Electrocatalytic CO2 Reduction: Monitoring of Catalytically Active, Downgraded, and Upgraded Cobalt Complexes.

The premise of most studies on the homogeneous electrocatalytic CO2 reduction reaction (CO2RR) is a good understanding of the reaction mechanisms. Yet, analyzing the reaction intermediates formed at the working electrode is challenging and not always attainable. Here, we present a new, general approach to studying the reaction intermediates applied for CO2RR catalyzed by a series of cobalt complexes. The cobalt complexes were based on the TPA-ligands (TPA = tris(2-pyridylmethyl)amine) modified by amino groups in the secondary coordination sphere. By combining the electrochemical experiments, electrochemistry-coupled electrospray ionization mass spectrometry, with density functional theory (DFT) calculations, we identify and spectroscopically characterize the key reaction intermediates in the CO2RR and the competing hydrogen-evolution reaction (HER). Additionally, the experiments revealed the rarely reported in situ changes in the secondary coordination sphere of the cobalt complexes by the CO2-initiated transformation of the amino substituents to carbamates. This launched an even faster alternative HER pathway. The interplay of three catalytic cycles, as derived from the experiments and supported by the DFT calculations, explains the trends that cobalt complexes exhibit during the CO2RR and HER. Additionally, this study demonstrates the need for a molecular perspective in the electrocatalytic activation of small molecules efficiently obtained by the EC-ESI-MS technique.

Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer's Disease Drug Candidate.

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21's selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some "off-targets" which may contribute to the drug's biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.

Kinetics of ligand exchange in solution: a quantitative mass spectrometry approach.

Complex speciation and exchange kinetics of labile ligands are critical parameters for understanding the reactivity of metal complexes in solution. We present a novel approach to determine ligand exchange parameters based on electrospray ionization mass spectrometry (ESI-MS). The introduction of isotopically labelled ligands to a solution of metal host and unlabelled ligands allows the quantitative investigation of the solution-phase equilibria. Furthermore, ion mobility separation can target individual isomers, such as ligands bound at specific sites. As a proof of concept, we investigate the solution equilibria of labile pyridine ligands coordinated in the cavity of macrocyclic porphyrin cage complexes bearing diamagnetic or paramagnetic metal centres. The effects of solvent, porphyrin coordination sphere, transition metal, and counterion on ligand dissociation are discussed. Rate constants and activation parameters for ligand dissociation in the solution can be derived from our ESI-MS approach, thereby providing mechanistic insights that are not easily obtained from traditional solution-phase techniques.

Disorder to order: how halide mixing in MAPbI3-xBrx perovskites restricts MA dynamics.

Mixed-halide lead perovskites are of particular interest for the design of tandem solar cells currently reaching record efficiencies. While halide phase segregation upon illumination of mixed perovskites is extensively studied, the effect of halide disorder on A cation dynamics is not well understood, despite its importance for charge carrier diffusion and lifetime. Here, we study the methylammonium (MA) reorientational dynamics in mixed halide MAPbI3-xBrx perovskites by a combined approach of experimental solid-state NMR spectroscopy and molecular dynamics (MD) simulations based on machine-learning force-fields (MLFF). 207Pb NMR spectra indicate the halides are randomly distributed over their lattice positions, whereas PXRD measurements show that all mixed MAPbI3-xBrx samples are cubic. The experimental 14N spectra and 1H double-quantum (DQ) NMR data reveal anisotropic MA reorientations depending on the halide composition and thus associated disorder in the inorganic sublattice. MD calculations allow us to correlate these experimental results to restrictions of MA dynamics due to preferred MA orientations in their local Pb8I12-nBrn "cages". Based on the experimental and simulated results, we develop a phenomenological model that correlates the 1H dipolar coupling and thus the MA dynamics with the local composition and reproduces the experimental data over the whole composition range. We show that the dominant interaction between the MA cations and the Pb-X lattice that influences the cation dynamics is the local electrostatic potential being inhomogeneous in mixed halide systems. As such, we generate a fundamental understanding of the predominant interaction between the MA cations and the inorganic sublattice, as well as MA dynamics in asymmetric halide coordinations.

Terahertz wave rectification in a ferroelectric triglycine sulfate single crystal.

The effect of optical rectification (OR) in the terahertz range (THz rectification, TR) is experimentally demonstrated. The effect consists of generating a DC voltage on the faces of a ferroelectric triglycine sulfate (TGS) single crystal under the action of pulsed radiation with a frequency of 1.57 and 1.96 THz and an electric field strength per pulse of 1.3 and 1.5 MV/m, respectively. The FLARE FELIX free-electron laser system (Radboud University, The Netherlands) was used as a THz radiation source. The TR effect makes it possible to directly determine the nonlinear susceptibilities of media (including those under conditions of strong absorption) without any reference or optical channel calibration and also without the need of Fourier transform.

Probing Polar-π Interactions Between Tetrazoles and Aromatic Rings.

The heterocyclic tetrazole, a well-established bioisosteric replacement of carboxylic acid, plays an important role in medicinal chemistry. To deepen the functional understanding of tetrazoles in chemical sciences, it is essential to investigate the noncovalent interactions between the tetrazole ring and aromatic rings. Here, we report synthetic, spectroscopic, structural and quantum chemical analyses on specially designed 2-arylphenyl-1H-tetrazoles to study the underlying noncovalent interactions between the tetrazole ring and the neighboring aromatic ring possessing substituents at para/meta position. pKa values and proton affinities of 2-arylphenyl-1H-tetrazoles correlate well with Hammett sigma values of para-substituents at the flanking aromatic ring. Molecular orbital and energy decomposition analyses reveal that through-space NH-π interactions and π-π interactions contribute to the trend of pKa values and proton affinities of 2-arylphenyl-1H-tetrazoles. The electrostatic interaction between tetrazole/tetrazolide interacting with the aromatic rings appears responsible for the observed acidity trends. These results will be helpful for the rational design of tetrazole-based drugs and materials.

