Diamidocarbene-Based Thiele and Tschitschibabin Hydrocarbons: Carbonyl Functionalized Kekulé Diradicaloids.

Herein, we report diamidocarbene (DAC)-based Thiele and Tschitschibabin hydrocarbons, diradicaloids that contain four carbonyl/amido functional groups. The impact of two different π-conjugated spacers, p-phenylene vs p,p'-biphenylene, has been realized. The quantum chemical calculations suggest diamidocarbene (DAC)-based Thiele hydrocarbon (p-phenylene bridged) closed-shell singlet is the ground state, whereas for the diamidocarbene (DAC)-based Tschitschibabin hydrocarbon (p,p'-biphenylene bridged), open-shell singlet is the ground state. The influence of two different π-conjugated spacers also has been reflected in their UV-vis spectra. To gain more information on the diamidocarbene (DAC)-based Thiele and Tschitschibabin hydrocarbons, we have also carried out cyclic voltammetry investigations along with UV-vis-NIR-spectroelectrochemical studies of their corresponding 2-e oxidized product.

Directed Design of a AuI Complex with a Reduced Mesoionic Carbene Radical Ligand: Insights from 1,2,3-Triazolylidene Selenium Adducts and Extensive Electrochemical Investigations.

Carbene-based radicals are important for both fundamental and applied chemical research. Herein, extensive electrochemical investigations of nine different 1,2,3-triazolylidene selenium adducts are reported. It is found that the half-wave potentials of the first reduction of the selones correlate with their calculated LUMO levels and the LUMO levels of the corresponding triazolylidene-based mesoionic carbenes (MICs). Furthermore, unexpected quasi-reversibility of the reduction of two triazoline selones, exhibiting comparable reduction potentials, was discovered. Through UV/Vis/NIR and EPR spectroelectrochemical investigations supported by DFT calculations, the radical anion was unambiguously assigned to be triazoline centered. This electrochemical behavior was transferred to a triazolylidene-type MIC-gold phenyl complex resulting in a MIC-radical coordinated AuI species. Apart from UV-Vis-NIR and EPR spectroelectrochemical investigations of the reduction, the reduced gold-coordinated MIC radical complex was also formed in situ in the bulk through chemical reduction. This is the first report of a monodentate triazolylidene-based MIC ligand that can be reduced to its anion radical in a metal complex. The results presented here provide design principles for stabilizing radicals based on MICs.

Forty Years after the Discovery of Its Nucleolytic Activity: [Cu(phen)2 ]2+ Shows Unattended DNA Cleavage Activity upon Fluorination.

[Cu(phen)2 ]2+ (phen=1,10-phenanthroline) is the first and still one of the most efficient artificial nucleases. In general, when the phen ligand is modified, the nucleolytic activity of its CuII complex is significantly reduced. This is most likely due to higher steric bulk of such ligands and thus lower affinity to DNA. CuII complexes with phen ligands having fluorinated substituents (F, CF3 , SF5 , SCF3 ) surprisingly showed excellent DNA cleavage activity-in contrast to the unsubstituted [Cu(phen)2 ]2+ -in the absence of the otherwise required classical, bioabundant external reducing agents like thiols or ascorbate. This nucleolytic activity correlates well with the half-wave potentials E1/2 of the complexes. Cancer cell studies show cytotoxic effects of all complexes with fluorinated ligands in the low µm range, whereas they were less toxic towards healthy cells (fibroblasts).

Chromium(0) and Molydenum(0) Complexes with a Pyridyl-Mesoionic Carbene Ligand: Structural, (Spectro)electrochemical, Photochemical, and Theoretical Investigations.

This work reports on the synthesis and in-depth electrochemical and photochemical characterization of two chromium(0) and molydenum(0) metal complexes with bidentate pyridyl-mesoionic carbene (MIC) ligands of the 1,2,3-triazol-5-ylidene type and carbonyl coligands. Metal complexes with MIC ligands have turned out to have very promising electrocatalytic and photochemical properties, but examples of MIC-containing complexes with early-transition-metal centers remain extremely rare. The electrochemistry of these new MIC complexes was studied by cyclic voltammetry and especially spectroelectrochemistry in the IR region consistent with a mainly metal-centered oxidation, which is fully reversible in the case of the chromium(0) complex. At the same time, the two reduction steps are predominantly ligand-centered according to the observed near-IR absorbance, with the first reduction step being reversible for both systems. The results of the electron paramagnetic resonance studies on the oxidized and reduced species confirm the IR spectroelectrochemistry experiments. The photochemical reactivity of the complexes with a series of organic ligands was investigated by time-resolved (step-scan) Fourier transform infrared (FTIR) spectroscopy. Interestingly, the photoreactions in pyridine and acetonitrile are fully reversible with a slow dark reverse reaction back to the educt species over minutes and even hours, depending on the metal center and reagent. This reversible behavior is in contrast to the expected loss of one or several CO ligands known from related homoleptic as well as heteroleptic M(CO)4L2 α-diimine transition-metal complexes.

