Towards the Application of Purely Inorganic Icosahedral Boron Clusters in Emerging Nanomedicine.

Traditionally, drugs were obtained by extraction from medicinal plants, but more recently also by organic synthesis. Today, medicinal chemistry continues to focus on organic compounds and the majority of commercially available drugs are organic molecules, which can incorporate nitrogen, oxygen, and halogens, as well as carbon and hydrogen. Aromatic organic compounds that play important roles in biochemistry find numerous applications ranging from drug delivery to nanotechnology or biomarkers. We achieved a major accomplishment by demonstrating experimentally/theoretically that boranes, carboranes, as well as metallabis(dicarbollides), exhibit global 3D aromaticity. Based on the stability-aromaticity relationship, as well as on the progress made in the synthesis of derivatized clusters, we have opened up new applications of boron icosahedral clusters as key components in the field of novel healthcare materials. In this brief review, we present the results obtained at the Laboratory of Inorganic Materials and Catalysis (LMI) of the Institut de Ciència de Materials de Barcelona (ICMAB-CSIC) with icosahedral boron clusters. These 3D geometric shape clusters, the semi-metallic nature of boron and the presence of exo-cluster hydrogen atoms that can interact with biomolecules through non-covalent hydrogen and dihydrogen bonds, play a key role in endowing these compounds with unique properties in largely unexplored (bio)materials.

Water-Stable Carborane-Based Eu3+/Tb3+ Metal-Organic Frameworks for Tunable Time-Dependent Emission Color and Their Application in Anticounterfeiting Bar-Coding.

Luminescent lanthanide metal-organic frameworks (Ln-MOFs) have been shown to exhibit relevant optical properties of interest for practical applications, though their implementation still remains a challenge. To be suitable for practical applications, Ln-MOFs must be not only water stable but also printable, easy to prepare, and produced in high yields. Herein, we design and synthesize a series of m CB-Eu y Tb 1-y (y = 0-1) MOFs using a highly hydrophobic ligand mCBL1: 1,7-di(4-carboxyphenyl)-1,7-dicarba-closo-dodecaborane. The new materials are stable in water and at high temperature. Tunable emission from green to red, energy transfer (ET) from Tb3+ to Eu3+, and time-dependent emission of the series of mixed-metal m CB-Eu y Tb 1-y MOFs are reported. An outstanding increase in the quantum yield (QY) of 239% of mCB-Eu (20.5%) in the mixed mCB-Eu0.1Tb0.9 (69.2%) is achieved, along with an increased and tunable lifetime luminescence (from about 0.5 to 10 000 µs), all of these promoted by a highly effective ET process. The observed time-dependent emission (and color), in addition to the high QY, provides a simple method for designing high-security anticounterfeiting materials. We report a convenient method to prepare mixed-metal Eu/Tb coordination polymers (CPs) that are printable from water inks for potential applications, among which anticounterfeiting and bar-coding have been selected as a proof-of-concept.

o-Carborane-based fluorophores as efficient luminescent systems both as solids and as water-dispersible nanoparticles.

A set of o-carborane-appended π-conjugated fluorophores and their light-emitting properties in the solid state are reported. The aggregation-induced emission enhancement (AIEE) exhibited for one of the fluorenyl derivatives paved the way to successfully preparing o-carborane-containing organic nanoparticles (NPs) homogeneously dispersed in aqueous media that maintain their luminescence properties. Notably, NPs processed as thin films also show high fluorescence efficiency, suggesting potential optical and optoelectronic applications.

Ru(ii) and Ir(iii) phenanthroline-based photosensitisers bearing o-carborane: PDT agents with boron carriers for potential BNCT.

