Perkin Trans Research Articles

Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs

Phosphorus Fluoride Exchange (PFEx) represents a cutting-edge advancement in catalytic click-reaction technology. Drawing inspiration from Nature's phosphate connectors, PFEx facilitates the reliable coupling of P(V)-F loaded hubs with aryl alcohols, alkyl alcohols, and amines to produce stable, multidimensional P(V)-O and P(V)-N linked products. The rate of P-F exchange is significantly enhanced by Lewis amine base catalysis, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). PFEx substrates containing multiple P-F bonds are capable of selective, serial exchange reactions via judicious catalyst selection. In fewer than four synthetic steps, controlled projections can be deliberately incorporated along three of the four tetrahedral axes departing from the P(V) central hub, thus taking full advantage of the potential for generating three-dimensional diversity. Furthermore, late-stage functionalization of drugs and drug fragments can be achieved with the polyvalent PFEx hub, hexafluorocyclotriphosphazene (HFP), as has been demonstrated in prior research.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Crystal structures of tolfenamic acid polymorphic forms I and II with precise hydrogen-atom positions for nuclear magnetic resonance studies.

The structures of tolfenamic acid [TFA; 2-(3-chloro-2-methyl-anilino)benzoic acid, C14H12ClNO2] polymorph forms I and II have been redetermined [compare Andersen et al. (1989 ▸). J. Chem. Soc., Perkin Trans. 2, pp. 1443-1447] with improved precision using high-resolution X-ray diffraction data and Hirshfield atom refinement in order to better define both hydrogen-atom locations and their associated bond lengths. Covalent bond lengths to hydrogen were found to be significantly longer throughout both structures, especially for the anilino H atom, which is involved in an important intra-molecular N-H⋯O hydrogen bond to the carb-oxy-lic acid group. This hydrogen bond is shown to clearly perturb the electron density around both oxygen atoms in the latter group. The extended structures of both polymorphs feature carb-oxy-lic acid inversion dimers. These structures provide an improved foundation for nuclear magnetic resonance studies in both solution and the solid state.

Spontaneously self-assembled fluidic bilayer of cholesteryl nonanoate at interfaces: Thermal stability and post collapse scenario

We report our investigations on the thermal stability of the intermediate homologue of cholesteryl ester, cholesteryl nonanoate (ChN) at the air–water (A–W) and air–solid (A–S) interfaces. Surface manometry studies on ChN at the A–W interface reveal that the limiting area and the collapse pressure of the film decrease with an increase in the temperature. Brewster angle microscopy studies show the co-existing gas (G) and the homogeneous phase (bilayer) that, with compression, transforms to a bilayer phase followed by a collapse to circular domains. These collapsed circular domains (CCDs) coarsen and nucleate to form 3D structures, and their evolution and growth are further tracked at different temperatures using the reflection mode of the microscope. For temperatures between 288 K and 293 K, we find that the dendritic growth is favored. From 298 K to 303 K, the CCD transforms to a fractal domain with its branches changed from the left-handed to right-handed sense via an intermediate state. Based on these observations, a morphological phase diagram ChN in the collapsed state with different temperatures is constructed. Topography images of the ChN film using an atomic force microscope yield a thickness of about 3.5 nm, which is larger than its molecular length (2.7 nm). We attribute this to the partial vertical segregation of ChN molecules at the interfaces, which is consistent with the m-ii packing model proposed by Guerina and Craven (J. Chem. Soc., Perkin Trans. 2 1979, 1414). We have also investigated the thermal stability of the bilayer at the A–S interface through imaging ellipsometry. It highlights that the thermal dewetting of the confined bilayer proceeds via the random nucleation and growth of voids and the transition temperature is estimated to be 396.3 ± 1.2 K with a width of 7.6 ± 0.8 K.

Comparison of the C-H⋯O bonding in two crystalline phases of 1,4-di-thiane 1,1,4,4-tetra-oxide.

