Silyl Groups Are Strong Dispersion Energy Donors.

We present an experimental and computational study to investigate noncovalent interactions between silyl groups that are often employed as "innocent" protecting groups. We chose an extended cyclooctatetraene (COT)-based molecular balance comprising unfolded (1,4-disubstituted) and folded (1,6-disubstituted) valance bond isomers that typically display remote and close silyl group contacts, respectively. The thermodynamic equilibria were determined using nuclear magnetic resonance measurements. Additionally, we utilized Boltzmann weighted symmetry-adapted perturbation theory (SAPT) at the sSAPT0/aug-cc-pVDZ level of theory to dissect and quantify noncovalent interactions. Apart from the extremely bulky tris(trimethylsilyl)silyl "supersilyl" group, there is a preference for the folded 1,6-COT valence isomer, with London dispersion interactions being the main stabilizing factor. This makes silyl groups excellent dispersion energy donors, a finding that needs to be taken into account in synthesis planning.

Assessing the Experimental Hydrogen Bonding Energy of the Cyclic Water Dimer Transition State with a Cyclooctatetraene-Based Molecular Balance.

We have conducted an experimental and computational study of cyclooctatetraene-1,4/1,6-dimethanol (1,4 and 1,6) as a molecular balance with the goal in mind to determine the otherwise inaccessible hydrogen bonding energy (HBE) of the cyclic water dimer, which constitutes a transition state. The 1,4/1,6 folding equilibrium is governed by an intramolecular hydrogen bond in the folded 1,6-isomer, in which the OH groups adopt a cyclic planar geometry, akin to the structure of the cyclic water dimer transition state. We characterized hydrogen bonding in 1,6 and reference complexes utilizing SAPT2 + (3)δMP2/aug-cc-pVTZ and selected quantum theory of atoms in molecule descriptors at M06-2XD3(0)/ma-def2-TZVPP. Additionally, we computed HBEs at the DLPNO-CCSD(T)/aug-cc-pVQZ level of theory. We find that hydrogen bonding in 1,6 is very similar to the interaction in the Ci symmetric cyclic water dimer TS, both in magnitude and character. We experimentally determined the Gibbs free energy of the folding process (ΔGeq) in a variety of organic solvents via nuclear magnetic resonance spectroscopy measurements at room temperature. By combining experimentally obtained ΔGeq values with corrections derived from accurate computational methods, we provide estimates for the HBE of cyclic water dimers and the cyclic water dimer TS, as the most stable cyclic water dimer.

Generation of Flavor-Active Compounds by Electrochemical Oxidation of (R)-Limonene.

Terpenes may be converted by electrochemical oxidation to various oxidized products with appealing aroma properties. In this study, (R)-limonene was anodically oxidized in the presence of ethanol, and the resulting mixture exhibited a pleasing fruity, herbal, citrus-like, and resinous odor. The aroma-active compounds were purified by means of preparative high-performance liquid chromatography, and their structures were elucidated by means of gas chromatography (GC)-mass spectrometry and nuclear magnetic resonance spectroscopy. In addition, the odor of the isolated compounds was determined by means of GC-olfactometry. Seventeen compounds were isolated, and for only four of them, analytical data had been reported previously in the literature. Furthermore, only for two of the compounds, an odor description had been available in the literature.

London Dispersion Favors Sterically Hindered Diarylthiourea Conformers in Solution.

We present an experimental and computational study on the conformers of N,N'-diphenylthiourea substituted with different dispersion energy donor (DED) groups. While the unfolded anti-anti conformer is the most relevant for thiourea catalysis, intramolecular noncovalent interactions counterintuitively favor the folded syn-syn conformer, as evident from a combination of low-temperature nuclear magnetic resonance measurements and computations. In order to quantify the noncovalent interactions, we utilized local energy decomposition analysis and symmetry-adapted perturbation theory at the DLPNO-CCSD(T)/def2-TZVPP and sSAPT0/6-311G(d,p) levels of theory. Additionally, we applied a double-mutant cycle to experimentally study the effects of bulky substituents on the equilibria. We determined London dispersion as the key interaction that shifts the equilibria towards the syn-syn conformers. This preference is likely a factor why such thiourea derivatives can be poor catalysts.

Gauging the Steric Effects of Silyl Groups with a Molecular Balance.

