Advancements in thermal neutron generation technologies within clinical environments have led to a renewed interest in developing boron-containing compounds for boron neutron capture therapy (BNCT). Previous syntheses of several key boron cluster-based therapeutics with clinical relevance are low-yielding and have complicated workup procedures. Using electrolytic methods, we report the in situ oxidation of pseudohalides, [SCN]- and [SeCN]-, to synthesize pseudohalogenated products, B12H11YCN2- (Y = S or Se). Further, these compounds can be reduced to their respective thiol or selenol, [B12H11SH]2- (BSH) or [B12H11SeH]2- (BSeH), which are exceedingly nucleophilic and able to form zwitterionic sulfonium and selenonium compounds using alkyl-based electrophiles. The newly reported preparation of BSH and BSeH provides an efficient and convenient route to the preparation of key chalcogenated boron cluster building blocks for the biomedical and materials science communities.

Functionalization of carboranes, icosahedral boron-carbon molecular clusters, is of great interest as they have wide applications in medicinal and materials chemistry. Thus, site- and enantioselective synthesis of carboranes requires complete control of the reaction. Herein, we describe the asymmetric Rh(II)-catalyzed insertion reactions of carbenes into cage B-H bond of carboranes. This reaction thereby generates carboranes possessing a carbon-stereocenter adjacent to cage boron of the carborane, in excellent site- and enantioselectivity under mild reaction conditions. The fully computed transition structures of Rh(II)-catalyzed carbene insertion process through density functional theory are reported. These B-H insertion transition structures, in conjunction with topographical proximity surfaces analyses, visually reveal the region between the carborane and the phthalimide ligands responsible for the selectivities of this reaction.

Despite significant progress in the B-H functionalization of carboranes, the development of cost-effective catalytic systems devoid of noble metals, coupled with mechanistic validation of regioselectivity control, remains a formidable challenge. Herein, we disclose an Ag salt-free, redox-neutral, and inexpensive ruthenium(ii)-catalyzed protocol that enables exclusive B(4)-H acylmethylation of o-carboranes through a novel post-coordination strategy. By exploiting weakly coordinating carboxylic acid as a traceless directing group, this method achieves excellent mono-site selectivity for B-C(sp3) bond formation using diverse sulfoxonium ylides, demonstrating both functional group tolerance and synthetic scalability. This work not only establishes a practical synthetic platform but also addresses critical mechanistic questions unresolved in prior analogous studies. Through deuterium labeling, in situ high-resolution mass spectrometry (HRMS) tracking, and single-crystal X-ray analysis of critical Ru intermediates, we unequivocally demonstrate that the mono-site selectivity originates from a unique post-coordination mode of Ru(ii). The Ru catalyst simultaneously engages both the carboxylic acid and the enolizable acylmethyl moiety in the mono-acylated intermediate, thereby dictating the B(4)-H activation trajectory. Our findings establish a generalizable platform for regiocontrolled carborane functionalization while defining mechanistic paradigms in transition metal-mediated B-H activation chemistry.

Synthetic methods that feature mild reaction conditions and broad functional group tolerance are highly desired for the development of third-generation boron delivery agents, which are highly significant for boron neutron capture therapy (BNCT), a selective cancer treatment technique. Molecules containing carborane are promising candidates as boron delivery compounds for BNCT. Herein, we report an efficient radical thiol-ene "click" reaction involving carboranyl thiols and unactivated alkenes under photoredox conditions. This reaction affords moderate to excellent isolated yields. The current methodology allows for the incorporation of carborane, a valuable moiety with a high boron content, into molecules under mild reaction conditions. The outstanding functional group tolerance of this method makes it suitable for the late-stage introduction of boron into bioactive molecules. The radical addition reactivity of carboranyl thiol radical was investigated by DFT calculations to uncover the impact of the 3D aromaticity of carborane on the stabilization of a sulfur centered radical.

