Dehydrogenative Coupling Reactions with Guanidino-Functionalized Aromatics.

Dehydrogenative coupling (DC) reactions are of importance for the construction of new carbon-element bonds in synthetic organic chemistry. In this work, we report on the synthesis and characterization of several redox-active guanidino-functionalized aromatic molecules (GFAs) for use in DC (C-C and C-O) reactions. In a systematic approach, we first characterize the new DC reagents in all relevant redox and protonation states, and compare their performance in competitive test proton-coupled electron transfer (PCET) reactions.

Small Ring Molecules Comprising 3-6 Boron Atoms: An Account on Synthesis, Structure, and Orbital Engineering.

ConspectusUnlike carbon, boron does not usually form ring compounds due to its electron-deficiency-driven affinity toward polyhedral geometries. The polyhedral boranes having -, -, -, or -shapes can be structurally and electronically correlated using various electron counting rules developed by Wade, Mingos, and one of us. However, in the last few decades, boron chemistry progressed significantly toward ring systems.

Aggregation of N-Heteropolycyclic Aromatic Molecules: The Acridine Dimer and Trimer.

Polycyclic aromatic hydrocarbons and their nitrogen-substituted analogues are of great interest for various applications in organic electronics. The performance of such devices is determined not only by the properties of the single molecules, but also by the structure of their aggregates, which often form via self-aggregation. Gaining insight into such aggregation processes is a challenging task, but crucial for a fine-tuning of the materials properties.

Discovery of IRAK4 Inhibitors (Zabedosertib) and .

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, (zabedosertib) and , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity.

No Influence of Asundexian on Cardiac Repolarization.

Inhibition of activated factor XI reduces thrombogenesis while maintaining physiological hemostasis, with the expectation of reduced bleeding risk compared with standard of care in the clinical setting. Asundexian (BAY 2433334), an activated factor XI inhibitor, is in clinical development for the prevention of thromboembolic events. The effect of asundexian and its plasma metabolite M10 on cardiac repolarization and potential interactions with the hNav1.

Peculiar Differences between Two Copper Complexes Containing Similar Redox-Active Ligands: Density Functional and Multiconfigurational Calculations.

Transition metal complexes featuring redox-active ligands often exhibit multiple redox states, influenced by the interplay between the metal center and the ligand. This study delves into the electronic structures of two mononuclear complexes of copper with two similar redox-active urea azine ligands. The ligands differ by the replacement of an NCH moiety by an S atom in the ligand backbone.

Metal-Free B-B Dehydrocoupling Reaction of a Simple Borane Adduct: Convenient Access to a Nucleophilic Diborane(4).

The selective formation of homonuclear bonds is of key importance in synthetic chemistry. Especially, dehydrocoupling reactions are attractive as ecologically and economically friendly alternatives to established reductive bond forming reactions, since they do not require the use of stoichiometric amounts of a reducing reagent and produce only valuable dihydrogen as by-product. Here, we report on a metal-free B-B dehydrocoupling reaction that starts directly from a simple, easily accessible BH adduct, providing convenient access to a new nucleophilic dihydridodiborane in excellent yield.

Isolated Dimers Versus Solid-State Dimers of N-Heteropolycycles: Matrix-Isolation Spectroscopy in Concert with Quantum Chemistry.

In this work, matrix-isolation spectroscopy and quantum-chemical calculations are used together to analyse the structure and properties of weakly bound dimers of the two isomers benzo[a]acridine and benzo[c]acridine. Our measured experimental electronic absorbance spectra agree with simulated spectra calculated for the equilibrium structures of the dimers in gas-phase, but in contrast, disagree with the simulated spectra calculated for the structures obtained by optimising the experimental solid-state structures. This highlights the sensitivity of the electronic excitations with respect to the dimer structures.

Hexaguanidino-Triptycenes and Triphenylenes: Electronic Coupling in Molecules Containing Three Redox-Active o-Diguanidinobenzene Units Connected either Directly or Interacting Through Homoconjugation.

Novel redox-active hexaguanidine molecules with multiple redox states were synthesized by connecting three o-diguanidinobenzene units. In 2,3,6,7,14,15-hexaguanidino-triptycenes, the three redox-active o-diguanidinobenzene units are connected through C-C bonds to the sp -hybridized bridgehead C atoms, and in 2,3,6,7,10,11-hexaguanidino-triphenylenes they are directly connected. The connectivity difference leads to different electronic coupling between the three redox-active o-diguanidinobenzene units, with homoconjugation being present in the triptycene, but not in the triphenylene compounds.