Four novel transition metal-carborane photosensitisers were prepared by Sonogashira cross-coupling of 1-(4-ethynylbenzyl)-2-methyl-o-carborane (A-CB) with halogenated Ru(ii)- or Ir(iii)-phenanthroline complexes. The resulting boron-rich complexes with one (RuCB and IrCB) or two carborane cages (RuCB2 and IrCB2) were spectroscopically characterised, and their photophysical properties investigated. RuCB displayed the most attractive photophysical properties in solution (λem 635 nm, τT 2.53 µs, and φp 20.4%). Nanosecond time-resolved transient absorption studies were used to explore the 3MLCT nature of the triplet excited states, and the highest singlet oxygen quantum yields (ΦΔ) were obtained for the mono-carborane-phenanthroline complexes (RuCB: 52% and IrCB: 25%). None of the complexes produce dark toxicity in SKBR-3 cells after incubation under photodynamic therapy (PDT) conditions. Remarkably, mono-carboranes RuCB and IrCB were the best internalised by the SKBR-3 cells, demonstrating the first examples of tris-bidentate transition metal-carborane complexes acting as triplet photosensitisers for PDT with a high photoactivity; RuCB or IrCB killed ∼50% of SKBR-3 cells at 10 µM after irradiation. Therefore, the high-boron content and the photoactive properties of these photosensitisers make them potential candidates as dual anti-cancer agents for PDT and Boron Neutron Capture Therapy (BNCT).

Reversibly Switchable Fluorescent Molecular Systems Based on Metallacarborane-Perylenediimide Conjugates.

Icosahedral metallacarboranes are θ-shaped anionic molecules in which two icosahedra share one vertex that is a metal center. The most remarkable of these compounds is the anionic cobalt-based metallacarborane [Co(C2 B9 H11 )2 ]- , whose oxidation-reduction processes occur via an outer sphere electron process. This, along with its low density negative charge, makes [Co(C2 B9 H11 )2 ]- very appealing to participate in electron-transfer processes. In this work, [Co(C2 B9 H11 )2 ]- is tethered to a perylenediimide dye to produce the first examples of switchable luminescent molecules and materials based on metallacarboranes. In particular, the electronic communication of [Co(C2 B9 H11 )2 ]- with the appended chromophore unit in these compounds can be regulated upon application of redox stimuli, which allows the reversible modulation of the emitted fluorescence. As such, they behave as electrochemically-controlled fluorescent molecular switches in solution, which surpass the performance of previous systems based on conjugates of perylendiimides with ferrocene. Remarkably, they can form gels by treatment with appropriate mixtures of organic solvents, which result from the self-assembly of the cobaltabisdicarbollide-perylendiimide conjugates into 1D nanostructures. The interplay between dye π-stacking and metallacarborane electronic and steric interactions ultimately governs the supramolecular arrangement in these materials, which for one of the compounds prepared allows preserving the luminescent behavior in the gel state.

Tuning the Cell Uptake and Subcellular Distribution in BODIPY-Carboranyl Dyads: An Experimental and Theoretical Study.

A set of BODIPY-carboranyl dyads synthesized by a Sonogashira cross-coupling reaction, where different C-substituted ortho- and meta-carboranyl fragments have been linked to a BODIPY fluorophore is described. Chemical, photophysical and physicochemical analyses are presented, including NMR and single XRD experiments, optical absorption/emission studies and partition coefficient (log P) measurements. These studies, supported by DFT computations (M06-2X/6-31G**), provide an explanation to the largely divergent cell income that these fluorescent carboranyl-based fluorophores display, for which a structural or physicochemical explanation remains elusive. By studying the cell uptake efficiency and subcellular localization for our set of dyads on living HeLa cells, we tracked the origins of these differences to significant variations in their static dipole moments and partition coefficients, which tune their ability to interact with lipophilic microenvironments in cells. Remarkably, m-carboranyl-BODIPY derivatives with a higher lipophilicity are much better internalised by cells than their homologous with o-carborane, suggesting that m-isomers are potentially better theranostic agents for in vitro bioimaging and boron carriers for boron neutron capture therapy.

Blue Emitting Star-Shaped and Octasilsesquioxane-Based Polyanions Bearing Boron Clusters. Photophysical and Thermal Properties.

