Rearrangement of dicarboranyl methyl cation to icosahedral C3 B9 H12 + : An ab initio dynamics view.

Closo-carborane anions are prominent, whereas the cations of the same are less abundant in the literature. As these ions have similar size and are weakly coordinating, the ionic liquids of these two ions could have important applications in many areas of chemistry. In view of limited number of polyhedral carborane cations available, we revisited the rearrangement of dicarboranyl methyl cation (7-CH2 7,9-nido-C2 B9 H10 + ) using ab initio molecular dynamics calculations with metadynamics. Our simulations confirmed the concerted mechanism of the rearrangement. We believe this work will resume the interest in its synthesis and carborane cations in general.

B-H⋯π and C-H⋯π interactions in protein-ligand complexes: carbonic anhydrase II inhibition by carborane sulfonamides.

Among non-covalent interactions, B-H⋯π and C-H⋯π hydrogen bonding is rather weak and less studied. Nevertheless, since both can affect the energetics of protein-ligand binding, their understanding is an important prerequisite for reliable predictions of affinities. Through a combination of high-resolution X-ray crystallography and quantum-chemical calculations on carbonic anhydrase II/carborane-based inhibitor systems, this paper provides the first example of B-H⋯π hydrogen bonding in a protein-ligand complex. It shows that the B-H⋯π interaction is stabilized by dispersion, followed by electrostatics. Furthermore, it demonstrates that the similar C-H⋯π interaction is twice as strong, with a slightly smaller contribution of dispersion and a slightly higher contribution of electrostatics. Such a detailed insight will facilitate the rational design of future protein ligands, controlling these types of non-covalent interactions.

Employment of chiral columns with superficially porous particles in chiral separations of cobalt bis (dicarbollide) and nido-7,8-C2 B9 H12 (1-) derivatives.

Derivatives of the nido-7,8-C2 B9 H12 (1-) (dicarbollide ion) and [3,3'-Co-(1,2-C2 B9 H11 )2 ](1-) cobalt sandwich (COSAN) ion represent groups of extremely chemically and thermally stable abiotic compounds. They are being investigated in many research areas, that is, medicinal chemistry, material sciences, analytical chemistry, and electrochemistry. The chirality of these compounds remains still grossly overlooked, what is also reflected in limited number of reports on their chiral separations. Continued progress depends on reliable, fast, and cost-effective methods for such separations. Recently, chiral separations of COSAN derivatives were achieved in liquid chromatography and supercritical fluid chromatography. Only five anionic derivatives of nido-7,8-C2 B9 H12 (1-) were successfully enantioseparated in liquid chromatography. Efforts to separate anionic nido-7,8-C2 B9 H12 (1-) in supercritical chromatography have failed, and only a few dicarbollide ions were separated using liquid chromatography. Generally, all chiral separations in liquid chromatography took about 30 min. Herein, we identify a versatile column capable of separating both COSAN and nido-7,8-C2 B9 H12 (1-) derivatives and achieve faster analyses times employing commercially available superficially porous chiral stationary phases. The semisynthetic hydroxypropyl ß-cyclodextrin-based column (CDShell-RSP) is identified as the column of choice from the tested columns by separating 19 of 27 compounds from each structural motifs tested mainly in less than 10 min. The dihydroxyalkyl, oxygen-bridged hydroxyalkyl, and bisphenylene-bridged COSAN derivatives were baseline separated in less than 5 min exceeding the results of supercritical fluid chromatography. Methods developed herein will aid synthetic chemists without the possession of a supercritical fluid chromatograph to achieve fast chiral separations of COSAN and derivatives of nido-7,8-C2 B9 H12 (1-) on a common liquid chromatograph without the need of dedicated instrumentation.

DFT Surface Infers Ten-Vertex Cationic Carboranes from the Corresponding Neutral closo Ten-Vertex Family: The Computed Background Confirming Their Experimental Availability.

