Solid state NMR and computational studies on cyclopentadienyl lithium.

Lithiumcyclopentadienide, previously identified to be an endless polymer in the ligand-free solid state, was investigated by 13C- and 6Li-CP/MAS NMR spectra, and by B3LYP-GIAO theoretical calculations. By spectra simulation, the axially symmetric 13C-shift tensor components were identified to be δ11 = δ22 = 151.5 ppm, δ33 = 15.5 ppm. The 6Li-tensor components are δ11 = δ22 = +1.0 ppm, δ33 = -43.0 ppm. This extremely high field component is due to cumulative ring current effects. B3LYP-GIAO/TZVP calculations on the tensor principal components agree remarkably well with the measurements. A new and very simple method of preparing air-sensitive compounds for solid-state NMR analyses is described. Graphical abstract Shielding tensor main components from slow-speed solid state NMR spectra.

Deeper Insight into the Six-Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products.

The straightforward and efficient synthesis of complex aza- and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal-free six-step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen-containing molecules. Presented here is a deeper investigation of this atom-economical domino process by extending the scope of aldehydes, performing post-modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi-empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin-containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparum 3D7 are presented. Remarkably, in vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071-1.8 µm), outperforming the clinical reference drug ganciclovir (EC50 2.6 µm). Against P. falciparum 3D7, three of the investigated artemisinin-derived domino products (EC50 0.72-1.8 nm) were more potent than the clinical drug chloroquine (EC50 9.1 nm).

Production of the Cytotoxic Cardenolide Glucoevatromonoside by Semisynthesis and Biotransformation of Evatromonoside by a Digitalis lanata Cell Culture.

Recent studies demonstrate that cardiac glycosides, known to inhibit Na+/K+-ATPase in humans, have increased susceptibility to cancer cells that can be used in tumor therapy. One of the most promising candidates identified so far is glucoevatromonoside, which can be isolated from the endangered species Digitalis mariana ssp. heywoodii. Due to its complex structure, glucoevatromonoside cannot be obtained economically by total chemical synthesis. Here we describe two methods for glucoevatromonoside production, both using evatromonoside obtained by chemical degradation of digitoxin as the precursor. 1) Catalyst-controlled, regioselective glycosylation of evatromonoside to glucoevatromonoside using 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as the sugar donor and 2-aminoethyldiphenylborinate as the catalyst resulted in an overall 30 % yield. 2) Biotransformation of evatromonoside using Digitalis lanata plant cell suspension cultures was less efficient and resulted only in overall 18 % pure product. Structural proof of products has been provided by extensive NMR data. Glucoevatromonoside and its non-natural 1-3 linked isomer neo-glucoevatromonoside obtained by semisynthesis were evaluated against renal cell carcinoma and prostate cancer cell lines.

Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal-Free Six-Step Domino Reaction.

Aza- and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six-step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult-to-access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X-ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC50 up to 0.071 µM for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC50 2.6 µM).

Synthesis and Atropisomerism of Cascaded Tetraphenylporphyrin-[60]Fullerene Hybrids.

Flexible, linked dendritic tetraphenylporphyrin (TPP)-fullerene hybrids were synthesized. They were designed to gain insight into and mimic the primary events in the natural photosynthetic reaction center. These multiporphyrin moieties are based on a light-harvesting concept. Moreover, they incorporate multiple redox components aligned along a redox gradient. Newkome-type dendrons were added to these TPP-fullerene hybrids. In principle they can mediate pH-dependent water solubility, which, however, could not be observed in this case. A protecting-group strategy using tert-butyldiphenylsilyl groups allows convergent synthesis of the dendritic compounds. The dendritic multiporphyrins were synthesized separately and can be used as individual building blocks. Atropisomerism was observed in the dendritic compounds, and single atropisomers could be assigned to the corresponding peaks of a characteristic pattern in the NMR spectra. Deprotection of the Newkome-type dendrons was shown to be feasible under mild conditions that leave the redox gradient intact.

Preparation of candidate reference materials for the determination of phosphorus containing flame retardants in styrene-based polymers.