We present an experimental and computational study of a cyclooctatetraene (COT)-based molecular balance disubstituted with commonly used silyl groups. Such groups often serve as protecting groups and are typically considered innocent bystanders. Our motivation here is to determine the actual steric effects of such groups by employing a molecular balance. While in the unfolded 1,4-valence isomer the silyl groups are far apart (dσ-σ ≥ 5.15 Å), the folded 1,6-isomer is affected greatly by noncovalent interactions due to close σ-σ contacts (dσ-σ ≤ 2.58 Å). In order to investigate the thermodynamic equilibrium between the 1,6- and 1,4-valence isomers, we employed temperature-dependent nuclear magnetic resonance measurements. Additionally, we assessed the nature of attractive and repulsive interactions in 1,6-disilyl-COT derivatives via a combination of local energy decomposition analysis (LED) and symmetry-adapted perturbation theory (SAPT) at the DLPNO-CCSD(T)/def2-TZVP and sSAPT0/aug-cc-pVDZ levels of theory. We identified London dispersion interactions as the main contributor to the molecular stability of the folded states, whereas Pauli exchange repulsion and a resulting internal strain favor the unfolded diastereomer.

Formation of Diastereomeric Dihydromenthofurolactones by Cystostereum murrayi and Aroma Dilution Analysis Based on Dynamic Headspace Extraction.

Submerged cultures of the basidiomycota Cystostereum murrayi emit an intensive coconut-like, sweetish, and buttery smell. For identification of the key aroma compounds, an aroma dilution analysis using dynamic headspace was performed by adjusting the split ratio of the GC inlet system. Flavor dilution (FD) factors varied from 22 up to ≥218, whereby the largest class of compounds represented terpenoids, including two rare stereoisomers of 3,6-dimethyl-2,3,3a,4,5,7a-hexahydrobenzofuran (dill ether, ee ≥ 99.9). By means of nuclear magnetic resonance spectroscopy, the substances with the highest FD factors (29, 212, and 218) were identified as diastereomers of 3,6-dimethyl-3a,4,5,6,7,7a-hexayhydro-3H-1-benzofuran-2-one (dihydromenthofurolactone) and as its corresponding C3-unsaturated lactone. The latter two compounds have not been described for Cystostereum murrayi or for any other basidiomycota previously. Supplementation studies using 2-13C-d-glucose indicated that these lactones as well as the two stereoisomers of dill ether and other terpenoids were formed de novo by the fungus.

Synthesis and antiproliferative activity of hindered, chiral 1,2-diaminodiamantane platinum(II) complexes.

Platinum-based antineoplastic agents play a major role in the treatment of numerous types of cancer. A new bulky, lipophilic, and chiral ligand based on 1,2-diaminodiamantane in both of its enantiomeric forms was employed for the preparation of new platinum(ii) complexes with chloride and oxalate ligands. The dichloride complexes have a higher solubility and were evaluated as anti-proliferation agents for human ovarian cancer cell lines A2780 and cisplatin-resistant A2780cis. Its R,R-enantiomer showed increased efficacy compared to cisplatin for both cancer cell lines. A chromatographic approach was used to estimate the solvent partition coefficient of the dichloride complex. The binding of diamondoid-based platinum complexes to nucleotides was tested for both enantiomers with guanosine monophosphate (GMP) and deoxyguanosine monophosphate (dGMP) and occurs at a similar or faster rate for both isomers compared to cisplatin despite greatly increased steric demand. These findings highlight the potential in 1,2-diaminodiamantane as a viable pharmacophore.

[1,2]-Rearrangement of iminium salts provides access to heterocycles with adamantane scaffold.

We describe a Brønsted acid-catalysed cascade reaction consisting of a Wagner-Meerwein rearrangement and a subsequent intra- or intermolecular Friedel-Crafts reaction leading to adamantane-based heterocycles. In contrast to the reported W.-M. rearrangements, in this case an iminium moiety serves as the acceptor of a migrating nucleophilic alkyl group in a [1,2]-alkyl shift.

Tuning the Reactivity of Peroxo Anhydrides for Aromatic C-H Bond Oxidation.

Phenol moieties are key structural motifs in many areas of chemical research from polymers to pharmaceuticals. Herein, we report on the design and use of a structurally demanding cyclic peroxide (spiro[bicyclo[2.2.1]heptane-2,4'-[1,2]dioxolane]-3',5'-dione, P4) for the direct hydroxylation of aromatic substrates. The new peroxide benefits from high thermal stability and can be synthesized from readily available starting materials. The aromatic C-H oxidation using P4 exhibits generally good yields (up to 96%) and appreciable regioselectivities.

Directed C-H Bond Oxidation of Bridged Cycloalkanes Catalyzed by Palladium(II) Acetate.

We have developed a synthesis of 1,2-substituted adamantane carboxylic acids and further bridged cycloalkanes (cage compounds) by palladium acetate-catalyzed C-H bond oxidation. Acetoxylation of cycloalkane framework was performed using picolylamide as a directing group. Modification of the substrate, ligand design and variation of reaction conditions enabled us to study the mechanism of acetoxylation of aliphatic compounds. Post-functionalization reactions and cleavage of the directing group were developed. For the first time the synthesis and characterization of a ß-C3 -tri-substituted adamantane derivatives was achieved.