Modern computational protocols based on the density functional theory (DFT) infer that polyhedral closo ten-vertex carboranes are key starting stationary states in obtaining ten-vertex cationic carboranes. The rearrangement of the bicapped square polyhedra into decaborane-like shapes with open hexagons in boat conformations is caused by attacks of N-heterocyclic carbenes (NHCs) on the closo motifs. Single-point computations on the stationary points found during computational examinations of the reaction pathways have clearly shown that taking the "experimental" NHCs into account requires the use of dispersion correction. Further examination has revealed that for the purposes of the description of reaction pathways in their entirety, i.e., together with all transition states and intermediates, a simplified model of NHCs is sufficient. Many of such transition states resemble in their shapes those that dictate Z-rearrangement among various isomers of closo ten-vertex carboranes. Computational results are in very good agreement with the experimental findings obtained earlier.

Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds.

This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).

Determination of acidity constants, ionic mobilities, and hydrodynamic radii of carborane-based inhibitors of carbonic anhydrases by capillary electrophoresis.

Capillary electrophoresis (CE) has been applied for determination of the thermodynamic acidity constants (pKa ) of the sulfamidoalkyl and sulfonamidoalkyl groups, the actual and limiting ionic mobilities and hydrodynamic radii of important compounds, eight carborane-based inhibitors of carbonic anhydrases, which are potential new anticancer drugs. Two types of carboranes were investigated, (i) icosahedral cobalt bis(dicarbollide)(1-) ion with sulfamidoalkyl moieties, and (ii) 7,8-nido-dicarbaundecaborate with sulfonamidoalkyl side chains. First, the mixed acidity constants, pKamix , of the sulfamidoalkyl and sulfonamidoalkyl groups of the above carboranes and their actual ionic mobilities were determined by nonlinear regression analysis of the pH dependences of their effective electrophoretic mobility measured by capillary electrophoresis in the pH range 8.00-12.25, at constant ionic strength (25 mM), and constant temperature (25°C). Second, the pKamix were recalculated to the thermodynamic pKa s using the Debye-Hückel theory. The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the pKa s in the range 10.78-11.45 depending on the type of carborane cluster and on the position and length of the alkyl chain on the carborane scaffold. These pKa s were in a good agreement with the pKa s (10.67-11.27) obtained by new program AnglerFish (freeware at https://echmet.natur.cuni.cz), which provides thermodynamic pKa s and limiting ionic mobilities directly from the raw CE data. The absolute values of the limiting ionic mobilities of univalent and divalent carborane anions were in the range 18.3-27.8 TU (Tiselius unit, 1 × 10-9 m2 /Vs), and 36.4-45.9 TU, respectively. The Stokes hydrodynamic radii of univalent and divalent carborane anions varied in the range 0.34-0.52 and 0.42-0.52 nm, respectively.

Thiaborane Icosahedral Barrier Increased by the Functionalization of all Terminal Hydrogens in closo-1-SB11H11.

The electrophilic substitution of icosahedral closo-1-SB11H11 with methyl iodide has resulted in two B-functionalized thiaboranes, 7,12-I2-2,3,4,5,6,8,9,10,11-(CH3)9-1-closo-SB11 and 7,8,12-I3-2,3,4,5,6,9,10,11-(CH3)8-closo-1-SB11, with the former being significantly predominant. These two icosahedral thiaboranes are the first cases of polysubstituted polyhedral boron clusters with another vertex that differs from B and C. Such polyfunctionalizations have increased the earlier observed thiaborane icosahedral barrier, not exhibiting any reactivity toward bases, unlike the parent thiaborane. The search for methylation pathways has revealed that the complete B11-methylation is impossible, like in the case of decaborane(14), where this seems to be a result of the positively charged upper parts of these two molecules.

Direct Introduction of an Alkylsulfonamido Group on C-sites of Isomeric Dicarba-closo-dodecaboranes: The Influence of Stereochemistry on Inhibitory Activity against the Cancer-Associated Carbonic Anhydrase IX Isoenzyme.

Carbonic anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba-closo-dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba-closo-dodecaboranes with a different geometric position of carbon atoms. The closo-compounds from the ortho- and meta-series were then degraded to corresponding 11-vertex dicarba-nido-undecaborate(1-) anions. All compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant (Ki ) and selectivity towards CA IX. Decreasing trends in Ki and selectivity index (SI ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity.