The crystal structures of two crystalline phases of 1,4-di-thiane 1,1,4,4-tetra-oxide, C4H8O4S2, have been determined in order to examine the nature of possible inter-molecular hydrogen bonds. Phase 1 is monoclinic, space group C2/m, with unit-cell dimensions of a = 9.073 (8), b = 7.077 (6), c = 5.597 (5) Å and β = 105.89 (1)°. The mol-ecule adopts 2/m symmetry and all of the mol-ecules are related by translation and thus have the same orientation. Phase 2 is also monoclinic but in space group P21/n with unit-cell dimensions of a = 7.1305 (5), b = 5.7245 (4), c = 8.3760 (6) Å and β = 91.138 (2)°. In this phase, the mol-ecule sits on an inversion center and the mol-ecules within the unit cell adopt quite different orientations. In both phases, examination of the potential C-H⋯O hydrogen bonds around each of the independent oxygen atoms (one axial and the other equatorial) shows the general O⋯H patterns to be quite similar with each oxygen atom in contact with four neighboring H atoms, and each H atom contacting two neighboring O atoms. While none of the H⋯O contacts is particularly short (all are greater than 2.5 Å), each mol-ecule has 32 such contacts that form an extensive inter-molecular network. A 1H NMR spectrum of the compound dissolved in DMSO shows a singlet of 8H at δ 3.677 which indicates that the C-H bonds are only moderately polarized by the single adjacent -SO2- moiety: strongly polarized C-H bonds have δ values in the 5-6 range [Li & Sammes (1983 ▸). J. Chem. Soc. Perkin Trans. 1, pp. 1303-1309]. The phase 1 crystal studied was non-merohedrally twinned.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Electrochemical Behavior of 2-Halo-N-Phenylacetamides at a Carbon Cathode

Haloacetamides and haloacetanilides have been utilized for the synthesis of many compounds such as, but not limited to, β-lactams,1 N,N-bis-(phenylcarbamoylmethyl) dimethylammonium,2 and oxazolidine-2,4-diones.3 Therefore, it is important to understand fully how these haloacetamides behave as well as the reaction pathways they undergo. Electrochemical studies of 2-chloro-N-phenylacetamide have been reported at carbon cathodes, and were successful in demonstrating the reductive cleavage of the carbon–halogen bond. A mechanism for the aforementioned reduction has been proposed.4 This project’s primary objective is to compare the electrochemical behavior of a series of 2-halo-N-phenylacetamides and to elucidate a more complete mechanistic picture for the reduction of this class of compounds. In the present investigation, we have conducted cyclic voltammetry and controlled-potential electrolysis studies of 2-iodo-N-phenylacetamide and 2-bromo-N-phenylacetamide at a carbon cathode to understand further the electrochemical behavior of 2-halo-N-phenylacetamides. Reduction of 2-bromo-N-phenylacetamide and 2-iodo-N-phenylacetamide in dimethylformamide (DMF) containing 0.05 M tetramethylammonium tetrafluoroborate (TMABF4) results in cyclic voltammetry peaks at –0.9 and –1.4 V (bromo) and –0.6 and –1.1 V (iodo) vs. a Cd(Hg) reference electrode. Analysis of the products resulting from controlled-potential electrolyses of both analytes by means of gas chromatography–mass spectrometry (GC–MS) indicates the presence of dehalogenated species as the primary products. Casadei, M. A.; Di Rienzo, B.; Inesi, A.; Moracci, F. M., Electrochemical studies on haloamides. Part 3. Haloacetamides and halo-acetohydroxamates. J. Chem. Soc., Perkin Trans. 1 1992, 375–378.Walker, M. J., Treating cough and tussive attacks. Google Patents: 2012.Casadei, M. A.; Cesa, S.; Inesi, A., Electrochemical studies on haloamides. Part XII. Electrosynthesis of oxazolidine-2,4-diones. Tetrahedron 1995, 51, 5891–5900.Pasciak, E. M.; Sengupta, A.; Mubarak, M. S.; Raghavachari, K.; Peters, D. G., Electrochemical reduction of 2-chloro-N-phenylacetamides at carbon and silver cathodes in dimethylformamide. Electrochim. Acta 2014, 127, 159–166.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Preferential Solvation of a Highly Medium Responsive Pentacyanoferrate(II) Complex in Binary Solvent Mixtures: Understanding the Role of Dielectric Enrichment and the Specificity of Solute-Solvent Interactions.

