Functionalization of Dodecaborates by Mild and Efficient Pd-Catalyzed Formation of B-C Bonds with Boronic Acids.

Hybrid organic-inorganic molecules have recently received great interest due to their unique properties, which give access to their implementation in biological and material sciences. Herein, a new synthetic approach for the direct-linkage of the purely inorganic dodecaborate cluster to organic building blocks through B-C bond is established, using boronic acids as functional groups on the organic moiety, reacting under Suzuki-Miyaura coupling conditions with iodo-undecahydridododecaborate. The choices of ligand (DavePhos) and solvent (N-methylpyrrolidone for electron-poor, CD3 CN for electron-rich groups) are essential for the successful coupling. Ultimately, the newly described methodology is found to be functional-group tolerant covering a wide spectrum of substrates including electron-poor arenes.

Facile Attachment of Halides and Pseudohalides to Dodecaborate(2-) via Pd-catalyzed Cross-Coupling.

Cross-coupling reactions with [B12H11I]2- as one partner have been used successfully for Kumada and Buchwald Hartwig couplings with Pd catalysis. Here, we found that the iodide could be substituted easily, and unexpectedly, with other halides such as Br and Cl, and with pseudohalides such as cyanide, azide, and isocyanate. We found that for Cl, Br, N3, and NCO, tetrabutylammonium salts-or sodium salts-were successful halide sources, whereas for cyanide, CuCN was the only halide source that allowed a successful exchange. The azide could be reacted further in a click reaction with triazoles. While no substitution with fluoride occurred, tetrabutylammonium fluoride in the presence of water led to [B12H11OH]2-. Yields were high to very high, and reaction times were short when using a microwave oven as a heating source.

High-Affinity Binding of Metallacarborane Cobalt Bis(dicarbollide) Anions to Cyclodextrins and Application to Membrane Translocation.

Metallacarboranes are a class of inorganic boron clusters that have recently been recognized as biologically active compounds. Herein, we report on the host-guest complexation of several cobalt bis(1,2-dicarbollide) anions (COSANs) with cyclodextrins (CDs) in aqueous solution. The binding affinities reach micromolar values, which are among the highest known values for native CDs, and exceed those for neutral hydrophobic organic guest molecules. The entrapment of the COSANs inside the cavity of CDs was confirmed using NMR and UV-visible spectroscopy, mass spectrometry, cyclic voltammetry, and isothermal titration calorimetry. Complexation by CDs greatly influences the photophysical and electrochemical properties of COSANs. In combination with indicator displacement assays, a label-free fluorescence-based method was developed to allow real-time monitoring of the translocation of COSANs through lipid bilayer membranes.

Host-Guest Chemistry of Carboranes: Synthesis of Carboxylate Derivatives and Their Binding to Cyclodextrins.

Polyhedral carboxymethyl carborane (C2 B10 H12 ) derivatives, including mono- and disubstituted o-, m-, and p-isomers, have been synthesized. Supramolecular host-guest complexation of these derivatives with cyclodextrins (CDs; namely, α-, ß-, and γ-CD) has been investigated in water. The globular structure of the carborane binding moiety and its hydrophobic character qualify it as an ideal recognition site to form stable inclusion complexes with macrocyclic host molecules in aqueous solution. The measured binding affinities for the carborane derivatives were in the millimolar range (Ka =103 -104 m-1 ) with differently sized CDs, and preferential binding to ß-CD.

High-affinity host-guest chemistry of large-ring cyclodextrins.

The host-guest chemistry of large-ring cyclodextrins (LRCDs) has been largely unexplored due to the lack of suitable guest molecules that bind with significant affinities to enable potential applications. Herein, we report their complexation with dodecaborate anions (B12X12(2-)), a novel class of guest molecules. The binding constants of the inorganic guests (10(4)-10(6) M(-1)) allow their classification as the first tight binders for LRCDs.

Water Structure Recovery in Chaotropic Anion Recognition: High-Affinity Binding of Dodecaborate Clusters to γ-Cyclodextrin.