Face-Fusion of Icosahedral Boron Hydride Increases Affinity to γ-Cyclodextrin: closo,closo-[B21 H18 ]- as an Anion with Very Low Free Energy of Dehydration.

The supramolecular recognition of closo,closo-[B21 H18 ]- by cyclodextrins (CDs) has been studied in aqueous solution by isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. These solution studies follow up on previous mass-spectrometric measurements and computations, which indicated the formation and stability of CD ⋅ B21 H18- complexes in the gas phase. The thermodynamic signature of solution-phase binding is exceptional, the association constant for the γ-CD complex with B21 H18- reaches 1.8×106  M-1 , which is on the same order of magnitude as the so far highest observed value for the complex between γ-CD and a metallacarborane. The nature of the intermolecular interaction is also examined by quantum-mechanical computational protocols. These suggest that the desolvation penalty, which is particularly low for the B21 H18- anion, is the decisive factor for its high binding strength. The results further suggest that the elliptical macropolyhedral boron hydride is another example of a CD binder, whose extraordinary binding affinity is driven by the chaotropic effect, which describes the intrinsic affinity of large polarizable and weakly solvated chaotropic anions to hydrophobic cavities and surfaces in aqueous solution.

Electrophilic Methylation of Decaborane(14): Selective Synthesis of Tetramethylated and Heptamethylated Decaboranes and Their Conjugated Bases.

The paper reports specific syntheses of methylated decaborane(14), nido-B10H14 (1), derivatives. The reaction of 1 with an excess of neat MeI and AlCl3 yields 1,2,3,4-Me4-nido-B10H10 (2) essentially quantitatively when performed at room temperature. Heating the same mixture to 120 °C provides 1-I-2,3,4,5,7,8,10-Me7-nido-B10H6 (3a). The formation of analogous 1-CF3SO2O-2,3,4,5,7,8,10-Me7-nido-B10H6 (3b) is achieved by heating 1 or 2 with an excess of MeSO3CF3 in the presence of a catalytic amount of HOSO2CF3 to 120 °C. Compounds 2 and 3 can be deprotonated to yield the corresponding anions [1,2,3,4-Me4-nido-B10H9]- (2-), [1-I-2,3,4,5,7,8,10-Me7-nido-B10H5]- (3a-), and [1-CF3SO2O-2,3,4,5,7,8,10-Me7-nido-B10H5]- (3b-). The structure of all the compounds isolated has been unambiguously confirmed by multinuclear (11B and 1H) NMR measurements, and the structures of 2-, 3a, 3a-, and 3b have been established by X-ray diffraction analyses. The very high volatility of 2 has made it impossible to apply X-ray diffraction in this case; therefore, its structure has been derived computationally using the ab initio/GIAO/NMR tool. DFT-based computational protocols have also outlined the reason why it is impossible to obtain an octamethyl derivative of 1 experimentally.

The structural basis for the selectivity of sulfonamido dicarbaboranes toward cancer-associated carbonic anhydrase IX.

Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.

The Influence of Halogenated Hypercarbon on Crystal Packing in the Series of 1-Ph-2-X-1,2-dicarba-closo-dodecaboranes (X = F, Cl, Br, I).

Although 1-Ph-2-X-closo-1,2-C2B10H10 (X = F, Cl, Br, I) derivatives had been computed to have positive values of the heat of formation, it was possible to prepare them. The corresponding solid-state structures were computationally analyzed. Electrostatic potential computations indicated the presence of highly positive σ-holes in the case of heavy halogens. Surprisingly, the halogen•••π interaction formed by the Br atom was found to be more favorable than that of I.

Icosahedral Carbaboranes with Peripheral Hydrogen-Chalcogenide Groups: Structures from Gas Electron Diffraction and Chemical Shielding in Solution.

