A lithium-aluminium heterobimetallic dimetallocene.

Homobimetallic dimetallocenes exhibiting two identical metal atoms sandwiched between two η5 bonded cyclopentadienyl rings is a narrow class of compounds, with representative examples being dizincocene and diberyllocene. Here we report the synthesis and structural characterization of a heterobimetallic dimetallocene, accessible through heterocoupling of lithium and aluminylene fragments with pentaisopropylcyclopentadienyl ligands. The Al-Li bond features a high ionic character and profits from attractive dispersion interactions between the isopropyl groups of the cyclopentadienyl ligands. A key synthetic step is the isolation of a cyclopentadienylaluminylene monomer, which also enables the structural characterization of this species. In addition to their structural authentication by single-crystal X-ray diffraction analysis, both compounds were characterized by multinuclear NMR spectroscopy in solution and in the solid state. Furthermore, reactivity studies of the lithium-aluminium heterobimetallic dimetallocene with an N-heterocyclic carbene and different heteroallenes were performed and show that the Al-Li bond is easily cleaved.

Pd8(PDip)6: Cubic, Unsaturated, Zerovalent.

Atomically precise nanoclusters hold promise for supramolecular assembly and (opto)electronic- as well as magnetic materials. Herein, this work reports that treating palladium(0) precursors with a triphosphirane affords strongly colored Pd8(PDip)6 that is fully characterized by mass spectrometry, heteronuclear and Cross-Polarization Magic-Angle Spinning (CP-MAS) NMR-, infrared (IR), UV-vis, and X-ray photoelectron (XP) spectroscopies, single-crystal X-Ray diffraction (sc-XRD), mass spectrometry, and cyclovoltammetry (CV). This coordinatively unsaturated 104-electron Pd(0) cluster features a cubic Pd8-core, µ4-capping phosphinidene ligands, and is air-stable. Quantum chemical calculations provide insight to the cluster's electronic structure and suggest 5s/4d orbital mixing as well as minor Pd─P covalency. Trapping experiments reveal that cluster growth proceeds via insertion of Pd(0) into the triphosphirane. The unsaturated cluster senses ethylene and binds isocyanides, which triggers the rearrangement to a tetrahedral structure with a reduced frontier orbital energy gap. These experiments demonstrate facile cluster manipulation and highlight non-destructive cluster rearrangement as is required for supramolecular assembly.

Functionalization of Chlorotonils: Dehalogenil as Promising Lead Compound for In Vivo Application.

The natural product chlorotonil displays high potency against multidrug-resistant Gram-positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late-stage functionalization, we aimed to further optimize the molecule. Previously unknown reactions including a sulfur-mediated dehalogenation were revealed. Dehalogenil, the product of this reaction, was identified as the most promising compound so far, as this new derivative displayed improved solubility and in vivo efficacy while retaining excellent antimicrobial activity. We confirmed superb activity against multidrug-resistant clinical isolates of Staphylococcus aureus and Enterococcus spp. and mature transmission stages of Plasmodium falciparum. We also demonstrated favorable in vivo toxicity, pharmacokinetics and efficacy in infection models with S. aureus. Taken together, these results identify dehalogenil as an advanced lead molecule.

Tetrylene-Functionalized Si7-Siliconoids.

The core expansion of metallic or metalloid clusters by the addition of further homo- or heteronuclear vertices is pivotal to the nucleation and growth of particles. The exohedral grafting of a low-valent functionality followed by endohedral incorporation have been identified as key steps. Following previous work on the Si6 series, we now report the synthesis and full characterization of the amidinatotetrylene-functionalized seven-vertex siliconoids Si7R5[E(NtBu)2CPh] (E = Si, Ge, Sn). In the case of the silylene derivative, the solid-state structure was determined by single crystal X-ray diffraction.

Polyhedral Oligomeric Silsesquioxane D3h-(RSiO1.5)14.