Between Aromatic and Quinoid Structure: A Symmetrical UV to Vis/NIR Benzothiadiazole Redox Switch.

Reversibly switching the light absorption of organic molecules by redox processes is of interest for applications in sensors, light harvesting, smart materials, and medical diagnostics. This work presents a symmetrical benzothiadiazole (BTD) derivative with a high fluorescence quantum yield in solution and in the crystalline state and shows by spectroelectrochemical analysis that reversible switching of UV absorption in the neutral state, to broadband Vis/NIR absorption in the 1st oxidized state, to sharp band Vis absorption in the 2nd oxidized state, is possible. For the one-electron oxidized species, formation of a delocalized radical is confirmed by electron paramagnetic resonance spectroelectrochemistry. Furthermore, our results reveal an increasing quinoidal distortion upon the 1st and 2nd oxidation, which can be used as the leitmotif for the development of BTD based redox switches.

Redox-Responsive Host-Guest Chemistry of a Flexible Cage with Naphthalene Walls.

"Naphthocage", a naphthalene-based organic cage, reveals very strong binding (up to 1010 M-1) to aromatic (di)cationic guests, i.e., the tetrathiafulvalene mono- and dication and methyl viologen. Intercalation of the guests between two naphthalene walls is mediated by C-H···O, C-H···π, and cation···π interactions. The guests can be switched into and out of the cage by redox processes with high binding selectivity. Oxidation of the flexible cage itself in the absence of a guest leads to a stable radical cation with the oxidized naphthalene intercalated between and stabilized by the other two. Encapsulated guest cations are released from the cavity upon cage oxidation, paving the way to future applications in redox-controlled guest release or novel stimuli-responsive materials.

Tuning PtII -Based Donor-Acceptor Systems through Ligand Design: Effects on Frontier Orbitals, Redox Potentials, UV/Vis/NIR Absorptions, Electrochromism, and Photocatalysis.

Asymmetric platinum donor-acceptor complexes [(pimp)Pt(Q2- )] are presented in this work, in which pimp=[(2,4,6-trimethylphenylimino)methyl]pyridine and Q2- =catecholate-type donor ligands. The properties of the complexes are evaluated as a function of the donor ligands, and correlations are drawn among electrochemical, optical, and theoretical data. Special focus has been put on the spectroelectrochemical investigation of the complexes featuring sulfonyl-substituted phenylendiamide ligands, which show redox-induced linkage isomerism upon oxidation. Time-dependent density functional theory (TD-DFT) as well as electron flux density analysis have been employed to rationalize the optical spectra of the complexes and their reactivity. Compound 1 ([(pimp)Pt(Q2- )] with Q2- =3,5-di-tert-butylcatecholate) was shown to be an efficient photosensitizer for molecular oxygen and was subsequently employed in photochemical cross-dehydrogenative coupling (CDC) reactions. The results thus display new avenues for donor-acceptor systems, including their role as photocatalysts for organic transformations, and the possibility to introduce redox-induced linkage isomerism in these compounds through the use of sulfonamide substituents on the donor ligands.

A coordinatively unsaturated iridium complex with an unsymmetrical redox-active ligand: (spectro)electrochemical and reactivity studies.

Redox-active ligands, owing to their electron reservoir capability, are well suited for the generation of coordinatively unsaturated metal complexes. We present here iridium complexes with an unsymmetrically substituted o-phenylenediamine ligand. A coordinatively unsaturated, formally iridium(iii) complex with the fully reduced o-phenylenediamide (or o-diamidobenzene) ligand was isolated and structurally characterized. This coordinatively unsaturated metal complex undergoes methylation reactions with a CH3+ source to form a new species with an Ir-CH3 bond. The redox-active Ir-CH3 complex performs the activation of CDCl3. The same activation reaction was also tested for other haloforms. In all types of reactions, the masked coordination site at the metal center and the electron reservoir behavior of the redox-active ligand are used for reactivity. Furthermore, we show that the aforementioned iridium(iii) complex performs redox-induced dihydrogen activation. This activation process was used to catalytically transfer the electrons and protons of dihydrogen to a substrate molecule. Crystallographic, spectroscopic, electrochemical, spectroelectrochemical and DFT methods were used to elucidate the geometric and the electronic structures of the metal complex in the various redox forms and to probe the mechanism of the investigated reactions. We demonstrate here how the cooperative behavior between a catalytically active metal center and a redox non-innocent ligand can be utilized to perform substrate bond activation and transformation.