The selective functionalization of inert B-H bonds in carborane clusters has been a formidable challenge. Recent advances have witnessed such reactions through photoredox methods utilizing ultraviolet or visible light irradiation. However, high-energy light sources often suffer from poor energy efficiency, a limited substrate scope, undesired side reactions, and low scalability. Here, we present the first successful B-H bond functionalization under low-energy near-infrared (NIR) light using a carborane-based electron donor-acceptor complex. Both photophysical investigations and theoretical modeling reveal a facile single-electron transfer from the carborane cage to the electron-deficient photocatalyst, generating a carborane cage radical under NIR light irradiation. The follow-up radical pathway enables the direct coupling of carboranes with amino acids or oligopeptides, yielding a diverse array of carborane-functionalized amino acids or oligopeptides. Beyond expanding the known chemical space of boron cluster derivatives, we further demonstrate that carborane-based amino acids with imaging and targeting capabilities could serve as promising multifunctional boron carriers for boron neutron capture therapy. Thus, the selective B-H bond functionalization of the carboranes via NIR light not only provides a straightforward and practical strategy in boron cluster synthetic chemistry but also lays the foundation for the development of next-generation boron-containing biomolecules and advanced functional materials.

Highly regioselective B(12) substitutions of the monocarborane anion [CB11H12]- has been a challenge. Here, we synthesized a stable B-O-N zwitterionic compound with an impressive yield (isolated yield up to 98%) and excellent regioselectivity at the B(12) position under catalyst-free conditions. The kinetics, substituent effect, and capture experiments are paired with theoretical calculations, showing that the reaction mechanism is oxidation-induced nucleophilic substitution. The hydride anion at the B(12) position is abstracted by an oxoammonium oxidant with lower cleavage energy of 4.2 kcal mol-1 than B(7-11) positions, thereby changing the electronegativity upon the conversion of [CB11H12]- to neutral [CB11H11], in turn giving very high regioselectivity for nucleophilic substitution. This work presents an effective method for synthesizing B(12) oxygen derivatives of the [CB11H12]- anion.

Transition metal catalyzed selective cage B-H functionalization of carboranes has made significant progress in recent years, giving rise to the efficient synthesis of a large variety of cage B-functionalized carboranes including alkenylation, arylation, alkynylation, borylation, hydroxylation, acyloxylation, amination, and halogenation. However, the mechanisms of these catalytic B-X coupling reactions are not well understood. Herein, we describe the isolation and characterization of the catalytically relevant o-carborane based palladium(II) metallacycle, disclosing the details of Pd-catalyzed B-H functionalization of o-carboranes. As a result, highly selective catalytic B(3,6)-dihalogenation, -dimethylation, and -diarylation of o-carboranes have been achieved.

An efficient palladium-catalyzed intramolecular annulation of 1-acylamino-o-carboranes has been achieved for the synthesis of o-carboranoxazoles with good to excellent yields across a wide range of substrates. Chlorobenzene, acting as an external oxidant, plays a crucial role in this intramolecular dehydrogenative cross-coupling reaction.

Uranium metallocenes have played a pivotal role in advancing the understanding of low-valent uranium chemistry since the inception of this field, and they still find continued use today. Functionalization strategies for cyclopentadienyl (Cp) ligands used in uranium metallocenes have predominately focused on modifying the steric properties of the ligand through the incorporation of alkyl or silyl groups, which offer limited control over the electronic properties. Moreover, due to the flat, two-dimensional nature of Cp, functional groups will affect the coordination geometry of the uranium metallocene and can potentially present challenges in decoupling steric and electronic effects. In comparison, uranium metallacarboranes, which are boron cluster-based metallocene analogues that feature three-dimensional dianionic dicarbollide (dc) ligands, present a versatile platform that is potentially capable of not only stabilizing the low-valent uranium center but also providing control over the electronic properties of the resulting complex without significantly modifying the coordination geometry through the incorporation of a diverse range of groups onto the dc ligand at vertices directed away from the uranium center. In this work, we synthesized a series of uranium metallacarboranes featuring B-functionalized dc ligands with increasingly electron withdrawing aryl groups. A combination of cyclic voltammetry and density functional theory studies confirms that this strategy offers predictable control over the electronic properties of the uranium center. More broadly, this work establishes uranium metallacarboranes as a highly tunable class of complexes potentially capable of unlocking new insights into low-valent uranium chemistry.

Selective functionalization of o-carboranes has received tremendous attention, specifically in the regioselective modification of the ten chemically similar BH vertices within o-carborane cage. We disclose herein a strategy for palladium-catalyzed esterification of the B(3)-H bond in o-carboranes using tungsten hexacarbonyl as a carbon monoxide source. The corresponding functionalized o-carboranes were prepared in moderate to very good yields with excellent regioselectivity.