While smaller polyhedral oligomeric silsesquioxanes TnRn (POSS) are readily accessible or even commercially available, unambiguously authenticated larger systems (n>12) have barely been reported. Synthesis and isolation procedures are lengthy, and yields are often very low. Herein, we present the surprisingly straightforward and high-yielding access to the phenyl-substituted derivative of a so far only postulated second D3h-symmetric T14 isomer and with that the largest crystallographically characterized POSS cage with organic substituents. Treatment of the commercially available incompletely condensed T7Ph7(OH)3 silsesquioxane with catalytic amounts of trifluoromethanesulfonic acid results in high yields of the T14Ph14 framework, which is isolated in crystalline form by a simple work-up. D3h-T14Ph14 was analyzed by single crystal X-ray diffraction, multinuclear NMR spectroscopy and thermal analysis. The relative energies of all four theoretically possible T14Ph14 isomers were determined by optimization of the corresponding structure using DFT methods.

Oligo-Condensation Reactions of Silanediols with Conservation of Solid-State-Structural Features.

Oligo- and polysiloxanes are usually prepared by condensation reactions in solvents without control of stereochemistry. Here we present a solventless thermal condensation of stable organosilanols. We investigated the condensation reactions of organosilanediols with different organic substituents, having in common at least one aromatic group. The condensation kinetics of the precursors observed by NMR spectroscopy revealed a strong dependence on temperature, time, and substitution pattern at the silicon atom. SEC measurements showed that chain length increases with increasing condensation temperature and time and lower steric demand of the substituents, which also influences the glass transition temperatures (Tg) of the resulting oligo- or polymers. X-ray diffraction studies of the crystalline silanediols and their condensation products revealed a structural correlation between the substituent location in the crystalline precursors and the formed macromolecules induced by the hydrogen bonding pattern. In certain cases, it is possible to carry out topotactic polymerization in the solid-state, which has its origin in the crystal structure.

Incarceration of a gravid uterus with massive placental enlargement and fetal triploidy at 19 weeks of gestation - A case report on the simultaneous presence of two rare conditions.

This article reports a rare case of uterine incarceration in pregnancy concurrent with nonmolar fetal triploidy and massive placental enlargement in a 35-year-old primigravida. The patient presented with abdominal discomfort and peripheral edema at 19 weeks of gestation. Diagnostic assessments revealed a retroflexed uterus with a massively enlarged placenta and a severely growth-restricted fetus. Uterine repositioning was successfully achieved after rectal filling. However, spontaneous fetal demise led to vaginal delivery. The fetal autopsy confirmed female triploidy. Histopathology of the placenta showed no features of a partial mole. This case highlights the challenges in diagnosing uterine incarceration in pregnancy, the need for early intervention and the complexity of managing multiple concurrent pathologies.

Bis(tetrelocenes) - fusing tetrelocenes into close proximity.

We report the synthesis and structure of two bis(germanocenes) and a bis(stannocene), obtained by the reaction of unsymmetric ansa bis(cyclopentadienyl) ligands with germanium and tin dichloride. DFT calculations show that the formation of these bis(tetrelocenes) is energetically favoured over the formation of the corresponding [1]tetrelocenophanes. In the crystal structure authenticated structural motif, the two tetrel(II) centers are forced into close proximity to each other, resulting in weak donor-acceptor interactions, according to Natural Bond Orbital (NBO) and Atoms in Molecules (AIM) analyses.

Room temperature ionic liquids with two symmetric ions.

Room temperature ionic liquids typically contain asymmetric organic cations. The asymmetry is thought to enhance disorder, thereby providing an entropic counter-balance to the strong, enthalpic, ionic interactions, and leading, therefore, to lower melting points. Unfortunately, the synthesis and purification of such asymmetric cations is typically more demanding. Here we introduce novel room temperature ionic liquids in which both cation and anion are formally symmetric. The chemical basis for this unprecedented behaviour is the incorporation of ether-containing side chains - which increase the configurational entropy - in the cation. Molecular dynamics simulations indicate that the ether-containing side chains transiently sample curled configurations. Our results contradict the long-standing paradigm that at least one asymmetric ion is required for ionic liquids to be molten at room temperature, and hence open up new and simpler design pathways for these remarkable materials.