Halide-Coupled Double Electron Transfer with Electron-Rich Diboranes.

The ditriflato-diborane B (μ-hpp) (OTf) (hpp=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidinate) acts as a stable surrogate of the elusive dication [B (hpp) ] , being both electrophilic (vacant boron p orbitals) and nucleophilic (filled B-B bond orbital). This combination of seemingly contrasting behaviors could be used to develop a metallomimetic diborane chemistry, with Lewis σ-basic and π-acidic substrates being bound and reduced at the diborane. Here, we report on a novel reaction type within this general theme, in which double electron transfer from the diboron unit to the boron-bound organic substrate is coupled with halide transfer in the other direction.

Intramolecular Through-Space Double-Electron Transfer Between A Pair of Redox-Active Guanidine Units Aligned by Dithiolate Bridges.

Using unconventional synthesis protocols, two redox-active triguanidine units are connected by a dithiolate bridge, aligning the two redox-active units in close proximity. The reduced, neutral and the tetracationic redox states with two dicationic triguanidine units are isolated and fully characterized. Then, the dicationic redox states are prepared by mixing the neutral and tetracationic molecules.

Nonclinical Cardiovascular Assessment of the Soluble Guanylate Cyclase Stimulator Vericiguat.

Vericiguat and its metabolite M-1 were assessed for proarrhythmic risk in nonclinical in vitro and in vivo studies. In vitro manual voltage-clamp recordings at room temperature determined the effect of vericiguat on human Ether-a-go-go Related Gene (hERG) K channels. Effects of vericiguat and M-1 on hERG K, Nav1.

Quantitative Electromerism of a Well-defined Mononuclear Copper Complex Through Reversible Intramolecular Metal-Ligand Electron Transfer.

Copper amine oxidases are enzymes that exhibit in their active site a mononuclear copper complex and a 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor; in the oxidative half of the catalytic cycle, the enzymes regulate their activity by a temperature-dependent electron transfer equilibrium between the Cu complex with the reduced, aminoquinol form of the cofactor and the reactive Cu complex with the corresponding oxidized, semiquinone form of the cofactor. Here, we report the first mononuclear copper complex with redox-active ligands showing quantitative, reversible electromerism between a Cu eletromer with reduced, neutral ligand and a Cu electromer with an oxidized, radical monocationic ligand. The Cu form, being exclusively present at low temperature, exhibits a lower enthalpy (like the enzymes), but the Cu complex exhibits a higher entropy and is exclusively present at room temperature in CH Cl solution.

Pyridine Dimers and Their Low-Temperature Isomerization: A High-Resolution Matrix-Isolation Spectroscopy Study.

The bonding between two neutral aromatic compounds, especially small ones, has been controversially debated in the last decades, and terms like "π-stacking" had to be revised. Surprisingly, despite of many experimental and computational work, there is still no clear consensus about the structure of and the bonding in the pyridine dimer. In this work, for different isomeric forms of the pyridine dimer, the structures and bonding were elucidated by combining high-resolution matrix-isolation spectroscopic results with quantum-chemical calculations.

Interplay and Competition Between Two Different Types of Redox-Active Ligands in Cobalt Complexes: How to Allocate the Electrons?

The field of molecular transition metal complexes with redox-active ligands is dominated by compounds with one or two units of the same redox-active ligand; complexes in which different redox-active ligands are bound to the same metal are uncommon. This work reports the first molecular coordination compounds in which redox-active bisguanidine or urea azine (biguanidine) ligands as well as oxolene ligands are bound to the same cobalt atom. The combination of two different redox-active ligands leads to mono- as well as unprecedented dinuclear cobalt complexes, being multiple (four or six) center redox systems with intriguing electronic structures, all exhibiting radical ligands.

Bistriazoles Connected Through a B-B Bridge, Synthesized by Highly Selective Dipolar Cycloaddition Reactions of a Diazido-diborane(4).

In this work we report the first cycloaddition reactions between a diazido diborane(4) and terminal alkynes, providing unique access to bis-1,2,3-triazoles connected by a B-B bridge. The catalyst-free reactions are highly selective, yielding exclusively the thermodynamically disfavored bis-1,4-triazoles. The reactions are enabled by the high thermal stability of the diazido-diborane [B(hpp)(N )] (hpp=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-α]pyrimidinate).

Solvent-Induced Redox Isomerism of Cobalt Complexes with Redox-Active Bisguanidine Ligands.