Candidate reference materials (RM) for the analysis of phosphorus-based flame retardants in styrene-based polymers were prepared using a self-made mini-extruder. Due to legal requirements of the current restriction for the use of certain hazardous substances in electrical and electronic equipment, focus now is placed on phosphorus-based flame retardants instead of the brominated kind. Newly developed analytical methods for the first-mentioned substances also require RMs similar to industrial samples for validation and verification purposes. Hence, the prepared candidate RMs contained resorcinol-bis-(diphenyl phosphate), bisphenol A bis(diphenyl phosphate), triphenyl phosphate and triphenyl phosphine oxide as phosphorus-based flame retardants. Blends of polycarbonate and acrylonitrile-co-butadiene-co-styrene as well as blends of high-impact polystyrene and polyphenylene oxide were chosen as carrier polymers. Homogeneity and thermal stability of the candidate RMs were investigated. Results showed that the candidate RMs were comparable to the available industrial materials. Measurements by ICP/OES, FTIR and NMR confirmed the expected concentrations of the flame retardants and proved that analyte loss and degradation, respectively, was below the uncertainty of measurement during the extrusion process. Thus, the candidate RMs were found to be suitable for laboratory use.

Carbon nanodots: toward a comprehensive understanding of their photoluminescence.

We report the characterization of carbon nanodots (CNDs) synthesized under mild and controlled conditions, that is, in a microwave reactor. The CNDs thus synthesized exhibit homogeneous and narrowly dispersed optical properties. They are thus well suited as a testbed for studies of the photophysics of carbon-based nanoscopic emitters. In addition to steady-state investigations, time-correlated single-photon counting, fluorescence up-conversion, and transient pump probe absorption spectroscopy were used to elucidate the excited-state dynamics. Moreover, quenching the CND-based emission with electron donors or acceptors helped shed light on the nature of individual states. Density functional theory and semiempirical configuration-interaction calculations on model systems helped understand the fundamental structure-property relationships for this novel type of material.

Fused perylene-phthalocyanine macrocycles: a new family of NIR-dyes with pronounced basicity.

The synthesis and characterization of a new type of chromophore, namely PePc consisting of a central phthalocyanine core and four fused perylene-bisimide (PBI) units is described for the first time. The entire architecture represents a highly extended conjugated heterocyclic π-system with C4h symmetry. In order to guarantee pronounced solubility in organic solvents the corresponding PBI units were bay-functionalized with tert-butylphenoxy substituents. Next to the metal-free macrocycle, PePcH2 , also metallated macrocycles PePcM (M=Zn, Ni, Pb, Ru, Fe) were synthesized. The extensive fusion of the corresponding aromatic building blocks to the very large extended π-system leads to a very narrow HOMO-LUMO gap and as a consequence to transparency in the visible but light absorption in the NIR region. Significantly, the azomethine N-atoms N1N4 of PePcM and PePcH2 are highly basic. The corresponding tetraprotonated systems can only be deprotonated with very strong non-nucleophilic bases such as phosphazene bases. In the protonated forms PePcMH4 (4+) and PePcMH6 (4+) the absorption maximum is shifted back to the visible region due to the loss of conjugation. The experimental findings were corroborated with quantum mechanical calculations.

Optically active tetra-tert-butyl-P(5)-deltacyclene epimers: preparation, spectroscopy, dynamic equilibriums, H/D exchange, and transition-metal complex chemistry.

On the basis of isolated diastereomeric triorganylstannyl-P5 -deltacyclenes 7' and 7'', almost pure enantiomers of their destannylation products 8' and 8'' are now available. These stereochemically inert cage chiral species contain a configurationally labile P1H1 group that defines two epimers 8 a and 8 b of each of the enantiomers, which are connected by a rapid equilibrium. Mirror-symmetric circular dichroism (CD) spectra of the enantiomeric cages are compatible with the identification of epimers. A simulation of the CD spectrum of the major epimer 8'a relates the cage chirality of the system to the observed chiroptical effects. Both cage epimers and two of the phosphorus cage atoms are active as ligands with respect to [M(CO)5 ] fragments of Cr, Mo, and W. Four almost isoenergetic regio- and stereoisomers of the resulting mononuclear complexes are formed for these metals, but only one of the isomers per metal crystallized in the case of the racemic series of the complexes. The enantiopure versions of cages and cage complexes, however, did not crystallize at all, a well-known phenomenon for chiral compounds. CD spectra of the optically active complex isomer mixtures are close to identical with the CD spectra of the related free cages and point again to the chiral cages as the dominant source of the CD effects of the complexes. [(Benzene)RuCl2 ] complexes of the cage ligand 8 behave totally differently. Only a single species 12=[(benzene)RuCl2 ⋅8 b] is formed in almost quantitative yield and the minor epimer 8 b plays the role of the ligand exclusively. The reaction works as well for the separated enantiomeric cage versions to yield the highly enriched enantiomers 12' and 12'' separately. An efficient kinetic resolution process was identified as the main reason for this finding. It is based on a high stereo- and regiochemical flexibility of the PC cage ligand that is capable of adjusting to the specific requirements of a suitable transition-metal complex fragment. Such ligand flexibility is regularly observed in metalloenzymes, but is a very rare case in classical and organometallic complex chemistry.