Diboriranide σ-Complexes of d- and p-Block Metals.

Diboriranides are the smallest conceivable monoanionic aromatic cycles, yet only limited examples have been reported and their reactivity and complexation behavior remain completely unexplored. We report a straightforward synthesis of the first peraryl diboriranide c-(DurB)2 CPh- as its lithium salt in three steps via the corresponding non-classical diborirane from a readily available 1,2-dichlorodiborane(4) (Dur=2,3,5,6-tetramethylphenyl). With the preparation and complete characterization of representative complexes with tin, copper, gold and zinc, we demonstrate the strong preference of the diboriranide for σ-type coordination modes towards main group and transition metal centers under unperturbed retention of the three-membered B2 C-ring's 2e- π-system.

(CAAC)Pd(py) Catalysts Disproportionate to Pd(CAAC)2.

Palladium complexes with one N-heterocyclic carbene (NHC) and a pyridine ancillary ligand are powerful cross-coupling precatalysts. Herein, we report such complexes with a cyclic (alkyl)(amino)carbene (CAAC) ligand replacing the NHC. We find that the alleged reduced form, (CAAC)Pd(py), disproportionates to the (CAAC)2Pd0 complex and palladium nanoparticles. This notwithstanding, they are potent catalysts in the Buchwald-Hartwig amination with aryl chlorides under mild conditions (60 °C). In the presence of dioxygen, these complexes catalyze the formation of diazenes from anilines. The catalytic activities of the NHC- and CAAC-supported palladium(0) and palladium(II) complexes are similar in the cross-coupling reaction, yet the CAAC complexes are superior for diazene formation.

Digital droplet PCR-based quantification of ccfHPV-DNA as liquid biopsy in HPV-driven cervical and vulvar cancer.

PURPOSE: More than 99% of cervical cancers and up to 40% of vulvar cancers are human papillomavirus (HPV) related. HPV 16 and 18 are the most relevant subtypes. Novel technologies allow the detection of minimal amounts of circulating cell-free HPV DNA (ccfHPV-DNA). The aim of this study was to evaluate ccfHPV-DNA assessed by droplet digital PCR (ddPCR) as a biomarker for molecular therapy monitoring in early, advanced, relapsed and metastatic HPV-driven cervical and vulvar cancer. METHODS: Inclusion criteria of the study were histologically proven HPV 16/18-driven cervical and vulvar cancer with first diagnosed disease, newly diagnosed recurrence, or progression of disease. Blood samples were taken pre- and post-therapeutically. Circulating cell-free HPV DNA was quantified using ddPCR and the results were correlated with clinical data. RESULTS: The mean copy number of ccfHPV-DNA was 838.6 (± 3089.1) in pretreatment and 2.3 (± 6.4) in post-treatment samples (p < 0.05). The copy number of ccfHPV-DNA increased with higher FIGO stages (p < 0.05), which are commonly used for clinical staging/assessment. Furthermore, we compared the distribution of copy numbers between T-stage 1 versus T-stage 2/3. We could show higher copy number level of ccfHPV-DNA in T-stage 2/3 (p < 0.05). CONCLUSIONS: Therapy monitoring with determination of ccfHPV-DNA by ddPCR with a small amount of plasma reflects response to therapy and appears feasible for patients in advanced cancer stages of cervical and vulvar cancer. This promising tool should be examined as marker of therapy monitoring in particular in novel HPV-directed therapies.

The Disorazole Z Family of Highly Potent Anticancer Natural Products from Sorangium cellulosum: Structure, Bioactivity, Biosynthesis, and Heterologous Expression.