A new series of o-carborane-fused pyrazoles has been recently successfully synthesized. This fusion was expected to create a hybrid 3D/2D aromatic system, combining the 3D aromaticity of o-carborane with the 2D aromaticity of pyrazole. However, while the boron cage retains its aromatic character, the pyrazole's aromaticity is lost. As a result, rather than forming o-carborane-fused pyrazoles, the synthesis yielded o-carborane-fused pyrazolines, which are non-aromatic. The limited overlap between the π molecular orbitals (MOs) of the planar heterocycle and the n + 1 MOs of the carborane prevents significant electronic delocalization between the two fused components. This contrasts with the fusion of pyrazole and benzene to form indazole, where both rings maintain their 2D aromaticity. Our findings demonstrate that the peripheral σ-aromaticity of carborane and the π-aromaticity of the heterocycle are orthogonal, making a true 3D/2D aromatic system unachievable. The carborane is highly aromatic, generating highly negative NICS values (-25 to -30 ppm). We have observed that these high NICS values extend to fused rings, leading to incorrect estimations of aromaticity. Therefore, relying solely on NICS can be misleading, and other computational indicators, along with experimental or structural data, should be used to accurately assess aromaticity.

Carboranyl amines are distinct from typical organic amines. Due to the electronic influence of the carborane cage, they have low nucleophilicity and are reluctant to alkylate. Moreover, asymmetric synthesis of chiral carboranes is still in its infancy. Herein we have achieved the first catalytic asymmetric N-alkylation of o-carboranyl amine, providing general access to diverse secondary o-carboranyl amines with high efficiency and enantioselectivity under mild conditions. For the first time, asymmetric organocatalysis was introduced to carborane chemistry. Key to the success is the use of in situ generated (naphtho-)quinone methides as the alkylating reagents and suitable chiral acid catalysts. This protocol is also applicable to the asymmetric S-alkylation of 1-SH-o-C2B10H11. Control experiments and kinetic studies provided important insights into the reaction mechanism, which likely involves rate-determining generation of the quinone methide followed by fast and enantio-determining nucleophilic addition.

Metal migration strategy can offer BH functionalization of o-carboranes at different positions from where initial bond activation occurs to achieve bifunctionalized o-carboranes in one reaction. We report in this article an enantioselective 3,4-bifunctionalization of o-carboranes via asymmetric Pd migration with a high efficiency and up to 98 % ee. This asymmetric catalysis has a broad substrates scope, leading to the preparation of a class of chiral-at-cage o-carborane derivatives. The enantiocontrol model is suggested on the basis of density functional theory (DFT) results, where the chiral Trost ligand plays a crucial role in this enantioselective Pd migration from exo-alkenyl sp2 C to the cage B(4) position of o-carborane.

Rh(III)-catalyzed B(4)-azo coupling reactions of o-carborane acids with aryl diazonium tetrafluoroborates have been developed, leading to the regioselective formation of B(4)-azo-coupled o-carboranes. Moreover, B(4)-azo-coupled o-carboranes can be further functionalized by introducing a second azo group, producing B(4)-C(1)-di(arylazo) o-carborane. The B(4)-azo group as an efficient directing group enables catalytic C-H amidation reactions, providing a new synthetic route for complex o-carborane derivatives.

Boranes with closed polyhedral structures feature peculiar bonding and structural characteristics, rendering them widely applicable in diverse research areas ranging from basic functionalization reactions to applications such as medicine, nanomaterials, molecular electronics, and neutron capture therapy. Among the closed borane family, the neutral and cationic heptaborane B7 clusters have been missing in contemporary boron cluster chemistry to date. Herein, we report a polyhedral expansion protocol to construct a neutral derivative of closo-heptaborane (B7) from closo-hexaborane (B6) mediated by borane. Conversion of the neutral derivative of closo-heptaborane to a cationic derivative is also demonstrated. X-ray crystallographic and spectroscopic analyses with the aid of quantum chemical calculations reveal that both neutral and cationic derivatives of closo-heptaborane exhibit a pentagonal-bipyramidal geometry and involve the delocalized σ skeletal electrons, leading to three-dimensional aromaticity. Moreover, the B7 core of the former undergoes a complexation reaction with silver tetrafluoroborate, representing the first experimental demonstration of the nucleophilic nature of the closo-heptaborane.