In this work, the preferential solvation of an intensely solvatochromic ferrocyanide(II) dye involving a 4,4'-bipyridine-based ligand was examined in various binary solvent mixtures. Its solvatochromic behavior was rationalized in terms of specific and nonspecific solute-solvent interactions. An exceptional case of solvatochromic inversion was observed when going from alcohol/water to amide/water mixtures. These effects were quantified using Onsager's solvent polarity function. Furthermore, the sensitivity of the solvatochromism of the dye was determined using various solvatochromic parameters such as π* expressing the dipolarity/polarizability of solvents and α expressing the hydrogen-bond-donor acidity of solvents. This analysis was useful for the rationalization of the selective solvation phenomena occurring in the three types of alcohol/water and amide/water mixtures studied. Furthermore, two preferential solvation models were employed for the interpretation of the experimental spectral results in binary solvent mixtures, namely, the model of Suppan on dielectric enrichment [J. Chem. Soc. Faraday Trans. 1 1987, 83, 495-509] and the model of Bosch, Rosés, and co-workers [J. Chem. Soc., Perkin Trans. 2, 1995, 8, 1607-1615]. The first model successfully predicted the charge transfer energies of the dye in formamide/water and N-methylformamide/water mixtures, but in the case of MeOH/water mixtures, the prediction was less accurate because of the significant contribution of specific solute-solvent interactions in that case. The second model gave more insights for both specific solute-solvent as well as solvent-solvent interactions in the cybotactic region. The role of dielectric enrichment and specific interactions was discussed based on the findings.

Electrochemical Investigation of Benzil/Aluminum Ion Interactions

Introduction Benzil has been investigated as a model diketone in various electrochemical studies (1-4 ). Previous work in this laboratory has dealt with the effect of metal ion addition on the electrochemical behavior of 9-fluorenone (5). In the present work, the effect of aluminum ion additions to acetonitrile solutions of benzil has been studied. The presence of adjacent carbonyl groups in benzil suggests that benzil reduction products may be effective ligands toward added metal ions. The goal of this study is to determine the effects of these metal/ligand interactions upon the cyclic voltammetric characteristics of the benzil system. Experimental Acetonitrile (AN), benzil, and aluminum trifluoromethansulfonate [aluminum triflate, Al(TfO)3] were obtained from Aldrich Chemical Co. Tetraethylammonium tetrafluoroborate [TEA BF4] was purchased from Southwestern Analytical Chemicals (SACHEM). Voltammograms were acquired with a PAR283 potentiostat using PowerSuiteTM software. Potentials are reported with respect to a Ag/AgCl (0.1M EMICl in EMI BF4) reference electrode (Cypress Systems). Vitreous carbon electrodes were obtained from Cypress Systems. All experiments were carried out in a Vacuum Atmospheres drybox. Results and Discussion Benzil undergoes two successive electron-transfers in acetonitrile/TEA BF4 (Figure 1a), although the second process is somewhat irreversible due to proton donation from acetonitrile (2-4). The addition of Al(TfO)3 at the 1:1 Al(TfO)3 : benzil level produces a new reduction peak at -0.70V, which is assigned to the reduction of a benzil:Al3+ complex. The second reduction process has become shifted to slightly more positive potentials, suggesting interaction of the benzil radical anion with Al3+. The reduction process at -1.80 in Figure 1a is due to the reduction of Al3+ in the solution. Addition of further Al(TfO)3 to give 2:1 Al(TfO)3 : benzil (Figure 1b) gives the -0.7 V reduction process as the predominant response. This general behavior supports a strong interaction of Al3+ with benzil reduction products, ultimately giving the benzil dianion with each oxygen complexed with one Al3+. References H. E. Stapelfeldt and S. P. Perone, Analytical Chemistry, 41(4), 623 (1969).M. D. Ryan and D. H. Evans, J. Electroanal. Chem., 67, 333 (1976).M. Chandrasekaran, M. Noel and V. Krishnan, J. Chem. Soc., Perkin Trans.2, 979 (1992).G. T. Cheek, ECS Transactions, 6(6), 47 (2007).D. Canby, E. Sanders,and G. T. Cheek, J. Electrochem. Soc., 160(7), G3159 (2013). Figure 1