Dodecaborate anions of the type B12X12(2-) and B12X11Y(2-) (X=H, Cl, Br, I and Y=OH, SH, NH3(+), NR3(+)) form strong (K(a) up to 10(6) L mol(-1), for B12Br12(2-)) inclusion complexes with γ-cyclodextrin (γ-CD). The micromolar affinities reached are the highest known for this native CD. The complexation exhibits highly negative enthalpies (up to -25 kcal mol(-1)) and entropies (TΔS up to -18.4 kcal mol(-1), both for B12I12(2-)), which position these guests at the bottom end of the well-known enthalpy-entropy correlation for CDs. The high driving force can be traced back to a chaotropic effect, according to which chaotropic anions have an intrinsic affinity to hydrophobic cavities in aqueous solution. In line with this argument, salting-in effects revealed dodecaborates as superchaotropic dianions.

[FeFe]-hydrogenase models assembled into vesicular structures.

Compartmentalization is a major prerequisite for the origin of life on earth according to Wächtershäuser "Iron-Sulfur-World". The hypothesis is mainly based on an autocatalytic inorganic energy reproducing redox system consisting of iron and sulfur as requirement for the subsequent synthesis of complex organic structures. Here, we modified [FeFe]-hydrogenase models by means of covalent coupling to either oleic acid or the amphiphilic block copolymer polybutadiene-polyethyleneoxide (PB-PEO) and incorporated those into the membranes of vesicles composed of phospholipids (liposomes) or the unmodified amphiphilic polymer (polymersomes). We employed a [2Fe-2S] cluster as a hydrogenase model, since these structures are known to be suitable catalysts for the generation of H2 in the presence of weak acids. Successful incorporation was confirmed by spectrophotometric iron quantification and the vesicles formed were characterized by size determination (photon correlation spectroscopy (PCS)), and zeta potential as well as by cryo-transmission electron microscopy (Cryo-TEM). The modified models could be incorporated into liposomes or polymersomes up to molar proportions of 3.15% and 28%, respectively. Due to the immobilization in vesicular bilayers the [FeFe]-hydrogenase models can even exhibit catalytic action under the particular conditions of the intravesicular microenvironment. Our results suggest that the vesicular systems described may be applied as a nanoreactor for the reduction of encapsulated substances by generating hydrogen and thus as a minimal cell model.

On the gas-phase dimerization of negatively charged closo-dodecaborates: a theoretical study.

We have studied the intriguing gas-phase dimerization of the B12In(-) (n = 9, 8) anions to B24I2n(2-) dianions by means of density functional theory calculations. The dimerization of B12I9(-) to B24I18(2-) has been detected experimentally in a previous study (Phys. Chem. Chem. Phys., 2011, 13, 5712) utilizing electrospray ionization ion trap mass spectrometry (ESI-IT-MS), whereas the formation of B24I16(2-) from B12I8(-) is modeled here prior to experiment. Calculations are carried out to determine the molecular and electronic structures, the bonding situation and the stability of the dimers relative to the respective monomers. The dimerization process is found to be thermodynamically favorable, and the stability of the lowest-energy structures is substantiated by molecular dynamics simulations. The calculations imply that the experimentally observed B24I18(2-) and the hypothetical B24I16(2-) species are formed through dimerization of the respective B12In(-) (n = 9, 8) monomers, rather than through loss of two I radicals from B24I2n+2(2-) dimers. Electronic properties such as natural charges, vertical detachment energies (VDEs), frontier molecular orbitals (FMOs), and HOMO-LUMO gaps are computed and analyzed in detail for all monomers and dimers. The analysis shows that the most stable B24I2n(2-) dimers are formed through two 2c-2e B-B and two 3c-2e B-I-B bridges between the parent B12In(-) (n = 9, 8) monomers. These new bridging bonds engage the deiodinated (bare) faces of the two B12 icosahedra, as well as one (per monomer) of the nearest boron neighbors and its iodine substituent.

Brilliant Blue G as protective agent against trypan blue toxicity in human retinal pigment epithelial cells in vitro.