Carbaboranes 1,2-(EH)2 -closo-1,2-C2 B10 H10 (E=S, Se) were prepared, in the case of E=Se for the first time. Their semi-experimental equilibrium molecular structures were established by the concerted use of quantum-chemical calculations and gas electron diffraction. A method was developed and implemented to quantify the contribution of experimental data to each refined structural parameter. The accuracy of the experimental structures and those calculated at the MP2 level of theory were gauged by comparison of experimental 11 B NMR chemical shifts with quantum-chemically computed values; the inclusion of electron correlation (GIAO-MP2) provided superior results. For the purpose of geometrical prediction, the remaining group 16 elements were considered, and the icosahedral structures for E=O and Te were also computed; for E=O the same theoretical approach was used as for E=S, and for E=Te a description similar to that for E=Se was employed.

Investigation of Thiaborane closo- nido Conversion Pathways Promoted by N-Heterocyclic Carbenes.

The 12-X- closo-SB11H10 (X = H or I) thiaboranes react with one or two molar equivalents of various N-heterocyclic carbenes (NHCs) to give the deprotonated 12-vertex species of [12-X-SB11H9·NHC]-[NHC-H]+composition as kinetic products. The use of one molar equivalent of a sterically more hindered NHC reactant leads to the formation of 12-X-SB11H10·NHC adducts with a heavily distorted cage and the nido electron count. Further reaction of 12-I-SB11H10·NHC to deboronated 12-X-SB10H9·NHC proceeds in acetone to complete the closo- nido reaction pathway under the thermodynamic control. The structures of all compounds have been investigated by NMR spectroscopy and diffraction techniques. The results are supported by theoretical methods.

Synthesis of closo-1,2-H2C2B8Me8 and 1,2-H2C2B8Me7X (X = I and OTf) Dicarbaboranes and Their Rearrangement Reactions.

Methyl-camouflaged dicarbaboranes closo-1,2- and 1,10-H2C2B8Me8 have been prepared in high yields either from nido-5,6-H2C2B8H10 or closo-1,2-H2C2B8H8 via electrophilic methylation reactions and cluster-rearrangement methods. Prepared were also monosubstituted derivatives of general formulation closo-H2C2B8Me7-X (X = I or OTf). The permethylated compounds exhibit extreme air stability in comparison to unprotected counterparts as a consequence of rigid, egg-shaped hydrocarbon structures incorporating inner C2B8 carborane scaffolding. The structures of all compounds isolated were confirmed unambiguously by multinuclear (11B, 1H, 13C, and 19F) NMR measurements, supported by X-ray diffraction analyses and geometry optimization methods on several compounds.

Surface termination of MgB2 unveiled by a combination of adsorption experiments and theoretical calculations.

Superconductivity in polycrystalline and thin-film MgB2 is strongly affected by the termination of its surface, but a reliable determination of the surface termination is still a challenging task of surface chemistry. Here, the surface properties of superconducting MgB2 were investigated using a combination of inverse gas chromatography and van der Waals corrected density functional theory calculations. The dispersive surface energy was measured as a function of the surface coverage and its value (58 mJ m-2 to 48 mJ m-2) was verified by high-level non-local EXX + RPA calculations, which predicted that the dispersive contribution to the cleavage energy was 56 mJ m-2. The isosteric adsorption enthalpies of cyclohexane, dioxane, acetone and acetonitrile molecules were measured on an MgB2 sample and compared to the DFT calculated enthalpies for the Mg-terminated MgB2, B-terminated MgB2 and MgO(001) surfaces. The close agreement between theory and experiment for the Mg-terminated surface suggested that the magnesium termination is the dominant surface phase of MgB2. Thus, combining inverse gas chromatography experiments with theoretical calculations may provide information about the surface termination.

Unusual Closure of the Ten-Vertex Nido Cage via Alkylation: Regiospecific Synthesis of 3-Alkyl Derivatives of closo-1,2-C2B8H10.

