible with a wide range of functional groups. Considering the deuteration, products are obtained in good yields with a high level of deuterium incorporation.

Fluorescent microspheres of zinc 1,2-dicarbomethoxy-1,2-dithiolate complex decorated with carbon nanotubes

A new discrete bis-dithiolene complex, [PPh4]2[Zn(DMED)2] (1; DMED = 1,2-dicarbomethoxy-1,2-dithiolate) with sulfur-based radical character was synthesized and structurally characterized. Complex 1 is stable and exhibits a square planar geometry around the zinc metal. 1 forms nanospheres through a one-pot water-induced self-assembly in a mixture of solvents (acetonitrile–water). These nanospheres were further decorated with water-soluble carbon nanotubes (wsCNTs) through hydrogen bonding between the peripheral –COOCH3 groups of 1 and surfacial carboxyl groups of wsCNTs to assemble into a spherical nanocomposite. The as-prepared nanocomposite showed fluorescence emissions in visible region due to the separation of energy states of the nanospheres assisted by wsCNTs, suggesting the future possibilities of these new materials for use in biomedical application.

Regioselective (Hetero)aryl C–H Thianthrenation and Late-Stage Transformations

In their recent report in Nature, Ritter and co-workers took advantage of a persistent sulfur-based radical cation to regioselectively install a thianthrene motif in simple or complex (hetero)arenes, and the resulting thianthrenium salts could undergo divergent late-stage transformations, offering chemists a powerful platform for introducing versatile functional groups and substituents in (hetero)arene rings.

Adding complexity to aromatics

Chemists have a few choices when they want to transform aromatic C–H bonds into something more complicated. Brominating and borylating these bonds are popular options, but those reactions usually produce a mixture of isomers. While seeking a more selective strategy, Tobias Ritter and colleagues at the Max Planck Institute for Kohlenforschung discovered that the tetrafluorothianthrene radical cation will react with aromatics almost exclusively at the para position (Nature 2019, DOI:10.1038/s41586-019-0982-0). “We had to develop new chemistry to quantify the selectivity, as it was so high,” Ritter says. Previously, chemists generated related persistent sulfur-based radical cations using moisture-sensitive, explosive thianthrenium perchlorate radical salts. But Ritter’s group developed a new method using a bench-stable, fluorinated, sulfoxide-based thianthrene reagent. They can use this reagent to functionalize aromatic C–H bonds in the presence of many functional groups, including amines, alcohols, esters, ...

Site-selective and versatile aromatic C-H functionalization by thianthrenation.

Direct C-H functionalization can quickly increase useful structural and functional molecular complexity1-3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns1-4-in the absence of such functionality, most aromatic C-H functionalization reactions provide more than one product isomer for most substrates1,4,5. Development of a C-H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C-H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C-H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.

POSSIBLE NATURE OF THE RADIATION-INDUCED SIGNAL IN NAILS: HIGH-FIELD EPR, CONFIRMING CHEMICAL SYNTHESIS, AND QUANTUM CHEMICAL CALCULATIONS.

Exposure of finger- and toe-nails to ionizing radiation generates an Electron Paramagnetic Resonance (EPR) signal whose intensity is dose dependent and stable at room temperature for several days. The dependency of the radiation-induced signal (RIS) on the received dose may be used as the basis for retrospective dosimetry of an individual's fortuitous exposure to ionizing radiation. Two radiation-induced signals, a quasi-stable (RIS2) and stable signal (RIS5), have been identified in nails irradiated up to a dose of 50 Gy. Using X-band EPR, both RIS signals exhibit a singlet line shape with a line width around 1.0 mT and an apparent g-value of 2.0044. In this work, we seek information on the exact chemical nature of the radiation-induced free radicals underlying the signal. This knowledge may provide insights into the reason for the discrepancy in the stabilities of the two RIS signals and help develop strategies for stabilizing the radicals in nails or devising methods for restoring the radicals after decay. In this work an analysis of high field (94 GHz and 240 GHz) EPR spectra of the RIS using quantum chemical calculations, the oxidation-reduction properties and the pH dependence of the signal intensities are used to show that spectroscopic and chemical properties of the RIS are consistent with a semiquinone-type radical underlying the RIS. It has been suggested that semiquinone radicals formed on trace amounts of melanin in nails are the basis for the RIS signals. However, based on the quantum chemical calculations and chemical properties of the RIS, it is likely that the radicals underlying this signal are generated from the radiolysis of L-3,4-dihydroxyphenylalanine (DOPA) amino acids in the keratin proteins. These DOPA amino acids are likely formed from the exogenous oxidation of tyrosine in keratin by the oxygen from the air prior to irradiation. We show that these DOPA amino acids can work as radical traps, capturing the highly reactive and unstable sulfur-based radicals and/or alkyl radicals generated during the radiation event and are converted to the more stable o-semiquinone anion-radicals. From this understanding of the oxidation-reduction properties of the RIS, it may be possible to regenerate the unstable RIS2 following its decay through treatment of nail clippings. However, the treatment used to recover the RIS2 also has the ability to recover an interfering, mechanically-induced signal (MIS) formed when the nail is clipped. Therefore, to use the recovered (regenerated) RIS2 to increase the detection limits and precision of the RIS measurements and, therefore, the dose estimates calculated from the RIS signal amplitudes, will require the application of methods to differentiate the RIS2 from the recovered MIS signal.