On the Mechanism of Phenolic Formylation Mediated by TiCl4 Complexes: Existence of Diradical Intermediates Induced by Valence Tautomerism

AbstractThe conventional electrophilic intramolecular aromatic substitution pathway proposed by Cresp et al. [J. Chem. Soc., Perkin Trans. 1 1973, 340–345] is confirmed by the observed products of phenolic formylation mediated by TiCl4. However, when the nucleophilic path is quenched by appropriate ligand modification, the initial equilibria between the possible neutral complexes of TiCl4 with 3,5‐dimethoxyphenol and/or diethyl ether lead to different stable diradical intermediates induced by valence tautomerism that provide valuable activated reagents. Some of these species have been detected by EPR, characterized theoretically and captured by TEMPO, thus providing a consistent mechanism for the reaction with one or more equivalents of TEMPO per phenol.

Electrochemical Investigations of Benzil in Nonaqueous Media

Introduction The electrochemical behavior of the aromatic diketone benzil has been studied in a number of solvents (1-4). The benzil system is particularly interesting because of its ability to undergo various reactions accompanying the reduction process. Most of the solvent systems studied to date have involved proton-donating properties to some degree, so the use of the ionic liquid 1-butyl-1-methylpyrrolidinium trifluoromethanesulfonate ( BMPY TfO ) provides a useful contrast to the other solvents. Experimental All electrochemical experiments were carried out in a Vacuum Atmospheres glovebox. Cyclic voltammograms were obtained on a PAR 283 potentiostat using PowerSuite software. Potentials are reported with respect to an Ag/AgCl reference electrode. 1-butyl-1-methylpyrrolidinium trifluoromethylsulfonate (BMPY TfO) was prepared by a literature method (5). Benzil was obtained from Aldrich Chemical Company.Results and Discussion As can be observed from Figure 1(a), benzil undergoes electrochemical reduction in BMPY TfO in two successive, reversible electron-transfer steps. Figure 1(b) shows the voltammetric behavior for only the first process. In contrast, reduction in other nonaqueous solvents such as acetonitrile and dimethylformamide (2,3) involves considerable irreversibility for the second process. The low proton-donating ability of BMPY TfO seems largely to account for this effect. The ionic liquid BMPY TfO, then, serves as a suitable solvent for observing relatively uncomplicated voltammetric behavior of benzil, presenting the possibility of studying the effect of added proton donors in this solvent.ReferencesH. E. Stapelfeldt and S. P. Perone, Analytical Chemistry, 41(4), 623 (1969).M. D. Ryan and D. H. Evans, J. Electroanal. Chem., 67, 333 (1976).M. Chandrasekaran, M. Noel and V. Krishnan,J. Chem. Soc., Perkin Trans.2, 979 (1992).G. T. Cheek, ECS Transactions, 6(6), 47 (2007).L. Crowhurst, N. L. Lancaster, J. M. P. Arlandis, and T. Welton, J. Am. Chem. Soc., 126, 11549 (2004). Figure 1. Cyclic voltammetry of 40 mM benzil in BMPY TfO at glassy carbon ( 1 mm diameter ). Scan rate 100 mV/s(a) Scan to -2.50 V [ black curve ] (b) Scan reversal at -1.50 V [ red curve ]

Redetermination of 1,3,6,8-tetra-aza-tri-cyclo-[4.4.1.1(3,8)]dodeca-ne.