Alkylation of the [nido-5,6-R12C2B8H9]- anions (where R1 = H and Me) with alkyl halides (RX, where R = primary and secondary alkyls) in boiling tetrahydrofuran (THF) proceeds via unusual H2 elimination, followed by cage closure to give a series of the neutral closo-1,2-R12C2B8H7-3-R derivatives in ∼70-80% yields. In contrast, treatment of the unsubstituted [nido-5,6-C2B8H11]- anion with tert-butyl bromide (t-BuBr) led to the formation of the parent closo-1,2-C2B8H10 in >85% yield. The constitution of all compounds isolated has been confirmed unambiguously by multinuclear (11B, 1H, and 13C) nuclear magnetic resonance measurements and α-shift correlation assessments.

Quantitative Assessment of Substitution NMR Effects in the Model Series of o-Carborane Derivatives: α-Shift Correlation Method.

The principles of a new α-shift correlation (ASC) NMR method are demonstrated on a model series of substituted derivatives of o-carborane for which reliable NMR data are available. This graphical method revealed an acceptable linear correlation between α(11B) or α(13C) shifts and those induced by substituents in unsubstituted (u) positions of the carborane cluster. The linearity holds for all nuclei involved in skeletal bonding: Δδ(N)u = g × α (where N = 11B, 13C, and 1H). The factor g (slope of the correlation line × 102) becomes an important measure of sensitivity of a given cage position to substituent changes. The ß, γ, and δ = A (= antipodal) shifts can be therefore derived from the α-shift, are linearly proportional, and reflect additive character in double substitution. The ASC method appears to be an important tool for quantitative assessment of substituent NMR effects in all exo-substituted boron-cluster systems.

Electrophilic Halogenation of closo-1,2-C2B8H10.

Initial studies on electrophilic halogenation of the dicarbaborane closo-1,2-C2B8H10 (1) have been carried out to reveal that the substitution takes place at B7 and B10 vertexes, which are the most removed from the CH positions. The course of the halogenation is strongly dependent on the nature of the halogenation agent and reaction conditions. Individual reactions led to the isolation of the monosubstituted compounds 1,2-C2B8H9-10-X (2) (where X = F, I) and 1,2-C2B8H9-7-X (3) (where X = Cl, I). Disubstituted carboranes 1,2-C2B8H8-7,10-X2 (4) (where X = Cl, Br, I) were obtained under more forcing conditions. Individual halo derivatives were characterized by mass spectrometry and high-field NMR (11B, 1H,13C) spectroscopy combined with two-dimensional [11B-11B]-COSY, 1H{11B(selective)}, and [11B-1H]-correlation NMR techniques. All of the derivatives bearing a halogen substituent in the B10 position exhibit a remarkable antipodal 13C and 1H NMR shielding at the CH1 vertex, increasing in the order H < I < Br < Cl < F. The structures of 1,2-C2B8H8-7,10-X2 derivatives (where X = Cl, I, 4b,d) were established by X-ray diffraction analyses.

Unusual Cage Rearrangements in 10-Vertex nido-5,6-Dicarbaborane Derivatives: An Interplay between Theory and Experiment.

The reaction between selected X-nido-5,6-C2B8H11 compounds (where X = Cl, Br, I) and "Proton Sponge" [PS; 1,8-bis(dimethylamino)naphthalene], followed by acidification, results in extensive rearrangement of all cage vertices. Specifically, deprotonation of 7-X-5,6-C2B8H11 compounds with one equivalent of PS in hexane or CH2Cl2 at ambient temperature led to a 7 → 10 halogen rearrangement, forming a series of PSH+[10-X-5,6-C2B8H10]- salts. Reprotonation using concentrated H2SO4 in CH2Cl2 generates a series of neutral carbaboranes 10-X-5,6-C2B8H11, with the overall 7 → 10 conversion being 75%, 95%, and 100% for X = Cl, Br, and I, respectively. Under similar conditions, 4-Cl-5,6-C2B8H11 gave ∼66% conversion to 3-Cl-5,6-C2B8H11. Since these rearrangements could not be rationalized using the B-vertex swing mechanism, new cage rearrangement mechanisms, which are substantiated using DFT calculations, have been proposed. Experimental 11B NMR chemical shifts are well reproduced by the computations; as expected δ(11B) for B(10) atoms in derivatives with X = Br and I are heavily affected by spin-orbit coupling.