Myxobacteria serve as a treasure trove of secondary metabolites. During our ongoing search for bioactive natural products, a novel subclass of disorazoles termed disorazole Z was discovered. Ten disorazole Z family members were purified from a large-scale fermentation of the myxobacterium Sorangium cellulosum So ce1875 and characterized by electrospray ionization-high-resolution mass spectrometry (ESI-HRMS), X-ray, nuclear magnetic resonance (NMR), and Mosher ester analysis. Disorazole Z compounds are characterized by the lack of one polyketide extension cycle, resulting in a shortened monomer in comparison to disorazole A, which finally forms a dimer in the bis-lactone core structure. In addition, an unprecedented modification of a geminal dimethyl group takes place to form a carboxylic acid methyl ester. The main component disorazole Z1 shows comparable activity in effectively killing cancer cells to disorazole A1 via binding to tubulin, which we show induces microtubule depolymerization, endoplasmic reticulum delocalization, and eventually apoptosis. The disorazole Z biosynthetic gene cluster (BGC) was identified and characterized from the alternative producer S. cellulosum So ce427 and compared to the known disorazole A BGC, followed by heterologous expression in the host Myxococcus xanthus DK1622. Pathway engineering by promoter substitution and gene deletion paves the way for detailed biosynthesis studies and efficient heterologous production of disorazole Z congeners. IMPORTANCE Microbial secondary metabolites are a prolific reservoir for the discovery of bioactive compounds, which prove to be privileged scaffolds for the development of new drugs such as antibacterial and small-molecule anticancer drugs. Consequently, the continuous discovery of novel bioactive natural products is of great importance for pharmaceutical research. Myxobacteria, especially Sorangium spp., which are known for their large genomes with yet-underexploited biosynthetic potential, are proficient producers of such secondary metabolites. From the fermentation broth of Sorangium cellulosum strain So ce1875, we isolated and characterized a family of natural products named disorazole Z, which showed potent anticancer activity. Further, we report on the biosynthesis and heterologous production of disorazole Z. These results can be stepping stones toward pharmaceutical development of the disorazole family of anticancer natural products for (pre)clinical studies.

Molecular Design of Luminescent Complexes of Eu(III): What Can We Learn from the Ligands.

The luminescent metal-organic complexes of rare earth metals are advanced materials with wide application potential in chemistry, biology, and medicine. The luminescence of these materials is due to a rare photophysical phenomenon called antenna effect, in which the excited ligand transmits its energy to the emitting levels of the metal. However, despite the attractive photophysical properties and the intriguing from a fundamental point of view antenna effect, the theoretical molecular design of new luminescent metal-organic complexes of rare earth metals is relatively limited. Our computational study aims to contribute in this direction, and we model the excited state properties of four new phenanthroline-based complexes of Eu(III) using the TD-DFT/TDA approach. The general formula of the complexes is EuL2A3, where L is a phenanthroline with -2-CH3O-C6H4, -2-HO-C6H4, -C6H5 or -O-C6H5 substituent at position 2 and A is Cl- or NO3-. The antenna effect in all newly proposed complexes is estimated as viable and is expected to possess luminescent properties. The relationship between the electronic properties of the isolated ligands and the luminescent properties of the complexes is explored in detail. Qualitative and quantitative models are derived to interpret the ligand-to-complex relation, and the results are benchmarked with respect to available experimental data. Based on the derived model and common molecular design criteria for efficient antenna ligands, we choose phenanthroline with -O-C6H5 substituent to perform complexation with Eu(III) in the presence of NO3¯. Experimental results for the newly synthesized Eu(III) complex are reported with a luminescent quantum yield of about 24% in acetonitrile. The study demonstrates the potential of low-cost computational models for discovering metal-organic luminescent materials.

Phosphanyl-substituted tin half-sandwich complexes.

Phosphanyl-substituted tin(ii) half sandwich complexes are reported. Due to the Lewis acidic tin center and Lewis basic phosphorous atom they form head-to-tail dimers. Their properties and reactivities were investigated both experimentally and theoretically. Furthermore, related transition metal complexes of these species are presented.

σ,π-Conjugated Bis(germylene) Adducts with NHC and CAACs.