Sulfur species in graphene oxide.

The structure of graphene oxide (GO) is of crucial importance for its chemical functionalization. However, the sulfur content present in GO prepared by Hummers' method has only been addressed by a few authors so far. It has been reported that hydrolysis of sulfur species takes place and that stable sulfonic groups are present in graphite oxide. In this manuscript, in contrast to earlier reports, sulfate species are identified that are covalently bound to GO and still present after extensive aqueous work-up. Additionally, we exclude the possibility that sulfonic groups are present in GO as major species after aqueous work up. Our results are based on bulk characterization of graphene oxide by thermogravimetry and subsequent analysis of the decomposition products using mass spectroscopy and infrared spectroscopy. Up to now, the combustion temperature between 200 and 300 °C remained almost unaddressed. In a temperature dependant experiment we reveal two main decomposition steps that differ in temperature and that are closely related to the sulfur species in GO. While the decomposition, between 200 and 300 °C, is related to the degradation of organosulfate, the other one, between 700 and 800 °C, is assigned to the pyrolysis of inorganic sulfate. Furthermore, organosulfate is to some extent responsible for the reactivity of GO. Therefore, the structural model of GO was extended by adding organosulfate in addition to epoxy and hydroxyl groups, which are predominantly covalently bound above and below the carbon skeleton. Furthermore, the identification of organosulfate groups beneath epoxy groups makes new molecular architectures feasible and can be used to explain the properties of GO in various applications.

On the way to graphane-pronounced fluorescence of polyhydrogenated graphene.

Chemistry meets graphane: a Birch-type reaction using frozen water as a gentle proton source causes the exfoliation of graphite and formation of hydrogenated graphene with electronically decoupled π-nanodomains. This highly functionalized graphene displays pronounced fluorescence.

Microenvironment engineering in ortho- and para-dendronized metalloporphyrin-fullerene conjugates involving a trans-2-bisaddition pattern.

A new series of dendronized metalloporphyrin-fullerene conjugates as photosynthetic reaction center mimics was developed in a highly regioselective fashion through tether-controlled synthesis. The microenvironment around the porphyrin core is dependent on the spatial substitution pattern and the nature and generation number of the dendrons, which was proven by cyclic voltammetry.

No shot in the dark: myxozoans chemically detect fresh fish.

This work reports the discovery of an hitherto unknown chemical recognition trait enabling a parasitic life cycle in aquatic habitats. We believe this is the first record of a natural, host-derived chemical molecule identified as a recognition cue for the phylum Myxozoa. The actinospores of these parasites attach to fish hosts via polar filaments that are extruded upon mechanical stimulation after preceding recognition of a chemical trigger contained in surface mucus. Our goal was to identify this signal. We separated compounds from a purified active fraction derived from trout mucus by a novel HPLC method. By subsequent nuclear magnetic resonance analysis of distinct components and testing in bioassays we elicited stimulation of polar filament discharge and sporoplasm emission in actinospores of three myxozoan spp., Myxobolus cerebralis, Myxobolus pseudodispar and Henneguya nuesslini, by the free nucleosides inosine, 2'-deoxyinosine and guanosine. These nucleosides also activated sporoplasm emission. Nucleosides appear to be appropriate cues for rapid host recognition by the waterborne parasite stages since they are continuously released into surface mucus. The recognition mechanism is not specific for susceptible host species, at least in the myxozoan spp. examined. In addition, a novel function of nucleobase derivatives as semiochemicals was uncovered and a wider impact of this molecule class in parasite recognition systems and aquatic chemical ecology is predicted. The relevance for disease prevention and cell culturing remains to be explored.

Dendronizing and metalating trans-2 C60 tetraaryl porphyrins--a versatile approach toward water-soluble donor-acceptor conjugates.

We have realized for the first time a series of truly water-soluble and tightly coupled porphyrin/C(60) electron-donor-acceptor conjugates in which the charge separation and charge recombination dynamics are controlled by modifying the nature of the dendrimer and/or the choice of the central metal atom.

Head-to-tail interactions in tyrosine/benzophenone dyads in the ground and the excited state: NMR and laser flash photolysis studies.