Enantiodivergent Sulfoxidation Catalyzed by a Photoswitchable Iron Salen Phosphate Complex.

Here we describe a photoswitchable iron(III) salen phosphate catalyst, which is able to catalyze the enantiodivergent oxidation of prochiral aryl alkyl sulfides to chiral aryl alkyl sulfoxides. The stable (S)-axial isomer of the catalyst produced enantioenriched sulfoxides with the (R)-configuration in up to 75 % e.e., whereas the photoisomerized metastable (R)-axial isomer of the catalyst favored the formation of (S)-sulfoxides in up to 43 % e.e. The maximum Δe.e. value obtained in the enantiodivergent sulfoxidation was 118 %, which is identical to the maximum Δe.e. value that was measured in the enantiodivergent epoxidation of alkenes by a related recently described Mn1 catalyst. This iron-based catalyst broadens the scope of photoswitchable enantiodivergent catalysts and may be used in the future to develop a photoswitchable catalytic system that can write digital information on a polymer chain in the form chiral sulfoxide functions.

Calciprotein Particle Synthesis Strategy Determines In Vitro Calcification Potential.

Circulating calciprotein particles (CPP), colloids of calcium, phosphate and proteins, were identified as potential drivers of the calcification process in chronic kidney disease. The present study compared CPP produced using different protocols with respect to particle morphology, composition, particle number and in vitro calcification potency. CPP were synthesized with 4.4 mM (CPP-A and B) or 6 mM (CPP-C and D) phosphate and 2.8 mM (CPP-A and B) or 10 mM (CPP-C and D) calcium, with either bovine fetuin-A (CPP-C) or fetal bovine serum (CPP-A, B and D) as a source of protein, and incubated for 7 (CPP-A2) or 14 days (CPP-B2), 12 h (CPP-C2, D2 and B1) or 30 min (CPP-D1). Particle number was determined with nanoparticle tracking and calcium content was measured in CPP preparations and to determine human vascular smooth muscle cell (hVSMC) calcification. Morphologically, CPP-C2 were the largest. Particle number did not correspond to the calcium content of CPP. Both methods of quantification resulted in variable potencies of CPP2 to calcify VSMC, with CPP-B2 as most stable inducer of hVSMC calcification. In contrast, CPP-B1 and D1 were unable to induce calcification of hVSMC, and endogenous CPP derived from pooled serum of dialysis patients were only able to calcify hVSMC to a small extent compared to CPP2.CPP synthesized using different protocols appear morphologically similar, but in vitro calcification potency is dependent on composition and how the CPP are quantified. Synthetic CPP are not comparable to endogenous CPP in terms of the calcification propensity.

Enantiodivergent epoxidation of alkenes with a photoswitchable phosphate manganese-salen complex.

The development of enantiodivergent catalysts capable of preparing both enantiomeric products from one substrate in a controlled fashion is challenging. Introducing a switching function into the catalyst can address this challenge, allowing the chiral reaction environment to reversibly change during catalysis. Here we report a photoswitchable phosphate ligand, derived from 2,2'-biphenol, which axially coordinates as the counter ion to an achiral manganese(III) salen catalyst, providing the latter with the ability to switch stereoselectivity in the epoxidation of alkenes. The enantiomers of the chiral ligand exist as a pair of pseudo-enantiomers, which can be interconverted by irradiation with light of different wavelengths. The opposite axial chirality of these pseudo-enantiomers is efficiently transferred to the manganese(III) salen catalyst. With this switchable supramolecular catalyst, the enantioselectivity of the epoxidation of a variety of alkenes can be controlled, resulting in opposite enantiomeric excesses of the epoxide products. This transfer of chirality from a photoswitchable anionic ligand to a metal complex broadens the scope of supramolecular catalysts.

Mechanistic Studies on the Epoxidation of Alkenes by Macrocyclic Manganese Porphyrin Catalysts.

Macrocyclic metal porphyrin complexes can act as shape-selective catalysts mimicking the action of enzymes. To achieve enzyme-like reactivity, a mechanistic understanding of the reaction at the molecular level is needed. We report a mechanistic study of alkene epoxidation by the oxidant iodosylbenzene, mediated by an achiral and a chiral manganese(V)oxo porphyrin cage complex. Both complexes convert a great variety of alkenes into epoxides in yields varying between 20-88 %. We monitored the process of the formation of the manganese(V)oxo complexes by oxygen transfer from iodosylbenzene to manganese(III) complexes and their reactivity by ion mobility mass spectrometry. The results show that in the case of the achiral cage complex the initial iodosylbenzene adduct is formed on the inside of the cage and in the case of the chiral one on the outside of the cage. Its decomposition leads to a manganese complex with the oxo ligand on either the inside or outside of the cage. These experimental results are confirmed by DFT calculations. The oxo ligand on the outside of the cage reacts faster with a substrate molecule than the oxo ligand on the inside. The results indicate how the catalytic activity of the macrocyclic porphyrin complex can be tuned and explain why the chiral porphyrin complex does not catalyze the enantioselective epoxidation of alkenes.