Redox-isomeric coordination compounds, in which the magnetic and optical properties could be varied by a stimulated intramolecular electron transfer between the metal and a redox-active ligand, are of interest for several applications in catalysis and materials science. In this work, the redox chemistry of cobalt complexes with redox-active bisguanidine ligands is studied; systematic modifications at the redox-active bisguanidine and the co-ligand units allow for fine-tuning of the electronic structure, which eventually leads to the first observation of redox isomerism for cobalt complexes with redox-active guanidine ligands. Redox isomerism is triggered by a change in the solvent properties.

Directed Synthesis and Chemistry of Unsymmetric Dicationic Diboranes and Their Use in Frustrated Lewis Pair-like Chemistry.

The chemistry of dicationic diboranes with two B atoms that are engaged in direct B-B bonding is by enlarge unexplored, although these molecules have intriguing properties due to their combined Lewis acidic and electron-donor properties. Unsymmetric dicationic diboranes are extremely rare, but especially attractive due to their polarized B-B bond. In this work we report the directed synthesis of several stable unsymmetric dicationic diboranes by reaction between the electron-rich ditriflato-diborane B (hpp) (OTf) (hpp=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-α]pyrimidinate) and phosphino-pyridines, establishing B-N and B-P bonds with the diborane concomitant with triflate elimination.

Derivatization of an especially electron-rich diborane.

Starting with electron-rich ditriflato-diborane B(hpp)(OTf) (hpp = 1,3,4,6,7,8-hexahydro-2-pyrimido[1,2-]pyrimidinate), novel symmetric and unsymmetric diboranes B(hpp)X and B(hpp)XY with X,Y = Br, NCS, N or OTf are synthesized by substitution reactions with S1 mechanisms. The stability of the unsymmetric diboranes with respect to dismutation equilibria is evaluated.

Polycationic Redox-Active Cyclophanes with Integrated Electron-Rich Diboron Units.

Cationic cyclophanes are widely used in a variety of applications in supramolecular chemistry and materials science. In this work the authors systematically study the integration of electron-rich diboron units with B atoms into polycationic cyclophanes with viologen-like electron-acceptor units. They also report a first hexacationic cage-compound in which three diboron units connect two tris(4-pyridyl)triazine acceptor units.

A Copper(I) Complex with Two Unpaired Electrons, Synthesised by Oxidation of a Copper(II) Complex with Two Redox-Active Ligands.

Two homoleptic copper(II) complexes [Cu(L1) ] and [Cu(L2) ] with anionic redox-active ligands were synthesised, one with urea azine (L1) and the other with thio-urea azine (L2) ligands. One-electron oxidation of the complexes initiates an unprecedented redox-induced electron transfer process, leading to monocationic copper(I) complexes [Cu(L1) ] and [Cu(L2) ] with two oxidised ligands. While [Cu(L1) ] is best described as a Cu complex with two neutral radical ligands that couple antiferromagnetically, [Cu(L2) ] is a Cu complex with two clearly different ligand units in the solid state and with a magnetic susceptibility close to a diamagnetic compound.

On the metal-ligand bonding in dinuclear complexes with redox-active guanidine ligands.

Coordination compounds with redox-active ligands are currently intensively studied. Within this research theme, redox-active guanidines have been established as a new, eminent class of redox-active ligands. In this work the variation of metal-guanidine bonding in dinuclear transition metal complexes with bridging redox-active tetrakisguanidine ligands is analysed.

Proton-Coupled Electron Transfer (PCET) with 1,4-Bisguanidino-Benzene Derivatives: Comparative Study and Use in Acid-Initiated C-H Activation.

Proton-coupled electron transfer (PCET) is of key importance in modern synthetic chemistry. Redox-active guanidines were established by our group as valuable alternatives to toxic high-potential benzoquinones in a variety of different PCET reactions. In this work, the PCET reactivity of a series of 1,4-bisguanidino-benzenes varying in their redox potentials and proton affinities is evaluated.

Switching from Metal- to Ligand-Based Oxidation in Cobalt Complexes with Redox-Active Bisguanidine Ligands.

The control of the redox reactivity, magnetic and optical properties of the different redox states of complexes with redox-active ligands permits their rational use in catalysis and materials science. The redox-chemistry of octahedrally coordinated high-spin Co complexes (three unpaired electrons) with one redox-active bisguanidine ligand and two acetylacetonato (acac) co-ligands is completely changed by replacing the acac by hexafluoro-acetylacetonato (hfacac) co-ligands. The first one-electron oxidation is metal-centered in the case of the complexes with acac co-ligands, giving diamagnetic Co complexes.