High boron content systems were prepared by the peripheral functionalisation of 1,3,5-triphenylbenzene (TPB) and octavinylsilsesquioxane (OVS) with two different anionic boron clusters: closo-dodecaborate (B12) and cobaltabisdicarbollide (COSAN). TPB was successfully decorated with three cluster units by an oxonium ring-opening reaction, while OVS was bonded to eight clusters by catalysed metathesis cross-coupling. The resulting compounds were spectroscopically characterised, and their solution-state photophysical properties analysed. For TPB, the presence of COSAN dramatically quenches the fluorescence emission (λem = 369 nm; ΦF = 0.8%), while B12-substituted TPB shows an appreciable emission efficiency (λem = 394 nm; ΦF = 12.8%). For octasilsesquioxanes, the presence of either COSAN or B12 seems to be responsible for ∼80 nm bathochromic shift with respect to the core emission, but both cases show low emission fluorescence (ΦF = 1.4-1.8%). In addition, a remarkable improvement of the thermal stability of OVS was observed after its functionalisation with these boron clusters.

Efficient blue light emitting materials based on m-carborane-anthracene dyads. Structure, photophysics and bioimaging studies.

Efficient monosubstitution of the non-iodinated, mono-iodinated and di-iodinated m-carborane cluster at one Ccluster has led to the preparation of three single organic molecule-carborane dyads (4-6), which exhibited exceptional fluorescence properties with quantum yield values of 100% in solution, for all of them, with maxima around 415 nm, which correspond to the locally excited state (LE) emission. These results suggest that simply linking the m-carborane fragment to one anthracene unit through a CH2 spacer produces a significant enhancement of the fluorescence in the final fluorophore, probably due to the free rotation of the anthracene linked to the Ccluster. Besides, the presence of one or two iodine atoms linked to boron atoms does not cause any influence on the photophysical properties of the dyads, as it is confirmed by TD-DFT calculations. Notably, the three conjugates show good fluorescence efficiency in the aggregate state with quantum yields in the range of 19-23%, which could be ascribed to the presence of CH2, particularly for 4, and the iodine atoms in 5 and 6, which prevent π-π stacking. All these results indicate that our dyads are extremely good emitters in solution while maintaining the emission properties in the aggregate state. Crystal packing, fingerprint plot analysis, and TD-DFT calculations for the three compounds support these results. Confocal microscopy studies show that 6 is the best-internalized compound by HeLa cells via endocytosis, although 4 and 5 also presented a high fluorescence intensity emission. Moreover, due to the blue emission, this compound is an excellent candidate to be applied as a fluorescent dye in bioimaging studies.

Periphery Decorated and Core Initiated Neutral and Polyanionic Borane Large Molecules: Forthcoming and Promising Properties for Medicinal Applications.

A mini-review based on radial growing macromolecules and core initiated Borane periphery decorated with o-carboranes and metallacarboranes that has been developed in the authors laboratories is reported. The review is divided into four sections; three of them are related to the design and synthesis of these large boron-containing molecules and the fourth deals with the unique properties of anionic metallacarborane molecules that provide a glimpse of their potential for their promising use in medicinal applications. Their unique stability along with their geometrical and electronic properties, as well as the precise steric structure of 1,2-closo-C2B10H12 (o-carborane) that has the potential for the incorporation of many substituents: at the carbon (Cc), at the boron and at both carbon and boron vertices, suggests this cluster as an innovative building block or platform for novel applications that cannot be achieved with organic hydrocarbon compounds. Poly(aryl-ether) dendrimers grown from fluorescent cores, such as 1,3,5-triarylbenzene or meso-porphyrins, have been decorated with boron clusters to attain rich boron containing dendrimers. Octasilsesquioxane cubes have been used as a core for its radial growth to get boron-rich large molecules. The unique properties of cobaltabisdicarbollide cluster, which include: i) self-assembly in water to produce monolayer nano-vesicles, ii) crossing lipid bilayer membranes, iii) interacting with membrane cells, iv) facilitating its visualization within cells by Raman and fluorescence techniques and v) their use as molecular platform for "in vivo" imaging are discussed in detail.