Heavier tetrylenes attract attention for their potential in synthesis, catalysis and small molecule activation. The coordination by N-heterocyclic carbenes (NHCs) and cyclic (alkyl)(amino)carbenes (CAACs) results in substantial structural and electronic differences although typically only one of these yields stable derivatives for one and the same tetrylene. We now report both NHC- and CAAC-coordination to a bridged bis(germylene) motif. The NHC-coordinated bis(germylene) exhibits pyramidal germanium centers with lone pairs of electrons, while with CAAC an unprecedented stable bis(germene) with two Ge=C bonds is isolated. Spectroscopic and crystallographic evidence as well as DFT calculations confirm the effects of σ,π-conjugation between the two germanium centers in both cases. The coordination of NHC is reversible as the reaction with BPh3 liberates the transient bis(germylene) and thus provides an alternative low-temperature route towards polymers with Ge=Ge bonds.

Anion and ether group influence in protic guanidinium ionic liquids.

Ionic liquids are attractive liquid materials for many advanced applications. For targeted design, in-depth knowledge about their structure-property-relations is urgently needed. We prepared a set of novel protic ionic liquids (PILs) with a guanidinium cation with either an ether or alkyl side chain and different anions. While being a promising cation class, the available data is insufficient to guide design. We measured thermal and transport properties, nuclear magnetic resonance (NMR) spectra as well as liquid and crystalline structures supported by ab initio computations and were able to obtain a detailed insight into the influence of the anion and the ether substitution on the physical and spectroscopic properties. For the PILs, hydrogen bonding is the main interaction between cation and anion and the H-bond strength is inversely related to the proton affinity of the constituting acid and correlated to the increase of 1H and 15N chemical shifts. Using anions from acids with lower proton affinity leads to proton localization on the cation as evident from NMR spectra and self-diffusion coefficients. In contrast, proton exchange was evident in ionic liquids with triflate and trifluoroacetate anions. Using imide-type anions and ether side groups decreases glass transitions as well as fragility, and accelerated dynamics significantly. In case of the ether guanidinium ionic liquids, the conformation of the side chain adopts a curled structure as the result of dispersion interactions, while the alkyl chains prefer a linear arrangement.

Stable Silapyramidanes.

Starting from tetrakis(trimethylsilyl)cyclobutadiene and an amidinate-supported silylene of the Roesky-type, a sequence of addition and reduction cleanly gives the elusive silapyramidane via an isolable cyclobutene intermediate with an exocyclic Si═C bond. The silapyramidane features an unusually shielded 29Si NMR resonance at -448.3 ppm for the apex silicon atom. Treatment with Fe2(CO)9 results in the formation of the corresponding silapyramidane-iron complex. Silapyramidane also reacts with the cyclobutadiene starting material to cleanly afford a fluorescent spirobis(silole).

Evidence of AlII Radical Addition to Benzene.

Electrophilic AlIII species have long dominated the aluminum reactivity towards arenes. Recently, nucleophilic low-valent AlI aluminyl anions have showcased oxidative additions towards arenes C-C and/or C-H bonds. Herein, we communicate compelling evidence of an AlII radical addition reaction to the benzene ring. The electron reduction of a ligand stabilized precursor with KC8 in benzene furnishes a double addition to the benzene ring instead of a C-H bond activation, producing the corresponding cyclohexa-1,3(orl,4)-dienes as Birch-type reduction product. X-ray crystallographic analysis, EPR spectroscopy, and DFT results suggest this reactivity proceeds through a stable AlII radical intermediate, whose stability is a consequence of a rigid scaffold in combination with strong steric protection.

Efficient Synthesis of Fluorescent Coumarins and Phosphorous-Containing Coumarin-Type Heterocycles via Palladium Catalyzed Cross-Coupling Reactions.

Quantum-chemical calculations on the spectral properties of some aryl substituted 3-phosphonocoumarins were performed, and the effect of the substituents in the aryl moiety was evaluated. The structures possessing promising fluorescent properties were successfully synthesized via Suzuki and Sonogashira cross-coupling. The synthetic protocol was also applied for the phosphorous chemoisomer of 3-phosphonocoumarin, 1,2-benzoxaphosphorin, and their carboxylate analogues. The optical properties of the arylated and alkynylated products were experimentally determined. The obtained quantum-chemical and experimental results give the possibility for a fine tuning of the optical properties of phosphorous-containing coumarin systems by altering the substituent at its C-6 position.