The formation of resonance-stabilized sulfur-based radical cations and their gas-phase reactivity

Gas-phase reactivity of several sulfur-based radical cations with various volatile neutrals was studied in a modified quadrupole ion trap mass spectrometer. The radical cations were formed by two methods. The first method (introduced by Siu and co-workers) involved electron transfer from the sulfur-containing ligand of interest (all with a CS double bond) to Cu2+ ion in a ternary complex upon collision-induced dissociation. The second method utilized aromatic/heterocyclic thiol compounds which upon oxidation formed disulfides. Collision-induced dissociation of protonated disulfides lead to homolytic cleavage of SS bond (often among other products). The radical cations produced by these two methods displayed very similar reactivity toward the five neutrals used in this study. This was explained by the resonance stabilization of these species within the NCS motif leading to similar structures. Density functional theory calculations showed that in all of these systems independent of the method of production most of the spin density resided on the sulfur atom and the CS bond held a partially double character.

Energy Efficient Capture and Release of Carbon Dioxide in Tetraalkyl Phosphonium and Tetraalkyl Ammonium Ionic Liquids

Described herein is an electrochemical method for the energy efficient capture and release of CO2 that employs electrochemically-generated thiolates as the CO2 capture agents. In N,N-dimethylformamide at glassy carbon electrodes the onset of CO2 reduction precludes capture by electrochemically generated thiolates. This is not the case in tetraalkyl phosphonium and tetraalkyl ammonium ionic liquids. In these media saturated with CO2, electrochemical reduction of disulfides to thiolates proceeds via a two-electron process with potential inversion.1 One-electron reduction of the disulfide results in dissociative electron transfer (DET), the first step of which is the formation of a short-lived radical anion.2 The S–S σ bond of the radical anion is subsequently cleaved leading to a thiolate and a sulfur-based radical.2 Resultant sulfur radicals are reduced at potentials positive of the potential applied for reduction of the corresponding disulfide. Thus, electrochemical thiolate generation is best formulated as a two-electron reduction with concomitant disulfide cleavage.3 In this presentation we will show that the potent, electrochemically generated sulfur nucleophiles capture CO2 via a facile SN2 reaction leading to formation of a thiocarbonate (Scheme 1). We will further demonstrate that the mechanism for the release of CO2 and regeneration of the disulfide is the one-electron Kolbe oxidation of the thiocarbonate followed by coupling of two sulfur radicals (Scheme 2).4 Cyclic voltammograms show that thiocarbonate oxidation occurs at potentials positive of thiolate oxidation. Increases in the peak-to-peak separation between thiolate oxidation and thiocarbonate oxidation have been ameliorated by targeted modifications to the disulfide. (1) Evans, D. H. Chem. Rev. 2008, 108, 2113–2144.(2) (a) Antonello, S.; Benassi, R.; Gavioli, G.; Taddei, F.; Maran, F. J. Am. Chem. Soc. 2002, 104, 7529–7538. (b) Meneses, A. B.; Antonello, S.; Arévalo, M. C.; Gonzáles, C. C.; Sharma, J.; Wallette, A. N.; Workentin, M. S.; Maran, F. Chem. Eur. J. 2007, 13, 7983–7995.(3) Hall, G. B.; Kottani, R.; Felton, G. A. N.; Yamamoto, T.; Evans, D. H.; Glass, R. S.; Lichtenberger, D. L. J. Am. Chem. Soc. 2014, 136, 4012–4018.(4) Vijh, A. K.; Conway, B. E.; Chem. Rev. 1967, 67, 623–664.

Structure and Reactivity of the Glutathione Radical Cation: Radical Rearrangement from the Cysteine Sulfur to the Glutamic Acid α-Carbon Atom.