BACKGROUND: Combinations of trypan blue (TB), Brilliant Blue G (BBG) and polyethyleneglycol had been shown before to be less toxic to ARPE retinal pigment epithelial cells than TB alone. We studied systematically the influence of combinations of dyes on cell damage. METHODS: ARPE cells were exposed to TB (concentration range 0.025 to 1 %), BBG (0.0025 to 0.5 %), and combinations of the two dyes, dissolved in phosphate buffered saline (PBS), for periods between 5 and 60 min. Cell damage was monitored with the WST-1 assay. The effect of different salt concentration was measured in the same way. RESULTS: TB in concentrations of 0.075 % and higher was toxic to the cells already after 30 min incubation. BBG was toxic after 30 min in concentration of 0.1 % and higher, but had a protective effect on cells with incubation time of 5 min and concentrations up to 0.1 %. BBG at concentrations of 0.025 % protected against TB-induced damage at 5 min and 30 min incubation. Salt concentrations between 113 and 225 mM did not influence cell survival even after 30 min. In the presence of TB, propidium iodide bound strongly to the cells. CONCLUSIONS: BBG acts as a protecting agent against TB toxicity.

Dyes for Eyes™: hydrodynamics, biocompatibility and efficacy of 'heavy' (dual) dyes for chromovitrectomy.

As epiretinal membranes (ERMs), the internal limiting membrane (ILM) and the vitreous cortex are essentially transparent tissues, or translucent structures, nontraumatic removal may be challenging in various types of macular surgery. Vital dyes stain these thin tissues, thus allowing for better visualization of these structures during vitrectomy and selective 'membrane peeling' from the underlying retina. To avoid swirling of the dye within the fluid-filled vitreous cavity, and to better target the dye onto the macula, a fluid-air exchange is commonly performed. However, this may jeopardize visualization of the macula during peeling due to clouding of the posterior lens capsule, and may lead to postoperative visual field defects. Recently, a new dye solution for staining the ERM and ILM simultaneously has been developed that circumvents the need for fluid-air exchange, i.e. MembraneBlue-Dual™. This paper will focus on the hydrodynamics and biocompatibility of this 'heavy' dual dye and its efficacy for staining of the ILM and/or ERMs during posterior segment surgery in a multicenter clinical setting.

An affordable gradient mixer for chromatography with aqueous and organic solvents.

A gradient mixer for preparative column chromatography has been developed, using a microcontroller, a three-way solenoid valve, and a one-channel pump of any chosen design, controlled by a microcontroller and with specifications for the gradient entered through a touchscreen. The gradient mixer is economical and can be produced with the design files provided.

From an icosahedron to a plane: flattening dodecaiodo-dodecaborate by successive stripping of iodine.

It has been shown by electrospray ionization-ion-trap mass spectrometry that B(12)I(12)(2-) converts to an intact B(12) cluster as a result of successive stripping of single iodine radicals or ions. Herein, the structure and stability of all intermediate B(12)I(n)(-) species (n=11 to 1) determined by means of first-principles calculations are reported. The initial predominant loss of an iodine radical occurs most probably via the triplet state of B(12)I(12)(2-), and the reaction path for loss of an iodide ion from the singlet state crosses that from the triplet state. Experimentally, the boron clusters resulting from B(12)I(12)(2-) through loss of either iodide or iodine occur at the same excitation energy in the ion trap. It is shown that the icosahedral B(12) unit commonly observed in dodecaborate compounds is destabilized while losing iodine. The boron framework opens to nonicosahedral structures with five to seven iodine atoms left. The temperature of the ions has a considerable influence on the relative stability near the opening of the clusters. The most stable structures with five to seven iodine atoms are neither planar nor icosahedral.

Structure and dynamics of dodecaborate clusters in water.

We have studied using molecular dynamics simulations the interaction of the dodecaborate anion, B(12)H(12)(2-), and its amino, trimethyl, and triethyl derivatives with water molecules. We found peculiar organization of the water molecules in the first solvation shell with the formation of a dihydrogen bond between the hydrogen atoms of the anions and the hydrogen atoms of the water molecules. The simulations also show that the organization of the hydration shell is strongly influenced by the substituents in the anions. These differences are likely to play an important role in understanding the interaction of the anions with biological systems like membranes and proteins in aqueous environments.

A Fluorescein-Substituted Perbrominated Dodecaborate Cluster as an Anchor Dye for Large Macrocyclic Hosts and Its Application in Indicator Displacement Assays.