Carborane-BODIPY Dyads: New Photoluminescent Materials through an Efficient Heck Coupling.

A small library of carborane-BODIPY/aza-BODIPY dyads were efficiently synthesized by means of a novel convergent synthetic approach, the key step of which is a Pd-catalyzed Heck coupling reaction. The structural characterization and photoluminescence properties of the newly synthesized dyads were evaluated. The presence of the carborane did not significantly alter the photophysical patterns of the BODIPY or aza-BODIPY in the final fluorophores, but it produced a decrease of the emission fluorescent quantum yields that was in the range from 1.4 % for aza-BODIPY to 48 % for BODIPY-dyads. The carborane-BODIPY dyads were successfully incorporated into cells, especially compounds 2, 4 and 13, demonstrating their cytoplasmic localization. The fluorescent and biocompatibility properties make these compounds good candidates for in vitro cell tracking.

Fluorescent BODIPY-Anionic Boron Cluster Conjugates as Potential Agents for Cell Tracking.

A series of novel fluorescent BODIPY-anionic boron cluster conjugates bearing [B12H12]2- (5, 6), [3,3'-Co(1,2-C2B9H11)2]- (7, 8), and [3,3'-Fe(1,2-C2B9H11)2]- (9) anions have been readily synthesized from meso-(4-hydroxyphenyl)-4,4-difluoro-4-bora-3 a,4 a-diaza- s-indacene (BODIPY 4), and their structure and photoluminescence properties have been assessed. Linking anionic boron clusters to the BODIPY (4) does not alter significantly the luminescent properties of the final fluorophores, showing all of them similar emission fluorescent quantum yields (3-6%). Moreover, the cytotoxicity and cellular uptake of compounds 5-9 have been analyzed in vitro at different concentrations of B (5, 50, and 100 µg B/mL) using HeLa cells. At the lowest concentration, none of the compounds shows cytotoxicity and they are successfully internalized by the cells, especially compounds 7 and 8, which exhibit a strong cytoplasmic stain indicating an excellent internalization efficiency. To the best of our knowledge, these are the first BODIPY-anionic boron cluster conjugates developed as fluorescent dyes aiming at prospective biomedical applications. Furthermore, the cellular permeability of the starting BODIPY (4) was improved after the functionalization with boron clusters. The exceptional cellular uptake and intracellular boron release, together with the fluorescent and biocompatibility properties, make compounds 7 and 8 good candidates for in vitro cell tracking.

Organotin Dyes Bearing Anionic Boron Clusters as Cell-Staining Fluorescent Probes.

Within the cell nucleus, in the nucleoli, ribosomal RNAs are synthesized and participate in several biological processes. To better understand nucleoli-related processes, their visualization is often required, for which specific markers are needed. Herein, we report the design of novel fluorescent organotin compounds derived from 4-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide and their cytoplasm and nucleoli staining of B16F10 cells in vitro. Tin compounds bearing an aliphatic carbon chain (-C12 H25 ) and an electron-donating group (-OH) were prepared, and the latter could be derivatized to bear the boron cluster anions [B12 H12 ]2- and [3,3'-Co(1,2-C2 B9 H11 )2 ]- (COSAN). All of the conjugates have been fully characterized and their luminescence properties have been assessed. In general, they show good quantum yields in solution (24-49 %), those for the COSAN derivatives being lower. Remarkably, the linking of [B12 H12 ]2- and COSAN to the complexes made them more soluble, without being detrimental to their luminescence properties. Living B16F10 cells were treated with all of the compounds to determine their fluorescence staining properties; the compounds bearing the aliphatic chain showed a reduced staining capacity due to the formation of aggregates. Notably, the complexes bearing different boron clusters showed different staining effects; those bearing [B12 H12 ]2- showed extraordinary staining of the nucleoli and cytoplasm, whereas those bearing COSAN were only detected in the cytoplasm. The remarkable fluorescence staining properties shown by these organotin compounds make them excellent candidates for fluorescence bioimaging in vitro.