Direct access to 2-aryl substituted pyrrolinium salts for carbon centre based radicals without pyrrolidine-2-ylidene alias cyclic(alkyl)(amino)carbene (CAAC) as a precursor.

The synthesis of organic radicals is challenging due to their inherent instability. In recent years, cyclic(alkyl)(amino)carbene (CAAC)-derived 2-substituted pyrrolinium salts have been used as synthons for the synthesis of isolable carbon-based radicals. Herein, we report a direct, easy and convenient method for the synthesis of 2-aryl substituted pyrrolinium salts without using CAAC as a precursor. These cations can be reduced to the corresponding radicals. The influence of the aryl substituent at the C-2 position on radical stabilization and dimerization has been investigated. Because of the large scope of our strategy (capability to modulate different substituents at all the C- and N-centres of the pyrrolinium salts), it has the merit to be an extremely effective and productive route for generating carbon-based radicals whose stability as well as reactivity can be varied.

New Dyes Based on Extended Fulvene Motifs: Synthesis through Redox Reactions of Naphthoquinones with Donor-Acceptor Cyclopropanes and Their Spectroelectrochemical Behavior.

Novel dyes based on extended fulvene motifs are reported. The carbon skeleton was generated by a catalyzed addition of donor-acceptor cyclopropanes to naphthoquinone. The hydroxy group at the central ring of the tricyclic fulvene motif was converted into the triflate, which reacted efficiently with a wide range of nucleophiles, resulting in substitution and thereby providing new derivatives. The synthetic versatility allowed us to investigate the absorption, electrochemical, and UV/Vis-NIR spectroelectrochemical properties of these dyes as a function of the substituents. The dyes were shown to participate in reductive electrochemistry, the reversibility of which can be improved by appropriate selection of the substituents. Additionally, first signs of NIR electrochromism are presented, opening new avenues for the future investigations of such dyes.

Redox-Induced Oxidative C-C Bond Cleavage of 2,2'-Pyridil in Diruthenium Complexes.

In the recent years, there has been an emerging research interest in the domain of C-C bond-cleavage reactions. The present contribution deals with the redox-mediated dioxygen activation and C-C bond cleavage in a diruthenium complex [(acac)2 RuII (µ-L1)RuII (acac)2 ], 1 (acac=acetylacetonate) incorporating 2,2'-pyridil (L1) as the bridging ligand. The above process leads to a C-C-cleaved monomeric product [(acac)2 RuIII (pic- )], 2 (pic- =piconilate). Intriguingly, similar diastereomeric complexes [(acac)2 RuII (µ-L2)RuII (acac)2 ], meso (ΔΛ): 3 a and rac (ΔΔ/ΛΛ): 3 b, involving an analogous diimine bridge (L2=N1,N2-diphenyl-1,2-di(pyridin-2-yl)ethane-1,2-diimine), were stable towards such oxidative transformations. Electrochemical and spectroelectrochemical studies, in combination, establish the potential non-innocent feature of the 2,2'-Pyridil (L1) and its derivative (L2) both in oxidation and reduction processes. Additionally, theoretical calculations have been employed to verify the redox states and their behavior. Furthermore, transition state (TS) calculations at the M06L/6-31G*/LANL2DZ level of theory together with detailed kinetic studies outline a putative mechanism for the selective transformation of 1→2 involving the formation of an intermediate bearing peroxide linkage to complex 1.

Diaminodicyanoquinones: Fluorescent Dyes with High Dipole Moments and Electron-Acceptor Properties.

