Assessing Alkali-Metal Effects in the Structures and Reactivity of Mixed-Ligand Alkyl/Alkoxide Alkali-Metal Magnesiates

Advancing the understanding of using alkali-metal alkoxides as additives to organomagnesium reagents in Mg−Br exchange reactions, a homologous series of mixed-ligand alkyl/alkoxide alkali-metal magnesiates [MMg(CH₂SiMe₃)₂(dmem)]₂ [dmem=2-{[2-(dimethylamino)ethyl]methylamino} ethoxide; M=Li, 1 ; Na, 2 ; (THF)K, 3 ] has been prepared. Structural and spectroscopic studies have established the constitutions of these heteroleptic/heterometallic species, which are retained in arene solution. Evaluation of their reactivity towards 2-bromoanisole has uncovered a marked alkali-metal effect with potassium magnesiate 3 being the most efficient of the three ate reagents. Studies probing the constitution of the exchange product from this reaction suggest that the putative [KMgAr₂(dmem)]₂ (Ar=o-OMe−C₆H₄) intermediate undergoes redistribution into its single metal components [KAr]_n and [MgAr(dmem)]₂ ( 5 ). This process can be circumvented by using a different potassium alkoxide containing an aliphatic chain such as KOR’ (R’=2-ethylhexyl) which undergoes co-complexation with Mg(CH₂SiMe₃) to give [KMg(CH₂SiMe₃)₂(OR’)]₂ ( 7 ). This ate, in turn, reacts quantitatively with 2-bromoanisole furnishing [KMgAr₂(OR’)]₂ ( 9 ) which is stable in solution as a bimetallic compound. Collectively this work highlights the complexity of these alkali-metal mediated Mg−Br exchange reactions, where each reaction component can have a profound effect not only on the success of the reaction; but also the stability of the final metalated intermediates prior to their electrophilic interception.     

Tuning Deazaflavins Towards Highly Potent Reducing Photocatalysts Guided by Mechanistic Understanding – Enhancement of the Key Step by the Internal Heavy Atom Effect

Deazaflavins are well suited for reductive chemistry acting via a consecutive photo-induced electron transfer, in which their triplet state and semiquinone – the latter is formed from the former after electron transfer from a sacrificial electron donor – are key intermediates. Guided by mechanistic investigations aiming to increase intersystem crossing by the internal heavy atom effect and optimising the concentration conditions to avoid unproductive excited singlet reactions, we synthesised 5-aryldeazaflavins with Br or Cl substituents on different structural positions via a three-component reaction. Bromination of the deazaisoalloxazine core leads to almost 100 % triplet yield but causes photo-instability and enhances unproductive side reactions. Bromine on the 5-phenyl group in ortho position does not affect the photostability, increases the triplet yield, and allows its efficient usage in the photocatalytic dehalogenation of bromo- and chloroarenes with electron-donating methoxy and alkyl groups even under aerobic conditions. Reductive powers comparable to lithium are achieved.     

Heavy Alkali Metal Manganate Complexes: Synthesis,Structures and Solvent-Induced Dissociation Effects

Rare examples of heavier alkali metal manganates [{(AM)Mn(CH₂SiMe₃)(N^‘Ar)₂}_∞] (AM=K, Rb, or Cs) [N^‘Ar=N(SiMe₃)(Dipp), where Dipp=2,6-iPr₂-C₆H₃] have been synthesised with the Rb and Cs examples crystallographically characterised. These heaviest manganates crystallise as polymeric zig-zag chains propagated by AM⋅⋅⋅π-arene interactions. Key to their preparation is to avoid Lewis base donor solvents. In contrast, using multidentate nitrogen donors encourages ligand scrambling leading to redistribution of these bimetallic manganate compounds into their corresponding homometallic species as witnessed for the complete Li - Cs series. Adding to the few known crystallographically characterised unsolvated and solvated rubidium and caesium s-block metal amides, six new derivatives ([{AM(N^‘Ar)}_∞], [{AM(N^‘Ar)⋅TMEDA}_∞], and [{AM(N^‘Ar)⋅PMDETA}_∞] where AM=Rb or Cs) have been structurally authenticated. Utilising monodentate diethyl ether as a donor, it was also possible to isolate and crystallographically characterise sodium manganate [(Et₂O)₂Na(ⁿBu)Mn[(N^‘Ar)₂], a monomeric, dinuclear structure prevented from aggregating by two blocking ether ligands bound to sodium.     

