Predicting 19F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex

The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable ¹⁹F chemical-shift predictions to deduce ligand-binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the ¹⁹F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein–inhibitor conformations as well as monomeric and dimeric inhibitor–protein complexes, thus rendering it the largest computational study on chemical shifts of ¹⁹F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.     

Nucleophilic Aromatic Substitution at Benzene with Powerful Strontium Hydride and Alkyl Complexes

Key to the isolation of the first alkyl strontium complex was the synthesis of a strontium hydride complex that is stable towards ligand exchange reactions. This goal was achieved by using the super bulky β‐diketiminate ligand ^DIPePBDI (CH[C(Me)N‐DIPeP]₂, DIPeP=2,6‐diisopentylphenyl). Reaction of ^DIPePBDI‐H with Sr[N(SiMe₃)₂]₂ gave (^DIPePBDI)SrN(SiMe₃)₂, which was converted with PhSiH₃ into [(^DIPePBDI)SrH]₂. Dissolved in C₆D₆, the strontium hydride complex is stable up to 70 °C. At 60 °C, H–D isotope exchange gave full conversion into [(^DIPePBDI)SrD]₂ and C₆D₅H. Since H–D exchange with D₂ is facile, the strontium hydride complex served as a catalyst for the deuteration of C₆H₆ by D₂. Reaction of [(^DIPePBDI)SrH]₂ with ethylene gave [(^DIPePBDI)SrEt]₂. The high reactivity of this alkyl strontium complex is demonstrated by facile ethylene polymerization and nucleophilic aromatic substitution with C₆D₆, giving alkylated aromatic products and [(^DIPePBDI)SrD]₂.     

Contingent derivatives and regularization for noncoercive inverse problems

Abstract

We study the inverse problem of parameter identification in noncoercive variational problems that commonly appear in applied models. We examine the differentiability of the set-valued parameter-to-solution map using the first-order and the second-order contingent derivatives. We explore the inverse problem using the output least-squares and the modified output least-squares objectives. By regularizing the noncoercive variational problem, we obtain a single-valued regularized parameter-to-solution map and investigate its smoothness and boundedness. We also consider optimization problems using the output least-squares and the modified output least-squares objectives for the regularized variational problem. We give a complete convergence analysis showing that for the output least-squares and the modified output least-squares, the regularized minimization problems approximate the original optimization problems suitably. We also provide the first-order and the second-order adjoint method for the computation of the first-order and the second-order derivatives of the output least-squares objective. We provide discrete formulas for the gradient and the Hessian calculation and present numerical results.     

A Deeper Insight in Solutions Containing the Hypothetical Labile Complex Species “Fe(CO)4THF”

In the literature it was proposed that the treatment of [Fe₂(CO)₉] in THF resulted, during dissolution, in deep red solutions which should presumably contain labile complexes “Fe(CO)₄THF”. This was supported by the fact that such solutions afforded, in the presence of N‐donor ligands like pyridine (py) or pyrazine (pz), metal carbonyl complexes of the formula [Fe(CO)₄(py)] and [Fe(CO)₄(pz)], respectively. Herein we describe how the true nature of these solutions can be better explained by a valence‐disproportionation reaction of the diiron nonacarbonyl, induced by the donor solvent THF, resulting in the compound [Fe(THF)₆][Fe₃(CO)₁₁]. The formation of the undecacarbonyl‐triferrate(2–) in such solutions was unambiguously confirmed by IR spectroscopy and by the isolation and crystallization of the corresponding salt (PPN)₂[Fe₃(CO)₁₁]; its molecular structure was determined, however, already described in the literature.     

New Transition Metal Oxo‐Thiostannate: Synthesis,Characterization, and Investigation of its Photocatalytic Properties

The new transition metal oxo‐thiostannate {[Ni(cyclen)]₆[Sn₆S₁₂O₂(OH)₆]} · 2(ClO₄) · 19H₂O ( 1 ) was prepared under hydrothermal conditions using Na₄SnS₄ · 14H₂O and [Ni(cyclen)](ClO₄)₂ as reactants. In the crystal structure the rare [Sn₆S₁₂O₂(OH)₆]^10– anion is observed, which is composed of SnS₂O(OH)₃ and SnS₄O₂ octahedra, and SnS₄ tetrahedra sharing edges and corners. The anion is expanded by six Ni²⁺ centered complexes via Ni–S and Ni–OH bonds. The photocatalytic properties for the visible light driven hydrogen evolution reaction shows that 26.6 mmol · g^–1 H₂ were evolved after 3 h.     