The formation of head-to-tail contacts in de novo synthesized benzophenone/tyrosine dyads, bp logical sum Tyr, was probed in the ground and excited triplet state by NMR techniques and laser flash photolysis, respectively. The high affinity of triplet-excited ketones towards phenols was used to trace the geometric demands for high reactivity in the excited state. A retardation effect on the rates with increasing hydrogen-bond-acceptor ability of the solvent is correlated with ground-state masking of the phenol. In a given solvent the efficiencies of the intramolecular hydrogen-atom-transfer reaction depend strongly on the properties of the linker: rate constants for the intramolecular quenching of the triplet state cover the range of 10(5) to 10(8) s(-1). The observed order of reactivity correlates to a) the probability of close contacts (from molecular-dynamics simulations) and b) the extent of the electronic overlap between the pi systems of the donor and acceptor moieties (from NMR). A broad survey of the NMR spectra in nine different solvents showed that head-to-tail interactions between the aromatic moieties of the bp logical sum Tyr dyads already exist in the ground state. Favourable aromatic-aromatic interactions in the ground state appear to correspond to high excited-state reactivity.

The formation of endo-complexes between calixarenes and amines--a reinvestigation.

The formation of an endo-complex between p-allylcalix[4]arene and t-butylamine was described by Gutsche in 1985. However, for a comparable system, it has been shown using NOE methods that the amine does not reside inside the calix. Instead, an exo-calix complex is formed. A reevaluation suggests that the previous conclusion is an artifact due to improper NMR-data processing. DFT (RB3LYP/6-31G(d)) calculations confirm the higher stability of the exo-complex over its endo-counterpart.

Ligand cleavage put into reverse: P--C bond breaking and remaking in an alkylphosphane iron complex.

Complex formation between FeX(2)6 H(2)O (X=BF(4) or ClO(4)) and the pyridine-derived tetrapodal tetraphosphane C(5)H(3)N[CMe(CH(2)PMe(2))(2)](2) (1) in methanol proceeds with solvent-induced cleavage of one PMe(2) group. Depending on the reaction temperature and the nature of the counterion, iron(II) is coordinated, in distorted square-pyramidal fashion, by the anionic remainder of the chelating ligand, C(5)H(3)N[CMe(CH(2)PMe(2))(2)][CMe(CH(2)PMe(2))(CH(2) (-))] (NP(3)C(-) donor set: X=BF(4), -50 degrees C: 2; X=ClO(4), RT: 4) or its protonated form C(5)H(3)N[CMe(CH(2)PMe(2))(2)][CMe(CH(2)PMe(2))(CH(3))], in which the methyl group is in agostic interaction with the metal centre (X=BF(4), RT: 3; X=ClO(4), +50 degrees C: 5). A monodentate phosphinite ligand Me(2)POMe, formed from the cleaved PMe(2) group and methanol, completes the coordination octahedron in both cases. Working in CD(3)OD (X=BF(4), RT) gives the deuterium-substituted analogue of 3, with ligands L(CH(2)D) (L=residual chelating ligand) and Me(2)POCD(3). A mechanism for the observed phosphorus-carbon bond cleavage is suggested. Complex 2, when isolated at -50 degrees C, is stable in the solid state even at room temperature. The reaction of 2 in methanol with carbon monoxide (10.5 bar) at elevated temperature forms, in addition to as yet unidentified side products, the carbonyl complex [(1)Fe(CO)](BF(4))(2) (7), in which the previous P--C bond cleavage has been reversed, reforming the original tetrapodal pentadentate NP(4) ligand 1. All compounds have been fully characterised, including X-ray structure analyses in most cases.

Solvent dependent reactivity: solvent activation vs. solvent coordination in alkylphosphane iron complexes.

The pyridine-derived tetrapodal tetraphosphane C5H3N[CMe(CH2PMe2)2]2 is susceptible to selective protonolysis of a phosphorus-carbon bond in the presence of iron(II) salts. Water produces dimethylphosphinic acid, Me2POH, and protonates the anionic remainder of the tetraphosphane. The resulting iron(II) complexes and (tetrafluoroborate and perchlorate salts, respectively) contain the residual chelate ligand in which a methyl group, derived from the ligand skeleton, is in agostic interaction with the metal centre, and in which Me2POH, unavailable in the free state owing to rapid tautomerisation, is metal-coordinated and thus stabilised. Full NMR details are presented, including 31P simulations. The reactivity towards alcohols is similar (compounds), and has been studied using deuterium labels (NMR). P-C bond cleavage may be suppressed only if all protic agents are rigorously excluded, as in the reaction of with Fe(SO3CF3)2.2CH3CN in acetonitrile solution, which produces the complex [Fe(NCMe)](SO3CF3)2. In it, the ligand acts as an NP4 coordination cap but is severely distorted from square-pyramidal geometry. The reaction of with anhydrous ferrous bromide, FeBr2, in methanol again produces a dimethylphosphinic acid ester ligand, but the complex now contains ferric iron coordinated by a carbanionic residual chelate ligand, implicating H+ as the oxidising agent under these conditions. Full spectroscopic and X-ray structural details are presented for all compounds.