Screening of Synthetic Cathinones by Potentiometric Sensor Array and Chemometrics

This work demonstrates the analytical applicability of single ion-selective membranes (ISMs) and potentiometric sensor array to distinguish and detect cathinone derivatives. Potentiometric data from ISMs based on cation exchanger and varying content of calix[4]arene derivative were processed by principal component analysis (PCA). Such a combination of methods allowed discriminating various individual synthetic cathinones and their recognition from the mixture comprising primary amines (substituted amphetamines+aminoindane). Analytical parameters of ISM containing 1wt % of calix[4]arene derivative were sufficient to detect 1.0×10⁻⁴ mol.l⁻¹ 1-(4-fluorophenyl)-2-(ethylamino)butan-1-one and 2-(methylamino)-1-phenylbutan-1-one (buphedrone) in both model and saliva samples.     

Derivatives of benzo[5,6]cyclohepta[1,2-b]thiophene. Synthesis of 2,3,7,8-tetrahydro-3-oxothieno[1,2-b]cyclohepta[5,6,7-de]isoquinoline and 1,2,3,7,8,11b-hexahydro-3-oxothieno[1,2-b]cyclohepta[5,6,7-de]isoquinoline

The synthesis of the title compounds was carried out by cyclization via isocyanate of (E)-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]-thiophene-10-ylideneacetic acid and 4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]-thiophene-10-ylacetic acid respectively, which were obtained by the Wadsworth-Emmons modification of the Wittig reaction of 4,5-dihydro-10H-10-oxobenzo[5,6]cyclohepta[1,2-b]thiophene and triethyl phosphonacetate. The structures of these new compounds are described.     

Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.     

Electroanalytical Techniques for the Detection of Selenium as a Biologically and Environmentally Significant Analyte—A Short Review

This short review deals with the properties and significance of the determination of selenium, which is in trace amounts an essential element for animals and humans, but toxic at high concentrations. It may cause oxidative stress in cells, which leads to the chronic disease called selenosis. Several analytical techniques have been developed for its detection, but electroanalytical methods are advantageous due to simple sample preparation, speed of analysis and high sensitivity of measurements, especially in the case of stripping voltammetry very low detection limits even in picomoles per liter can be reached. A variety of working electrodes based on mercury, carbon, silver, platinum and gold materials were applied to the analysis of selenium in various samples. Only selenium in oxidation state + IV is electroactive therefore the most of voltammetric determinations are devoted to it. However, it is possible to detect also other forms of selenium by indirect electrochemistry approach.     

Double Orthogonal Click Reactions for the Development of Antimicrobial Peptide Nanotubes

A new class of amphipathic cyclic peptides, which assemble in bacteria membranes to form polymeric supramolecular nanotubes giving them antimicrobial properties, is described. The method is based on the use of two orthogonal clickable transformations to incorporate different hydrophobic or hydrophilic moieties in a simple, regioselective, and divergent manner. The resulting cationic amphipathic cyclic peptides described in this article exhibit strong antimicrobial properties with a broad therapeutic window. Our studies suggest that the active form is the nanotube resulted from the parallel stacking of the cyclic peptide precursors. Several techniques, CD, FTIR, fluorescence, and STEM, among others, confirm the nanotube formation.     

An Adjustable Cleft Based on an 8-Sulfonamide-2-Naphthoic Acid with Oxyanion Hole Geometry

Cleft type receptors showing the oxyanion hole motif have been prepared in a straightforward synthesis starting from the commercial 3,7-dihidroxy-2-naphthoic acid. The double H-bond donor pattern is achieved by the introduction of a sulfonamide group in the C-8 position of naphthalene and a carboxamide at the C-2 position. This cleft, for which the geometry resembles that of an oxyanion hole, is able to adjust to different guests, as shown by the analysis of the X-ray crystal structures of associates with methanol or acetic acid. Combination of hydrogen bonds and charge-transfer interactions led to further stabilization of the complexes, in which the electron-rich aromatic ring of the receptor was close in space to the electron-deficient dinitroaromatic guests. Modelling studies and bidimensional NMR experiments have been carried out to provide additional information.