Monolayer Contact Doping from a Silicon Oxide Source Substrate.

Monolayer contact doping (MLCD) is a modification of the monolayer doping (MLD) technique that involves monolayer formation of a dopant-containing adsorbate on a source substrate. This source substrate is subsequently brought into contact with the target substrate, upon which the dopant is driven into the target substrate by thermal annealing. Here, we report a modified MLCD process, in which we replace the commonly used Si source substrate by a thermally oxidized substrate with a 100 nm thick silicon oxide layer, functionalized with a monolayer of a dopant-containing silane. The thermal oxide potentially provides a better capping effect and effectively prevents the dopants from diffusing back into the source substrate. The use of easily accessible and processable silane monolayers provides access to a general and modifiable process for the introduction of dopants on the source substrate. As a proof of concept, a boron-rich carboranyl-alkoxysilane was used here to construct the monolayer that delivers the dopant, to boost the doping level in the target substrate. X-ray photoelectron spectroscopy (XPS) showed a successful grafting of the dopant adsorbate onto the SiO2 surface. The achieved doping levels after thermal annealing were similar to the doping levels acessible by MLD as demonstrated by secondary ion mass spectrometry measurements. The method shows good prospects, e.g. for use in the doping of Si nanostructures.

Electrochemistry and Photoluminescence of Icosahedral Carboranes, Boranes, Metallacarboranes, and Their Derivatives.

Icosahedral boranes, carboranes, and metallacarboranes are extraordinarily robust compounds with desirable properties such as thermal and redox stability, chemical inertness, low nucleophilicity, and high hydrophobicity, making them attractive for several applications such as medicine, nanomaterials, molecular electronics, energy, catalysis, environmental chemistry, and other areas. The hydrogen atoms in these clusters can be replaced by convenient groups that open the way to a chemical alternative to conventional "organic" or "organometallic" realms. Icosahedral boron cluster derivatives have been reviewed from different perspectives; however, there is a need for a review dedicated to the redox and photophysical characteristics of easily accessible borane and carborane derivatives, which are excellent materials for a wide range of applications. This review deals with the redox properties and photoluminescence behavior of this collection of compounds, as well as their influence on the properties of materials and devices whose working principles are related to electron-transfer or electron-promotion phenomena. We hope that this review will be of great value to boron cluster scientists and researchers working in the photoluminescence and electrochemistry fields who are interested in exploring the possibilities of these unique and promising systems.

Redox-Active Metallacarborane-Decorated Octasilsesquioxanes. Electrochemical and Thermal Properties.

Polyanionic and electroactive hybrids based on octasilsesquioxanes bearing metallacarborane units are developed. They show remarkable solubility in organic solvents and outstanding thermal stability. The metallacarboranes act as independent units simultaneously undergoing the reversible redox process.

Photoluminescence in Carborane-Stilbene Triads: A Structural, Spectroscopic, and Computational Study.

A set of triads in which o- and m-carborane clusters are bonded to two stilbene units through Ccluster -CH2 bonds was synthesized, and their structures were confirmed by X-ray diffraction. A study on the influence of the o- and m- isomers on the absorption and photoluminescence properties of the stilbene units in solution revealed no charge-transfer contributions in the lowest excited state, as confirmed by (TD)DFT calculations. The presence of one or two B-I groups in m-carborane derivatives does not affect the emission properties of the stilbenes in solution, probably due to the rather large distance between the iodo substituents and the fluorophore. Nevertheless, a significant redshift of the photoluminescence (PL) emission maximum in the solid state (thin films and powder samples) compared to solution was observed; this can be traced back to PL sensitization, most probably due to more densely packed stilbene moieties. Remarkably, the PL absolute quantum yields of powder samples are significantly higher than those in solution, and this was attributed to the restricted environment and the aforementioned sensitization. Thus, the bonding of the carborane clusters to two stilbene units preserves their PL behavior in solution, but produces significant changes in the solid state. Furthermore, iodinated species can be considered to be promising precursors for theranostic agents in which both imaging and therapeutic functions could possibly be combined.