Catalytic Halogen Bond Activation in the Benzylic C-H Bond Iodination with Iodohydantoins.

This letter presents the side-chain iodination of electron-deficient benzylic hydrocarbons at rt using N-hydroxyphthalimide (NHPI) as radical initiator and 1,3-diiodo-5,5-dimethylhydantoin and 3-iodo-1,5,5-trimethylhydantoin (3-ITMH) as iodine source. Addition of a carboxylic acid increased the reactivity due to complex formation with and activation of 3-ITMH by proton transfer and halogen bond formation. No SEAr reactions were observed under the employed reaction conditions. Our method enables convenient product isolation and gives 50-72% yields of isolated products.

Detection of the tremorgenic mycotoxin paxilline and its desoxy analog in ergot of rye and barley: a new class of mycotoxins added to an old problem.

A newly developed enzyme immunoassay (EIA) for the detection of the tremorgenic indole-diterpene alkaloid paxilline (PAX) and closely related analogs was used to analyze ergot sclerotia collected from rye and barley fields. The mean EIA standard curve detection limit was 0.47 ± 0.14 ng/mL; relative cross-reactivity of toxin standard solutions was found for 11-hydroxy-paspaline (terpendole E, 1.1%) but not for lolitrem B or ergot alkaloids. Sclerotia from all fields were positive in the PAX-EIA at concentration levels of 620 ± 200 and 160 ± 37 µg/kg in ergot of rye and 130 ± 47 µg/kg in ergot of barley. Confirmatory analyses of sclerotia by liquid chromatography-tandem mass spectrometric detection identified PAX and its analog 13-desoxypaxilline. To the best of our knowledge, this is the first report on the natural occurrence of tremorgenic indole-diterpene alkaloid mycotoxins in ergot sclerotia from rye and barley. Along with details on the analytical methodology developed in this study, particularly PAX-antibody production, the relevance and implications of these findings for food and feed safety are discussed. Presence or absence of elevated levels of tremorgenic mycotoxins, along with the ergot alkaloids, would help in explaining the difference between the two distinct manifestations of historic ergotism, the convulsive and the gangrenous form. Further method development for paxilline and other tremorgenic mycotoxins in cereals used for food and feed is a prerequisite for a comprehensive risk assessment, which seems to be necessary in light of the findings reported here. Paxilline in ergot of rye.

NMR studies of dilithiostyrenes: aggregation, NMR parameters, and DFT calculations for (E)-1-Lithio-2-(o-lithiophenyl)-1-trimethylsilylethene.

The dilithio compound (E)-1-lithio-2-(o-lithiophenyl)-1-trimethylsilylethene (5) was synthesized from 2-trimethylsilylbenzo-[b]tellurophene (6) with lithium-6 and a detailed analysis of its 1 H, 6 Li, 13 C, and 29 Si NMR spectra showed 5 to form a dimer 52 in tetrahydrofuran and diethylether, while addition of tetramethylethylenediamine stabilizes a monomer 51 . A monomer-dimer equilibrium exists with K at 230 K = 1.25 and ΔG230o = -0.43 kJ mol-1 . Homonuclear 6 Li,6 Li coupling of 0.25 ± 0.07 Hz in the dimer was detected by a 1D-6 Li,6 Li INADEQUATE experiment, and scalar 6 Li,13 C coupling constants were obtained from 13 C satellites in the 6 Li spectrum, from 13 C multiplet simulation and 6 Li,13 C-HMQC spectra. In addition, structures and coupling constants of 51 and 52 were calculated by density functional theory (DFT) methods. It was found that the magnitude of the 6 Li,13 C spin-spin interactions shows an inverse correlation with the C-Li bond lengths. The intra-aggregate exchange in the dimer, caused by 180° rotation of one monomer unit within the solvent cage, was studied by 6 Li DNMR and line shape analysis and yielded ΔG298≠ = 60 ± 3 kJ mol-1 ; ΔH≠ = 84 ± 3 kJ mol-1 ; ΔS≠ = 80 ± 3 J mol-1 K-1 for this process. Copyright © 2015 John Wiley & Sons, Ltd.

Biotransformation of Dimethenamid-P by the basidiomycete Irpex consors.