Perhalogenated boron clusters derived from B12Br122-, a superchaotropic dianion with a globular icosahedral shape, serve as inorganic cavity binders for cyclodextrins (CDs), in particular for large CDs (γ-CD and δ-CD), with high binding affinity (Ka > 106 M-1) in aqueous solution. This opens the door for applications of this anchoring moiety by linking it to organic residues, prominently fluorescent dyes. We report here the synthesis of a novel fluorescein-substituted perbrominated dodecaborate cluster by a copper(I)-catalyzed azide-alkyne click reaction. The formation of host-guest inclusion complexes between the dodecaborate-modified fluorescein dye and CDs can be readily followed by optical titrations, which afforded a binding constant of ∼1 × 104 M-1 with γ-CD; that is, the cluster functionalization allows binding of an otherwise nonbinding dye to the macrocycle ("anchor dye"). The formation of the 1:1 host-guest inclusion complex between the dye and γ-CD occurs over a broad range of pH values, which allows its application as a sensitive reporter pair according to the indicator displacement method, e.g., for drug detection. In addition, the substituted dye shows outer-wall binding to cucurbiturils through the dodecaborate moiety, leading to the formation of aggregates and significant fluorescence quenching of the dye.

New approaches to the functionalization of the 1-carba-closo-decaborate anion.

Two new approaches to the functionalization of the 1-carba-closo-decaborate anion [1-CB9H10]- at boron atoms via the ring-opening of its 1,4-dioxane derivative with various nucleophiles and Pd-catalysed cross-coupling of its iodo derivative with aromatic amines and heteroaromatics were developed.

Binding affinity of aniline-substituted dodecaborates to cyclodextrins.

A new set of hybrid guest molecules bearing organic and inorganic residues have been studied for their recognition by cyclodextrins in aqueous solution. The guest molecules consist of nitroanilines linked through their amino group to the dodecahydrido-closo-dodecaborate cluster B12H122-, which serves as an anchor group. They show sizable affinity to cyclodextrins, and unexpected photophysical properties, with a very strong and low-energy charge-transfer band. The dodecaborate cluster increases the pKa of the anilines by 5.0 to 5.7 pH units, and the deprotonated forms of the o- and p-nitroaniline derivatives show strong charge transfer absorption bands in the visible part of the spectrum.

New dual dye for vitreoretinal surgery with increased transparency.

OBJECTIVES: To develop a new dye formulation for vitreoretinal surgery, which shows increased transparency for better intraoperative handling with better parameters important for use. METHODS AND ANALYSIS: A new blue dye, DDG, was synthesised and tested for toxicity and staining. Diglycerol as new density-increasing additive was identified, and its toxicity and lack of influence of the staining with trypan blue (TB) on a collagen membrane as model for the epiretinal membrane was determined. Transparency of the dye solution was evaluated. RESULTS: DDG is as alternative to Brilliant Blue G (BBG), with good staining properties for interna limitans models, and a good safety profile. Diglycerol is a new non-toxic additive replacing PEG3350, with reduced viscosity and no reduction in staining, allowing the reduction of TB to achieve the same staining level of the collagen membrane by 40%, with greater transparency of the dye solution and reduced viscosity. Both factors should facilitate a safe removal during surgery. CONCLUSION: A new dye preparation with improved performance in comparison to marketed combinations of BBG and TB was developed. Its reduced TB concentration and viscosity with maintained density allow better tolerance and handling.

Real-space indicators for chemical bonding. Experimental and theoretical electron density studies of four deltahedral boranes.

In an approach combining high-resolution X-ray diffraction at low temperatures with density functional theory calculations, two closo-borates, B(12)H(12)(2-) (1) and B(10)H(10)(2-) (2), and two arachno-boranes, B(10)H(12)L(2) [L = amine (3) or acetonitrile (4)], were analyzed by means of the atoms-in-molecules (AIM) theory and electron localizability indicator (ELI-D). The two-electron three-center (2e3c) bonds of the borane cages are investigated with the focus on real-space indicators for chemical bonding and electron delocalization. In compound 2, only two of the three expected bond critical points (bcp's) are found. However, a weakly populated ELI-D basin is found for this pair of adjacent B atoms and the delocalization index and the Source contributions are on the same order of magnitude as those for the other pairs. The opposite situation is found in the arachno-boranes, where no ELI-D basins are found for two types of B-B pairs, which, in turn, exhibit a bcp. However, again the delocalization index is on the same order of magnitude for this bonding interaction. The results show that an unambiguous real-space criterion for chemical bonding is not given yet for this class of compounds. The arachno-boranes carry a special B-B bond, which is the edge of the crown-shaped molecule. This bond is very long and extremely curved inward the B-B-B ring. Nevertheless, the corresponding bond ellipticity is quite small and the ELI-D value at the attractor position of the disynaptic valence basin is remarkably larger than those for all other B-B valence basins. Furthermore, the value of the ED is large in relation to the B-B bond length, so that only this bond type does not follow a linear relationship of the ED value at the bcp versus B-B bond distances, which is found for all other B-B bcp's. The results indicate that both 2e2c and 2e3c bonding play a distinct role in borane chemistry.