The innovation of synthetic strategies for selective B-H functionalization is a pivotal objective in the realm of boron cluster chemistry. However, the precise, efficient, and rapid functionalization of a B-H bond of carboranes that is distant from the existing functional groups remains intractable owing to the limited approaches for site-selective control from the established methods. Herein, we report a dative bonding activation strategy for the selective functionalization of a nonclassical remote B-H site of nido-carboranes. By leveraging the electronic effects brought by the exopolyhedral B(9)-dative bond, a cross-nucleophile B-H/S-H coupling protocol of the distal B(5)-H bond has been established. The dative bond not only amplifies the subtle reactivity difference among B-H bonds but also significantly changes the reactive sites, further infusing nido-carboranes with additional structural diversity. This reaction paradigm features mild conditions, rapid conversion, efficient production, broad scope, and excellent group tolerance, thus enabling the applicability to an array of complex bioactive molecules. The efficient and scalable reaction platform is amenable to the modular construction of photofunctional molecules and boron delivery agents for boron neutron capture therapy. This work not only provides an unprecedented solution for the selective diversification of distal B-H sites in nido-carboranes but also holds the potential for expediting the discovery of novel carborane-based functional molecules.

Heteropolycyclic molecular systems, which are essential components in the fields of materials and pharmacology, frequently consist of 2D extended organic aromatic rings. Here, we introduce a type of inorganic-organic hybrid 3D conjugates by merging an aromatic boron cluster with a phosphine and a π-conjugated unit. To achieve this, a couple-close synthetic strategy via B-H activation of nido-carboranes with alkynes has been developed, which leads to diverse boron cluster-extended phosphoniums in a twisted structure with high yields under mild conditions. Experimental and theoretical results reveal that the fusion between the boron cluster and the formed borophosphonium heterocycle facilitates electron delocalization throughout the structure. The unusual framework demonstrates distinct properties from bare boron clusters and pure aromatic ring-extended counterparts, such as improved thermal/chemical stability and photophysical properties. Thus, the boron cluster-based 3D conjugates expand the library of aromatic-based heterocyclics, showcasing great potential in functional materials.

Chemodynamic therapy (CDT) has received widespread attention as a tumor optical treatment strategy in the field of malignant tumor therapy. Nonmetallic multifunctional nanomaterials as CDT agents, due to their low toxicity, long-lasting effects, and safety characteristics, have promising applications in the integrated diagnosis and treatment of cancer. Here, we modified the supramolecular framework of boron clusters, coupled with a variety of dyes to develop a series of metal-free agent compounds, and demonstrated that these nonmetallic compounds have excellent CDT activities through experiments. Subsequently, the best performing Methylene Blue/[closo-B12H12]2- (MB@B12H12) was used as an example. Through theoretical calculations, electron paramagnetic resonance spectroscopy, and 808 nm light irradiation, we confirmed that MB@B12H12 exhibited photothermal performance and CDT activity further. More importantly, we applied MB@B12H12 to melanoma cells and subcutaneous tumor, demonstrating its effective suppression of melanoma growth in vitro and in vivo through the synergistic effects of photothermal performance and CDT activity. This study emphasizes the generalizability of the coupling of dyes to [closo-B12H12]2- with important clinical translational potential for CDT reagents. Among them, MB@B12H12 may have a brighter future, paving the way for the rapid development of metal-free CDT reagents.

The development of new synthetic methods for B-H bond activation has been an important research area in boron cluster chemistry, which may provide opportunities to broaden the application scope of boron clusters. Herein, we present a new reaction strategy for the direct site-selective B-H functionalization of nido-carboranes initiated by photoinduced cage activation via a noncovalent cage···π interaction. As a result, the nido-carborane cage radical is generated through a single electron transfer from the 3D nido-carborane cage to a 2D photocatalyst upon irradiation with green light. The resulting transient nido-carborane cage radical could be directly probed by an advanced time-resolved EPR technique. In air, the subsequent transformations of the active nido-carborane cage radical have led to efficient and selective B-N, B-S, and B-Se couplings in the presence of N-heterocycles, imines, thioethers, thioamides, and selenium ethers. This protocol also facilitates both the late-stage modification of drugs and the synthesis of nido-carborane-based drug candidates for boron neutron capture therapy (BNCT).

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

Picolyl group directed B(3,5)-dialkenylation and B(4)-monoalkenylation of o-carboranes has been developed with a very low palladium catalyst loading. The degree of substitution is determined by the cage C(2)-substituents due to steric reasons. On the basis of experimental results, a plausible mechanism is proposed including electrophilic palladation and alkyne insertion followed by protonation.