A gas-phase radical rearrangement through intramolecular hydrogen-atom transfer (HAT) was studied in the glutathione radical cation, [γ-ECG]+. , which was generated by a homolytic cleavage of the protonated S-nitrosoglutathione. Ion-molecule reactions suggested that the radical migrates from the original sulfur position to one of the α-carbon atoms. Experiments on the radical cations of dipeptides derived from the glutathione sequence, [γ-EC]+. and [CG]+. , pointed to the glutamic acid α-carbon atom as the most likely site of the radical migration. Infrared multiple-photon dissociation (IRMPD) spectroscopy was employed to generate complementary information. IRMPD of [γ-ECG]+. in the approximately 1000-1800 cm-1 region was inconclusive owing to the relatively broad, overlapping absorption bands. However, the IRMPD spectrum of [γ-EC]+. in this region was consistent with the radical migrating from the sulfur to the α-carbon atom of glutamic acid. IRMPD in the 2800-3700 cm-1 region performed on [γ-ECG]+. is consistent with a mixture of both the original sulfur-based radical and the resulting glutamic acid α-carbon-based species. Comparisons are made with previously published condensed and gas-phase studies on intramolecular HAT in glutathione.

Gas-Phase Reactivity of Peptide Thiyl (RS•), Perthiyl (RSS•), and Sulfinyl (RSO•) Radical Ions Formed from Atmospheric Pressure Ion/Radical Reactions

In this study, we demonstrated the formation of gas-phase peptide perthiyl (RSS•) and thiyl (RS•) radical ions besides sulfinyl radical (RSO•) ions from atmospheric pressure (AP) ion/radical reactions of peptides containing inter-chain disulfide bonds. The identity of perthiyl radical was verified from characteristic 65 Da (•SSH) loss in collision-induced dissociation (CID). This signature loss was further used to assess the purity of peptide perthiyl radical ions formed from AP ion/radical reactions. Ion/molecule reactions combined with CID were carried out to confirm the formation of thiyl radical. Transmission mode ion/molecule reactions in collision cell (q2) were developed as a fast means to estimate the population of peptide thiyl radical ions. The reactivity of peptide thiyl, perthiyl, and sulfinyl radical ions was evaluated based on ion/molecule reactions toward organic disulfides, allyl iodide, organic thiol, and oxygen, which followed in order of thiyl (RS•) > perthiyl (RSS•) > sulfinyl (RSO•). The gas-phase reactivity of these three types of sulfur-based radicals is consistent with literature reports from solution studies.

Nanospheres of copper(iii) 1,2-dicarbomethoxy-1,2-dithiolate and its composite with water soluble carbon nanotubes

We report here the synthesis and structural characterization of a new discrete bis-dithiolene complex, [PPh4][Cu(DMED)2] (1; DMED = 1,2-dicarbomethoxy-1,2-dithiolate), involving the reaction between a copper polysulfide precursor with activated acetylene. 1 is stable, showing a sulfur-based radical character, as observed by electronic, EPR and cyclic voltammetric studies. This complex, possessing terminal –COOCH3 groups, forms nanospheres by hydrogen bonding in a mixture of solvents containing water as one of the components. These nanospheres further aggregate with water soluble (carboxylated) carbon nanotubes (wsCNTs). These nano-composites are assisted by hydrogen bonding between the carboxylic acid groups of the wsCNTs and the peripheral –COOCH3 groups of the coordinated dithiolenes of the nanospheres, which is promoted by water molecules. Interaction between the nanospheres on wrapping with wsCNTs, in forming the nano-composites, showed a perturbed EPR signal of the sulfur radical originating from the oxidised dithiolate ligand of the discrete complex 1.

Gas-phase reactivity of sulfur-based radical ions of cysteine derivatives and small peptides

The gas-phase reactivity of sulfur-based radical ions of cysteine derivatives and Cys-containing small peptides was studied via the use of ion-molecule reactions inside a quadrupole ion trap mass spectrometer. Both the radical cations M+ and the anions (M−2H)− were generated via the gas-phase homolysis of the SNO bond of the S-nitrosylated precursors of the following: Cys, N-Ac-Cys, CysOMe, Gly-Cys, Cys-Gly, γ-Glu-Cys, γ-Glu-Cys-Gly, and Gly-Cys-Arg. The radical ions were allowed to react with the following volatile neutral reagents: allyl iodide, allyl bromide, nitric oxide, 1-propane thiol, 3-mercaptopropionic acid, dimethyl disulfide and dimethyl sulfide. The charge has little effect on the types of products formed, with typical S-based radical reactivity being observed. In several systems (N-Ac-Cys, Cys-Gly, Gly-Cys, γ-Glu-Cys-Gly, and Gly-Cys-Arg) the radical was found to lose its reactivity very rapidly, which is consistent with S-to-α-carbon radical rearrangement via hydrogen atom transfer. The observed radical reactivity serves as a model for studying the chemistry of cysteine-based thiyl radicals in protein systems.