Twenty-nine basidiomycetes were screened in surface and liquid cultures for their capability to biotransform the chloroacetamide herbicide Dimethenamid-P (DMTA-P). The basidiomycete Irpex consors converted 70% of the herbicide (0.5 g L-1 DMTA-P) in liquid cultures within 6 days, applying a minimal medium under non-ligninolytic conditions. Nine transformation products of DMTA-P were identified by liquid chromatography-mass spectrometry analysis of the culture supernatants. The four main metabolites were isolated and subjected to GC-MS analysis and NMR spectroscopy. The analyses revealed that the thiophene ring was oxidized at three different positions. Metabolite M1 was identified as the S-oxide, which was isolable and relatively stable at room temperature. In metabolite M2, one methyl substituent of the thiophene ring was hydroxylated. The two metabolites M3A and M3B were diastereomers, but fully separated by HPLC. Here, oxidation of the aromatic CH carbon resulted in prototropic rearrangement to an αß-unsaturated thiolactone. None of the three major metabolites of DMTA-P has been described before.

Defying Stereotypes with Nanodiamonds: Stable Primary Diamondoid Phosphines.

Direct unequal C-H bond difunctionalization of phosphorylated diamantane was achieved in high yield from the corresponding phosphonates. Reduction of the functionalized phosphonates provides access to novel primary and secondary alkyl/aryl diamantane phosphines. The prepared primary diamantyl phosphines are quite air stable compared to their adamantyl and especially alkyl or aryl analogues. This finding is corroborated by comparing the singly occupied molecular orbital energy levels of the corresponding phosphine radical cations obtained by density functional theory computations.

[2](1,3)Adamantano[2](2,7)pyrenophane: A Hydrocarbon with a Large Dipole Moment.

The fusion of the sp(3) -hybridized parent diamondoid adamantane with the sp(2) -hybridized pyrene results in a hybrid structure with a very large dipole moment which arises from bending the pyrene moiety. Presented herein is the synthesis, study of the electronic and optical properties, as well as the dynamic behavior of this new hydrocarbon.

Metal-Free Ammonia-Borane Dehydrogenation Catalyzed by a Bis(borane) Lewis Acid.

The storage of energy in a safe and environmentally benign way is one of the main challenges of today's society. Ammonia-borane (AB=NH3 BH3 ) has been proposed as a possible candidate for the chemical storage of hydrogen. However, the efficient release of hydrogen is still an active field of research. Herein, we present a metal-free bis(borane) Lewis acid catalyst that promotes the evolution of up to 2.5 equivalents of H2 per AB molecule. The catalyst can be reused multiple times without loss of activity. The moderate temperature of 60 °C allows for controlling the supply of H2 on demand simply by heating and cooling. Mechanistic studies give preliminary insights into the kinetics and mechanism of the catalytic reaction.

Biotransformation of the Antibiotic Danofloxacin by Xylaria longipes Leads to an Efficient Reduction of Its Antibacterial Activity.

Fluoroquinolones are considered as critically important antibiotics. However, they are used in appreciable quantities in veterinary medicine. Liquid manure and feces can contain substantial amounts of unmetabolized antibiotics and, thus, antibiotics can enter the environment if manure is used for soil fertilization. In this study, the microbial biotransformation of the synthetic veterinary fluoroquinolone danofloxacin by the ascomycete Xylaria longipes was investigated. Fungal submerged cultures led to a regioselective and almost quantitative formation of a single metabolite within 3 days. The metabolite was unequivocally identified as danofloxacin N-oxide by high-resolution mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopic techniques. An oxidation of the terminal nitrogen of the substituted piperazine moiety of the substance led to a remarkable reduction of 80% of the initial antibacterial activity. Thus, fungal enzymes involved in the biotransformation process might possess the potential to reduce the entrance of antibiotics via biotransformation of these compounds.

Aromaticity as stabilizing element in the bidentate activation for the catalytic reduction of carbon dioxide.

A new transition-metal-free mode for the catalytic reduction of carbon dioxide via bidentate interaction has been developed. In the presence of Li2[1,2-C6H4(BH3)2], CO2 can be selectively transformed to either methane or methanol, depending on the reducing agent. The bidentate nature of binding is supported by X-ray analysis of an intermediate analogue, which experiences special stabilization due to aromatic character in the bidentate interaction. Kinetic studies revealed a first-order reaction rate. The transformation can be conducted without any solvent.

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids.

The mucin MUC1 is a glycoprotein involved in fundamental biological processes, which can be found over-expressed and with a distinctly altered glycan pattern on epithelial tumor cells; thus it is a promising target structure in the quest for effective carbohydrate-based cancer vaccines and immunotherapeutics. Natural glycopeptide antigens indicate only a low immunogenicity and a T-cell independent immune response; however, this major drawback can be overcome by coupling of glycopeptide antigens multivalently to immunostimulating carrier platforms. In particular, gold nanoparticles are well suited as templates for the multivalent presentation of glycopeptide antigens, due to their remarkably high surface-to-volume ratio in combination with their high biostability. In this work the synthesis of novel MUC1-glycopeptide antigens and their coupling to gold nanoparticles of different sizes are presented. In addition, the development of a new dot-blot immunoassay to test the potential antigen-antibody binding is introduced.