The structure of the title compound, C8H16N4, which consists of four fused seven-membered rings, has been redetermined at 173 K. This redetermination corrects the orientation of two H atoms, which were located at unrealistic positions in the original room-temperature study [Murray-Rust (1974 ▶). J. Chem. Soc. Perkin Trans. 2, pp. 1136–1141]. The complete mol­ecule is generated by -42m symmetry, with one quarter of a mol­ecule [one N atom (site symmetry m), two C atoms (one with site symmetry m and the other with site symmetry 2) and two H atoms] in the asymmetric unit. No directional inter­actions beyond van der Waals contacts are apparent in the crystal structure.

Conductor‐like screening model for relaxed excited states: Implementation in the semiempirical method MSINDO

Two approaches to treat solvent polarization and reorientation effects for excited states of molecules and surfaces have been implemented in the recently developed MSINDO-sCIS method (Gadaczek, Krause, Hintze, Bredow, J. Chem. Theory Comput. 2011, 7, 3675). They allow for an efficient calculation of analytical energy gradients and hence open the opportunity to investigate fluorescence effects or photochemical reactions in solution for large molecules that are difficult to treat with high-level methods. Both approaches are based on the conductor-like screening model (COSMO) (Klamt and Schüürmann, J. Chem. Soc., Perkin Trans. 1993, 2, 799) in combination with the configuration interaction singles (CIS) method (Foresman, Head-Gordon, Pople, and Frisch, J. Phys. Chem. 1992, 96, 135). The paper gives a brief outline of the theoretical background. As a first application, solvent shifts of three well-studied, environment-sensitive fluorescent dyes (Kucherak, Didier, Mély, and Klymchenko, J. Phys. Chem. Lett. 2010, 1, 616) have been calculated and compared with experimental results and standard time-dependent density functional theory. A statistical evaluation of MSINDO-COSMO-sCIS is provided for a set of 39 molecules suggested recently by Jacquemin et al. (Jacquemin, Planchat, Adamo, and Mennucci, J. Chem. Theory Comput. 2012, 8, 2359). Calculated vertical and adiabatic excitation energies and fluorescence energies are compared to experimental data.

Invariant Kekulé structures in fullerene graphs

Abstract Fullerene graphs are trivalent plane graphs with only hexagonal and pentagonal faces. They are often used to model large carbon molecules: each vertex represents a carbon atom and the edges represent chemical bonds. A totally symmetric Kekule structure in a fullerene graph is a set of independent edges which is fixed by all symmetries of the fullerene and molecules with totally symmetric Kekule structures could have special physical and chemical properties, as suggested in [Austin, S.J, and J. Baker, P. W. Fowler, D. E. Manolopoulos, Bond-stretch Isomerism and the Fullerenes, J. Chem. Soc. Perkin Trans. 2 (1994), 2319–2323] and [Rogers, K.M., and P. W. Fowler, Leapfrog fullerenes, Huckel bond order and Kekule structures, J. Chem. Soc. Perkin Trans. 2 (2001), 18–22]. All fullerenes with at least ten symmetries were studied in [Graver, J.E. The Structure of Fullerene Signature, DIMACS Series of Discrete Mathematics and Theoretical Computer Science 64, AMS (2005), 137–166.] and a complete catalog was given in [Graver, J. E. Catalog of All Fullerene with Ten or More Symmetries DIMACS Series of Discrete Mathematics and Theoretical Computer Science 64 AMS (2005), 167–188]. Starting from this catalog in [Bogaerts, M., and G. Mazzuoccolo, G.Rinaldi, Totally symmetric Kekule structures in fullerene graphs with ten or more symmetries, MATCH Communications in Mathematical and in Computer Chemistry 69 (2013), 677–705] we established exactly which of them have at least one totally symmetric Kekule structure.

Two polymorphs of 1,8-dichloroanthracene

A second, monoclinic, polymorph of the title compound, C(14)H(8)Cl(2), has been found. In addition to the structure of this monoclinic form, the structure of the previously described orthorhombic form [Desvergne, Chekpo & Bouas-Laurent (1978). J. Chem. Soc. Perkin Trans. 2, pp. 84-87; Benites, Maverick & Fronczek (1996). Acta Cryst. C52, 647-648] has been redetermined at low temperature and using modern methods. The low-temperature structure of the orthorhombic form is of significantly higher quality than the previously published structure and additional details can be derived. A comparison of the crystal packing of the two forms with a focus on weak intermolecular C-H···Cl interactions shows the monoclinic structure to have one such interaction linking the molecules into infinite ribbons, while two crystallographically independent C-H···Cl interactions give rise to an interesting infinite three-dimensional network in the orthorhombic crystal form.