Cobaltabis(dicarbollides), ferrabis(dicarbollide), and their halogenated derivatives are the most studied metallacarboranes with great medical potential. These versatile compounds and their iodinated derivatives can be used in chemotherapy, radiotherapy, particle therapy, and bioimaging when isotopes are used. These metallacarboranes have been evaluated in vitro and recently in vivo with complex animal models. Lately, these studies have been complemented using the invertebrate Caenorhabditis elegans (C. elegans), a nematode largely used in toxicology. When evaluated at the L4 stage, cobaltabis(dicarbollides), ([o-COSAN]- and [8,8'-I2 -o-COSAN]- ), exhibited a higher mean lethal dose (LD50 ) than ferrabis(dicarbollides) ([o-FESAN]- and [8,8'-I2 -o-FESAN]- ). In this work, we used the C. elegans embryos since they are a complex biological barrier with concentric layers of polysaccharides and proteins that protect them from the environment. We assessed if the metal atom changes their biointeraction with the C. elegans embryos. First, we assessed the effects on embryo development for metallacarboranes and their di-iodinated derivatives. We observed changes in color and in their surface structure. An exhaustive physicochemical characterization was performed to understand better this interaction, revealing a stronger interaction of ferrabis(dicarbollide) compounds with C. elegans embryos than the cobaltabis(dicarbollide) molecules. Unveiling the biological interaction of these compounds is of great interest for their future biomedical applications.

A highly efficient Pd-catalyzed B(9)-H/B(9)-H oxidative dehydrogenation coupling of carboranes to synthesize 9,9'-bis-o-carboranes has been developed. The properties and derivatization of 9,9'-bis-o-carborane were also examined, which provided diverse bis-o-carborane derivatives and bis-nido-carborane.

Boron neutron capture therapy (BNCT) is a potential radiation therapy modality for cancer, and tumor-targeted stable boron-10 (10B) delivery agents are an important component of BNCT. Currently, two low-molecular-weight boron-containing compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) and boronophenylalanine (BPA), are mainly used in BNCT. Although both have suboptimal tumor selectivity, they have shown some therapeutic benefit in patients with high-grade glioma and several other tumors. To improve the efficacy of BNCT, great efforts have been devoted for the development of new boron delivery agents with better uptake and favorable pharmacokinetic profiles. This article reviews the application and research progress of boron nanomaterials as boron carriers in boron neutron capture therapy and hopes to stimulate people's interest in nanomaterial-based delivery agents by summarizing various kinds of boron nanomaterial patents disclosed in the past decade.

Ferrocene 1 and its dianionic Fe(bis)(dicarbollide) analogue 2 are classical compounds that display unusual stability. These compounds are not known to undergo transmetallation chemistry of the Fe-center and have been used extensively as chemical building blocks with consistent integrity. In this manuscript we describe the preparation of a charge compensated Fe(bis)(dicarbollide) species 3 Fe and its unprecedented transmetallation chemistry to Ir. Such reactions are hitherto unknown for any transition metal metallocene or metallacarborane complex. Additionally, we show that 3 Fe can be deprotonated to afford the corresponding bis(NHC) Li-carbenoid 5 that also displays unique reactivity. When 5 is reacted with [Ir(COD)Cl]2 it also undergoes a rapid transmetallation of the ferrocene "like" core to afford 6 but with the added twist that the Li-carbenoid moiety stays intact and does not transmetalate. However, when 6 is subsequently treated with CuCl, the Li-carbenoid transmetalates to Cu, which allows the controlled formation of the corresponding heterobimetallic Ir/Cu aggregate. Lastly, when Li-carbenoid 5 is treated directly with CuCl, a double transmetallation occurs from both Fe to Cu and Li-carbenoid to Cu, resulting in the trimetallic Cu cluster 8. These novel reactions pave the way for new synthetic methods to build complicated polymetallic clusters in a controlled fashion.