Fluorescent dyes are applied in various fields of research, including solar cells and light-emitting devices, and as reporters for assays and bioimaging studies. Fluorescent dyes with an added high dipole moment pave the way to nonlinear optics and polarity sensitivity. Redox activity makes it possible to switch the molecule's photophysical properties. Diaminodicyanoquinone derivatives possess high dipole moments, yet only low fluorescence quantum yields, and have therefore been neglected as fluorescent dyes. Here we investigate the fluorescence properties of diaminodicyanoquinones using a combined theoretical and experimental approach and derive molecules with a fluorescence quantum yield exceeding 90 %. The diaminodicyanoquinone core moiety provides chemical versatility and can be integrated into novel molecular architectures with unique photophysical features.

Spectroscopic and Electronic Properties of Molybdacarborane Complexes with Non-innocently Acting Ligands.

The molybdacarboranes [3-{L-κ2 N,N}-3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] (L=2,2'-bipyridine (2,2'-bpy, 1 a) or 1,10-phenanthroline (1,10-phen, 1 b)) incorporating well-known potentially non-innocent ligands (CO, 2,2'-bpy, 1,10-phen) and the "non-spectator" nido-carborane ([η5 -C2 B9 H11 ]2- ) ligand were prepared and fully characterised. High-resolution mass spectrometry, single-crystal X-ray diffraction methods, spectroscopy (IR, (resonance) Raman, NMR), cyclic voltammetry and spectroelectrochemistry (electrochemical properties) were supported by theoretical investigations of the electronic structure (DFT, CAS-SCF, TD-DFT).

Flexible vs. rigid bis(2-benzimidazolyl) ligands in Cu(II) complexes: Impact on redox chemistry and oxidative DNA cleavage activity.

Cu(II) complexes of bis(2-benzimidazolyl) ligands connected by different linker moieties (disulfide, ethylene, ortho-phenylene) were applied in DNA cleavage reactions. Hydroxyl radicals and hydrogen peroxide were proven as reactive oxygen species (ROS) in a DNA quenching experiment. Thus, an oxidative DNA cleavage mechanism is suggested. The binding affinity of the Cu(II) complexes to DNA was studied by UV-VIS (DNA melting), fluorescence (ethidium bromide displacement assay) and circular dichroism (CD) spectroscopy indicating a correlation between DNA binding and DNA cleavage efficiency. The most important finding was that oxidative nuclease activity correlated with flexibility of the linker between the benzimidazole moieties. A more flexible linker allowed for an easier switch between square planar (Cu(II)) and tetrahedral geometry (Cu(I)) for the complex, and thus resulted in an enhanced ROS generation. EPR spectroscopy and cyclic voltammetry were applied to investigate such changes in geometry and redox state.

Isolable Cu(I) Complexes of Extremely Electron-Poor, Completely Unreduced o-Quinone and "Di- o-Quinone" Ligands Stabilized through π-π Interactions in the Secondary Coordination Sphere.

The copper-quinone interaction plays important roles in diverse fields such as biochemistry, catalysis, and optically/magnetically switchable materials. Despite this fact, the isolation and thorough characterization of copper(I)-quinone complexes remains a highly challenging task owing to their intrinsic instability. We herein present systems where the stability imparted by the extended π-system of a pyrene ring is used to synthesize, isolate, and crystallographically characterize the first example of a dinuclear metal complex that is bridged by a completely unreduced "di- o-quinone"-type ligand. Additionally, we present the monocopper counterpart with the o-quinone-pyrene type of ligand. The copper complexes are redox-rich and display intriguing electrochemical, optical, and electron paramagnetic resonance (EPR) spectroscopic properties. The line-rich EPR spectra of the one-electron reduced copper(I) complexes were simulated and analyzed via density functional theory calculations. The results presented here establish π-π stacking as a viable alternative to stabilize otherwise unstable redox-active compounds with possible consequences for sensing and redox catalysis.

Accordion-Like Motion in Electrochemically Switchable Crown Ether/Ammonium Oligorotaxanes.

Reversible oxidation reactions in electrochemically switchable oligorotaxanes with tetrathiafulvalene (TTF) decorated 24-crown-8 ether wheels generate intramolecular mixed-valence and radical-cation interactions between the wheels. This induces shuttling of the wheels and a contraction of inter-wheel distances. Further oxidation generates repulsive forces between the TTFs and maximizes the inter-wheel distances instead. These interactions and co-conformational changes were not observed for structurally similar controls in which acetyl groups along the axle prevent translational motion of the wheels. This operation mode of oligorotaxanes, which is reminiscent of an accordion-like motion, is promising for functional materials and nanodevices such as piston-type rotaxane motors.

A New Highly Thyrotropin Receptor-Selective Small-Molecule Antagonist with Potential for the Treatment of Graves' Orbitopathy.