Characterization of a Citrulline 4‐Hydroxylase from Nonribosomal Peptide GE81112 Biosynthesis and Engineering of Its Substrate Specificity for the Chemoenzymatic Synthesis of Enduracididine

The GE81112 tetrapeptides are a small family of unusual nonribosomal peptide congeners with potent inhibitory activity against prokaryotic translation initiation. With the exception of the 3‐hydroxy‐l ‐pipecolic acid unit, little is known about the biosynthetic origins of the non‐proteinogenic amino acid monomers of the natural product family. Here, we elucidate the biogenesis of the 4‐hydroxy‐l ‐citrulline unit and establish the role of an iron‐ and α‐ketoglutarate‐dependent enzyme (Fe/αKG) in the pathway. Homology modelling and sequence alignment analysis further facilitate the rational engineering of this enzyme to become a specific 4‐arginine hydroxylase. We subsequently demonstrate the utility of this engineered enzyme in the synthesis of a dipeptide fragment of the antibiotic enduracidin. This work highlights the value of applying a bioinformatics‐guided approach in the discovery of novel enzymes and engineering of new catalytic activity into existing ones.     

Hyperpolarization of Amino Acids in Water Utilizing Parahydrogen on a Rhodium Nanocatalyst

NMR offers many possibilities in chemical analysis, structural investigations, and medical diagnostics. Although it is broadly used, one of NMR spectroscopies main drawbacks is low sensitivity. Hyperpolarization techniques enhance NMR signals by more than four orders of magnitude allowing the design of new contrast agents. Parahydrogen induced polarization that utilizes the para-hydrogen's singlet state to create enhanced signals is of particular interest since it allows to produce molecular imaging agents within seconds. Herein, we present a strategy for signal enhancement of the carbonyl ¹³C in amino acids by using parahydrogen, as demonstrated for glycine and alanine. Importantly, the hyperpolarization step is carried out in water and chemically unmodified canonical amino acids are obtained. Our approach thus offers a high degree of biocompatibility, which is crucial for further application. The rapid sample hyperpolarization (within seconds) may enable the continuous production of biologically useful probes, such as metabolic contrast agents or probes for structural biology.     

MOF‐on‐MOF: Oriented Growth of Multiple Layered Thin Films of Metal–Organic Frameworks

The precise alignment of multiple layers of metal–organic framework (MOF) thin films, or MOF‐on‐MOF films, over macroscopic length scales is presented. The MOF‐on‐MOF films are fabricated by epitaxially matching the interface. The first MOF layer (Cu₂(BPDC)₂, BPDC=biphenyl‐4,4′‐dicarboxylate) is grown on an oriented Cu(OH)₂ film by a “one‐pot” approach. Aligned second (Cu₂(BDC)₂, BDC=benzene 1,4‐dicarboxylate, or Cu₂(BPYDC)₂, BPYDC=2,2′‐bipyridine‐5,5′‐dicarboxylate) MOF layers can be deposited using liquid‐phase epitaxy. The co‐orientation of the MOF films is confirmed by X‐ray diffraction. Importantly, our strategy allows for the synthesis of aligned MOF films, for example, Cu₂(BPYDC)₂, that cannot be grown on a Cu(OH)₂ surface. We show that aligned MOF films furnished with Ag nanoparticles show a unique anisotropic plasmon resonance. Our MOF‐on‐MOF approach expands the chemistry of heteroepitaxially oriented MOF films and provides a new toolbox for multifunctional porous coatings.     

Mechanism of the Water–Gas Shift Reaction Catalyzed by Efficient Ruthenium‐Based Catalysts: A Computational and Experimental Study

Supported ionic liquid phase (SILP) catalysis enables a highly efficient, Ru‐based, homogeneously catalyzed water‐gas shift reaction (WGSR) between 100 °C and 150 °C. The active Ru‐complexes have been found to exist in imidazolium chloride melts under operating conditions in a dynamic equilibrium, which is dominated by the [Ru(CO)₃Cl₃]^? complex. Herein we present state‐of‐the‐art theoretical calculations to elucidate the reaction mechanism in more detail. We show that the mechanism includes the intermediate formation and degradation of hydrogen chloride, which effectively reduces the high barrier for the formation of the requisite dihydrogen complex. The hypothesis that the rate‐limiting step involves water is supported by using D₂O in continuous catalytic WGSR experiments. The resulting mechanism constitutes a highly competitive alternative to earlier reported generic routes involving nucleophilic addition of hydroxide in the gas phase and in solution.