A new polymorph of 2-(2H-benzotriazol-2-yl)acetic acid

A new polymorph of 2-(benzotriazol-2-yl)acetic acid, C8H7N3O2, crystallizes in the space group C2/c (Z = 8). The non-planar mol­ecule has a synplanar conformation of the carb­oxy group. The crystal structure features helices parallel to the b axis sustained by O—H⋯N hydrogen bonding which are similar to those in the known polymorph [Giordano & Zagari (1978 ▶). J. Chem. Soc. Perkin Trans. 2, pp. 312–315]. However, in the title structure, columns are formed by π–π stacking inter­actions between benzotriazole fragments of centrosymmetrically related adjacent mol­ecules [centroid-centroid distances = 3.593 (10) and 3.381 (10) Å] whereas π–π stacking inter­actions are not observed in the other polymorph. In the crystal of the title compound, C—H⋯O inter­actions are also observed.

Conjugation of Glutathione to Oxidized Tyrosine Residues in Peptides and Proteins

Tyrosine residues are sensitive to oxidation and can be converted to hydroperoxides either by superoxide reacting with the Tyr radical or by singlet oxygen. These hydroperoxides rearrange to bicyclic derivatives that are readily reduced to more stable hydroxides. The aromatic character of tyrosine is lost, but the product contains an α-β unsaturated carbonyl group and is, therefore, an electrophile. We have generated hydroxide derivatives of several Tyr-containing peptides and shown using liquid chromatography/mass spectrometry that they undergo Michael addition with GSH. For Tyr-Gly, rate constants of 9.2 and 11.8 m(-1)min(-1) were measured for the two chromatographically distinct isomers. Unusual for GSH addition to an electrophile, the reaction is reversible, with a half-life of many hours for the reverse reaction. These kinetics indicate that with a typical cellular concentration of 5 mm GSH, >95% Tyr-Gly hydroxide would become conjugated with a half-life of ∼15 min. Sperm whale myoglobin forms a hydroperoxide on Tyr-151 in a hydrogen peroxide/superoxide-dependent reaction. We show that its hydroxide derivative reacts with GSH to form a conjugate. Detection of the conjugate required stabilization by reduction; otherwise, the reverse reaction occurred during tryptic digestion and analysis. Our findings represent a novel mechanism for peptide or protein glutathionylation involving a carbon-sulfur cross-link between oxidized Tyr and Cys. As with other electrophiles, the oxidized Tyr should undergo a similar reaction with Cys residues in proteins to give intramolecular or intermolecular protein cross-links. This mechanism could give rise to protein cross-linking in conditions of oxidative stress.

Bis[(methylsulfanyl)carbonyl]disulfane

The title compound, C4H6O2S4, was prepared by repeating, with subtle improvements, a multi-step route originally described by Mott & Barany [J. Chem. Soc. Perkin Trans. 1 (1984) ▶, pp. 2615–2621]. The title compound was obtained for the first time as a crystalline material. The two [(methyl­sulfan­yl)carbon­yl]sulfenyl moieties are essentially perpendic­ular to each other, each approximately planar (r.m.s. deviations of 0.02 and 0.01 Å) and with a C—S—S—C torsion angle = 90.99 (6)°, which compares well with the theoretical value of 90°.

3-(1H-Indol-3-yl)-4-(morpholin-4-yl)cyclobut-3-ene-1,2-dione

3-(1H-Indol-3-yl)-4-(morpholin-4-yl)cyclobut-3-ene-1,2-dione was obtained in good yields (72–82%) by nucleophilic substitution of 3-chloro-4-(1H-indol-3-yl)cyclobut-3-ene-1,2-dione with morpholine.