BACKGROUND: The thyrotropin receptor (TSHR) is the target for autoimmune thyroid stimulating antibodies (TSAb) triggering hyperthyroidism. Whereas elevated thyroid hormone synthesis by the thyroid in Graves' disease can be treated by antithyroid agents, for the pathogenic activation of TSHR in retro-orbital fibroblasts of the eye, leading to Graves' orbitopathy (GO), no causal TSHR directed therapy is available. METHODS: Due to the therapeutic gap for severe GO, TSHR inhibitors were identified by high-throughput screening in Chinese hamster ovary cells expressing the TSHR. Stereo-selective synthesis of the screening hits led to the molecule S37, which contains seven chiral centers. Enantiomeric separation of the molecule S37 resulted in the enantiopure molecule S37a-a micro-molar antagonist of thyrotropin-induced cyclic adenosine monophosphate accumulation in HEK 293 cells expressing the TSHR. RESULTS: The unique rigid bent shape of molecule S37a may mediate the observed high TSHR selectivity. Most importantly, the closely related follitropin and lutropin receptors were not affected by this compound. S37a not only inhibits the TSHR activation by thyrotropin itself but also activation by monoclonal TSAb M22 (human), KSAb1 (murine), and the allosteric small-molecule agonist C2. Disease-related ex vivo studies in HEK 293 cells expressing the TSHR showed that S37a also inhibits cyclic adenosine monophosphate formation by oligoclonal TSAb, which are highly enriched in GO patients' sera. Initial in vivo pharmacokinetic studies revealed no toxicity of S37a and a remarkable 53% oral bioavailability in mice. CONCLUSION: In summary, a novel highly selective inhibitor for the TSHR is presented, which has promising potential for further development for the treatment of GO.

Switchable synchronisation of pirouetting motions in a redox-active [3]rotaxane.

In this study, the crown/ammonium [3]rotaxane R2 is reported which allows a switchable synchronisation of wheel pirouetting motions. The rotaxane is composed of a dumbbell-shaped axle molecule with two mechanically interlocked macrocycles which are decorated with a redox-active tetrathiafulvalene (TTF) unit. Electrochemical, spectroscopic, and electron paramagnetic resonance experiments reveal that rotaxane R2 can be reversibly switched between four stable oxidation states (R2, R2˙+, R22(˙+), and R24+). The oxidations enable non-covalent, cofacial interactions between the TTF units in each state-including a stabilised mixed-valence (TTF2)˙+ and a radical-cation (TTF˙+)2 dimer interaction-which dictate a syn (R2, R2˙+, and R22(˙+)) or anti (R24+) ground state co-conformation of the wheels in the rotaxane. Furthermore, the strength of these wheel-wheel interactions varies with the oxidation state, and thus electrochemical switching allows a controllable synchronisation of the wheels' pirouetting motions. DFT calculations explore the potential energy surface of the counter-rotation of the two interacting wheels in all oxidation states. The controlled coupling of pirouetting motions in rotaxanes can lead to novel molecular gearing systems which transmit rotational motion by switchable non-covalent interactions.

Metal coordination induced ring contraction of porphyrin derivatives.

A remarkable rearrangement of a diferrocenylporphyrin to give a silver(iii) corrole has been discovered. Compared to the previously reported porphyrin to corrole ring conversions (extremely rare and poor reaction yields), our methodology delivers near quantitative yield for this ring contraction.

Chromium Complexes with Oxido and Corrolato Ligands: Metal-Based Redox Processes versus Ligand Non-Innocence.

Metal- versus ligand-centered redox processes and the effects of substituents on the ligands on the spectroscopic properties of the metal complexes are at the heart of research on metal complexes with non-innocent ligands. This work presents three examples of chromium complexes that contain both oxido and corrolato ligands, with the substituents on the corrolato ligands being different in the three cases. Combined X-ray crystallographic, electrochemical, UV/Vis/NIR/EPR spectroelectrochemical, and EXAFS/XANES measurements, together with DFT calculations, have been used to probe the complexes in three different redox forms. This combined approach makes it possible to address questions related to chromium- versus corrolato-centered redox processes, and the accessibility (or not) of CrIV , CrV , and CrVI in these complexes, as well as their spin states. To the best of our knowledge, these are the first EXAFS/XANES investigations on Cr-corrolato complexes in different redox forms, and hence these data should set benchmarks for future investigations on such complexes by this method.