FeS-Induced Radical Formation and Its Effect on Plasmid DNA

Plasmid DNA was incubated at 25°C with aqueous solutions of dissolved Fe(II), S(-II), and nanoparticulate FeS with a mackinawite structure, FeSm. At ≥0.1 mM total dissolved Fe(II) and S(-II), an increase in the proportion of the relaxed plasmid DNA occurs, through scission of the DNA backbone. In solutions where FeSm was precipitated, nanoparticulate FeSm binds to the DNA molecules. In solutions with concentrations below the FeSm solubility product, nicking of supercoiled pDNA occurs. Plasmid DNA appears to be a sensitive proxy for radical reactions. The reactant is proposed to be a sulfur-based radical produced from the iron-catalyzed decomposition of bisulfide, in a manner analogous to the Fenton reaction. This is further supported by experiments that suggest that sulfide free radicals are produced during the photolysis of aqueous solutions of polysulfides. Supercoiling of DNA affects nearly all DNA–protein transactions so the observation of relaxation of supercoiled forms through reaction with FeS solutions has direct implications to biochemistry. The results of this experimentation suggest that genotoxicity in FeS-rich systems is a further contributory factor to the limited survival of organisms in sulfidic environments. Mutations resulting from the interactions of organisms and mobile elements, such as plasmids, in sediments will also be affected in sulfide-rich environments.

Characterization, stability, and origin of natural radiation-induced defects in the biogenic calcite of Belemnitella americana from the Upper Cretaceous: An electron paramagnetic resonance study

The rostrum of Belemnitella americana (Morton) from the Marshalltown formation (Kmt, Upper Cretaceous) of the Chesapeake and Delaware Canal was investigated by electron paramagnetic resonance (EPR) spectroscopy. The rostrum composed of biogenic calcite possessed inorganic radical centers CO 2 − , SO 2 − , and SO 3 − with isotropic resonances with g values of 2.0007, 2.0057, and 2.0031, respectively. SO 3 − was found to also display an axially symmetric resonance typical of that seen in calcite of geologic origin with g ⊥=2.0036 and g ∥=2.0021. Mn 2+ signals of orthorhombic symmetry and very narrow line width (∼0.1 mT) were also noted (| D|=9.3 mT (∼0.009 cm −1), | E|=3.1 mT (∼0.003 cm −1)). Isochronal annealing studies reveal that these inorganic radical species reside in energy traps that are significantly deeper than previously determined as revealed by their annealing temperatures: SO 2 − (isotropic), T *∼340 °C; SO 3 − (isotropic), T *∼230 °C; SO 3 − (axial), T *∼190 °C. These data suggest that these spin centers may be used to extend the upper limit for dating purposes to times on the order of 1 Ma for SO 3 − (axial) and 200–300 Ma for SO 3 − (isotropic). Spin–spin and spin–lattice relaxation studies employing progressive microwave saturation were determined for all sulfur-based radical species and found to be consistent with the supposition of the isotropic signals existing in environments that are conducive to dynamic averaging of the g-anisotropy.

Vibrational Markers for the Open-Shell Character of Transition Metal Bis-dithiolenes: An Infrared, Resonance Raman, and Quantum Chemical Study

Transition metal complexes involving the benzene-1,2-dithiol (L(2-)) and Sellmann's 3,5-di-tert-butylbenzene-1,2-dithiol(L(Bu 2-)) ligands have been studied by UV-vis, infrared (IR), and resonance Raman (rR) spectroscopies. Raman spectra were obtained in resonance with the intervalence charge transfer (IVCT) bands in the near-infrared region and ligand-to-metal charge transfer (LMCT) bands in the near-UV region. Geometry optimization and frequency calculations using density functional theory (DFT) have been performed for [M(L)(2)](z) and [M(L(Bu))(2)](z) species (M = Ni, Pd, Pt, Co, Cu, Au, z = -1; M = Au, z = 0). On the basis of frequency calculations and normal-mode analysis, we have assigned the most important totally symmetric vibrations as well as corresponding overtone and combination bands that appear in rR spectra of compounds [Ni(L)(2)](1-), [M(L(Bu))(2)](1-) (M = Ni, Pt, Co, Cu). Experimental values of dimensionless normal coordinate displacements in excited states have been determined by fitting of rR spectra together with the absorption band shape, based on the time-dependent theory of Heller. Time-dependent density functional theory (TD-DFT) and multireference post-Hartree-Fock ab initio calculations, using the difference dedicated configuration interaction (MR-DDCI) method, were carried out to evaluate dimensionless normal coordinate displacements quantum chemically. The calculations show encouraging agreement with the experimental values. The large distortions along several normal modes led to significant vibronic broadening of IVCT and LMCT bands, and the broadening was accounted for in the deconvolution of the absorption spectra. The presence of an intense rR band around approximately 1100 cm(-1) was found to be a reliable marker for the presence of sulfur-based radicals.

Evidence for Sulfur-Based Radicals in Thiolate Compound I Intermediates

Evidence for Sulfur-Based Radicals in Thiolate Compound I Intermediates