Collision-induced gas-phase reactions of perhalogenated closo-dodecaborate clusters--a comparative study.

The gas phase reactivity of perhalogenated closo-dodecaborate clusters [B(12)X(12)](2-) (X = F, Cl, Br, I) with N-tetraalkylated ammonium counter ions was investigated by electrospray ionization ion trap mass spectrometry (ESI-IT-MS). Collisions with the background gases introduced a broad variety of gas phase reactions. This study represents the first experimental approach to a new class of boron-rich boron clusters that are not accessible in the condensed phase. The anionic ion pair [B(12)X(12) + N(C(n)H(2n+1))(4)](-) is generally found as the ion of highest mass. Its reaction sequence starts with an alkyl transfer from the ammonium ion to the dodecaborate cluster. Subsequently, the alkylated intermediate [B(12)X(12) + C(n)H(2n+1)](-) decomposes to give very reactive ions of the general formula [B(12)X(11)](-). These ions possess a free boron vertex and immediately bind to the residual gases N(2) and H(2)O in the ion trap by formation of the corresponding adducts [B(12)X(11) + N(2)](-) and [B(12)X(11) + H(2)O](-). Subsequent fragmentations of the water adduct repetitively substitute halogen atoms by hydroxyl groups. The fragmentation process of the free anion [B(12)X(12)](2-) depends on the applied excitation energy and on the halogen substituent X. A radical dehalogenation of the B(12) unit is observed for X = I, whereas for X = Cl or F the loss of small molecules (mainly BX(3)) dominates. The different reaction behavior is explained by the different electron affinity of the halogens and the strength of the boron-halogen-bonds. Surprisingly, isolation of the fragment ion [B(12)I(9)](-) in the ion trap yields the highly stable [B(24)I(18)](2-) dianion. This observation suggests a reaction between two negative ions in the gas phase.

Charge transfer via the dative N-B bond and dihydrogen contacts. Experimental and theoretical electron density studies of four deltahedral boranes.

In an approach combining high resolution X-ray diffraction at low temperatures with density functional calculations, two closo-borates, B12H12(2-) (1) and B10H10(2-) (2), and two arachno-boranes, B10H12L2 (L = amine (3) or acetonitrile (4)), are studied by means of Atoms In Molecules (AIM) theory and Electron Localizability Indicator (ELI-D). The charge transfer via the dative N-B bonds in the arachno-boranes and via dihydrogen contacts in the closo-borates is quantified. The dative N-B bond in 4 is significantly shorter and stronger than that in 3 and in small N-B Lewis acid base adducts from the literature. It is even shorter in the gas phase than in the crystal environment in contrast to the bond shortening in the crystal generally found for N-B Lewis acid-base adducts. Furthermore, the calculated charge transfer in terms of AIM charges is opposite to the expected N → B direction but still weak as found for all other N-B bonds. The intramolecular charge redistributions due to intermolecular interactions are quantified by the AIM and ELI-D analysis of contact ion pairs. The latter method gives a deeper understanding of delocalization effects in the borane cages as well as in the counterions. Since dihydrogen bonds are rarely found in crystal structures, one focus was directed to the topologies of the large number of 58 experimentally found contacts of this type. The analysis reveals that the electron density at the bond critical point, the corresponding Laplace function, and the curvature along the bond path (λ3) show a behavior that clearly discriminates these interactions from classical hydrogen bonds, confirming earlier theoretical findings.