Highly Dispersible and Stable Anionic Boron Cluster-Graphene Oxide Nanohybrids.

An efficient process to produce boron cluster-graphene oxide nanohybrids that are highly dispersible in water and organic solvents is established for the first time. Dispersions of these nanohybrid materials in water were extraordinarily stable after one month. Characterization of hybrids after grafting of appropriate cobaltabisdicarbollide and closo-dodecaborate derivatives onto the surface of graphene oxide (GO) was done by FT-IR, XPS, and UV/Vis. Thermogravimetric analysis (TGA) clearly shows a higher thermal stability for the modified-GO nanohybrids compared to the parent GO. Of particular note, elemental mapping by energy-filtered transmission electron microscopy (EFTEM) reveals that a uniform decoration of the graphene oxide surface with the boron clusters is achieved under the reported conditions. Therefore, the resulting nanohybrid systems show exceptional physico-chemical and thermal properties, paving the way for an enhanced processability and further expanding the range of application for graphene-based materials.

Boosting the Boron Dopant Level in Monolayer Doping by Carboranes.

Monolayer doping (MLD) presents an alternative method to achieve silicon doping without causing crystal damage, and it has the capability of ultrashallow doping and the doping of nonplanar surfaces. MLD utilizes dopant-containing alkene molecules that form a monolayer on the silicon surface using the well-established hydrosilylation process. Here, we demonstrate that MLD can be extended to high doping levels by designing alkenes with a high content of dopant atoms. Concretely, carborane derivatives, which have 10 B atoms per molecule, were functionalized with an alkene group. MLD using a monolayer of such a derivative yielded up to ten times higher doping levels, as measured by X-ray photoelectron spectroscopy and dynamic secondary mass spectroscopy, compared to an alkene with a single B atom. Sheet resistance measurements showed comparably increased conductivities of the Si substrates. Thermal budget analyses indicate that the doping level can be further optimized by changing the annealing conditions.

Efficient Chemical Modification of Carbon Nanotubes with Metallacarboranes.

As-produced single-walled carbon nanotubes (SWCNTs) tend to aggregate in bundles due to π-π interactions. Several approaches are nowadays available to debundle, at least partially, the nanotubes through surface modification by both covalent and noncovalent approaches. Herein, we explore different strategies to afford an efficient covalent functionalization of SWCNTs with cobaltabisdicarbollide anions. Aberration-corrected HRTEM analysis reveals the presence of metallacarboranes along the walls of the SWCNTs. This new family of materials presents an outstanding water dispersibility that facilitates its processability for potential applications.

High-boron-content porphyrin-cored aryl ether dendrimers: controlled synthesis, characterization, and photophysical properties.

The synthesis and characterization of a set of poly(aryl ether) dendrimers with tetraphenylporphyrin as the core and 4, 8, 16, or 32 closo-carborane clusters are described. A regioselective hydrosilylation reaction on the allyl-terminated functions with carboranylsilanes in the presence of Karstedt's catalyst leads to different generations of boron-enriched dendrimers. This versatile approach allows the incorporation of a large number of boron atoms in the dendrimers' periphery. Translational diffusion coefficients (D) determined by DOSY NMR experiments permit estimation of the hydrodynamic radius (RH) and molecular size for each dendrimer. Furthermore, a notable correlation between D and the molecular weight (MW) is found and can be used to predict their overall size and folding properties. The UV-vis and emission behavior are not largely affected by the functionalization, therefore implying that the presence of carboranes does not alter their photoluminescence properties.