The utilization of carboranes in supramolecular chemistry has attracted considerable attention. The unique spatial configuration and weak interaction forces of carboranes can help to explore the properties of supramolecular complexes, particularly via host-guest chemistry. Additionally, certain difficulties encountered in carborane development─such as controlled B-H bond activation─can be overcome by judiciously selecting metal centers and their adjacent ligands. However, few studies are being conducted in this nascent research area. With advances in this field, novel carborane-based supramolecular complexes will likely be prepared, structurally characterized, and intrinsically investigated. To expedite these efforts, we present major findings from recent studies, including π-π interactions, host-guest associations, and steric effects, which have been leveraged to implement a regioselective process for activating B(2,9)-, B(2,8)-, and B(2,7)-H bonds of para-carboranes and B(4,7)-H bonds of ortho-carboranes. Future studies should clarify the unique weak interactions of carboranes and their potential for enhancing the utility of supramolecular complexes. Although carboranes exhibit several unique weak interactions (such as dihydrogen-bond [Bδ+-Hδ-···Hδ+-Cδ-], Bδ+-Hδ-···M+, and Bδ+-Hδ-···π interactions), the manner in which they can be utilized remains unclear. Supramolecular complexes, particularly those based on host-guest chemistry, can be utilized as a platform for demonstrating potential applications of these weak interactions. Owing to the importance of alkane separation, applications related to the recognition and separation of alkane isomers via dihydrogen-bond interactions are primarily summarized. Advances in the research of unique weak interactions in carboranes will certainly lead to more possibilities for supramolecular chemistry.

A photoinduced charge transfer complex (CTC)-enabled photoreduction of carborane phosphonium salts for the cage carbon (hetero)arylation of carboranes was developed. It offers a convenient approach for introducing a wide range of aryl and heteroaryl groups, such as pyrroles, thiophenes, indoles, thianaphthenes, benzofurans, pyridines, and benzenes, into carboranes. This strategy offers operational simplicity, mild reaction conditions, and a broad substrate scope, making it highly advantageous.

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.

Herein, we present a chemically robust and efficient synthesis route for B(9)-OH-o-carboranes by the oxidation of o-carboranes with commercially available 68% HNO₃ under the assistance of trifluoromethanesulfonic acid (HOTf) and hexafluoroisopropanol (HFIP). The reaction is highly efficient with a wide scope of carboranes, and the selectivity of B(9)/B(8) is up to 98:2. The success of this transformation relies on the strong electrophilicity and oxidizability of HNO₃, promoted through hydrogen bonds of the Brønsted acid HOTf and the solvent HFIP. Mechanism studies reveal that the oxidation of o-carborane involves an initial electrophilic attack of HNO₃ to the hydrogen atom at the most electronegative B(9) of o-carborane. In this transformation, the hydrogen atom of the B-H bond is the nucleophilic site, which is different from the electrophilic substitution reaction, where the boron atom is the nucleophilic site. Therefore, this is an oxidation-reduction reaction of o-carborane under mild conditions in which N(V) → N(III) and H(-I) → H(I). The derivatization of 9-OH-o-carborane was further examined, and the carboranyl group was successfully introduced to an amino acid, polyethylene glycol, biotin, deoxyuridine, and saccharide. Undoubtedly, this approach provides a selective way for the rapid incorporation of carborane moieties into small molecules for application in boron neutron capture therapy, which requires the targeted delivery of boron-rich groups.

The efficient and selective functionalization of icosahedral carboranes (C₂B₁₀H₁₂) at the boron vertexes is a long-standing challenge owing to the presence of 10 inert B-H bonds in a similar chemical environment. Herein, we report a new reaction paradigm for direct B-H functionalization of icosahedral carboranes via B-H homolysis enabled by a nitrogen-centered radical-mediated hydrogen atom transfer (HAT) strategy. Both the HAT process of the carborane B-H bond and the resulting boron-centered carboranyl radical intermediate have been confirmed experimentally. The reaction occurs at the most electron-rich boron vertex with the lowest B-H bond dissociation energy (BDE). Using this strategy, diverse carborane derivatization, including thiolation, selenation, alkynylation, alkenylation, cyanation, and halogenation, have been achieved in satisfactory yields under a photoinitiated condition in a metal-free and redox-neutral fashion. Moreover, the synthetic utility of the current protocol was also demonstrated by both the scale-up reaction and the construction of carborane-based functional molecules. Therefore, this methodology opens a radical pathway to carborane functionalization, which is distinct from the B-H heterolytic mechanism in the traditional strategies.

Despite the great interest in carborane-containing molecules, there is a lack of literature on the generation of central chiralities, via catalytic asymmetric transformations using prochiral carboranyl substrates. Herein, we have synthesized novel optically active icosahedral carborane-containing diols via Sharpless catalytic asymmetric dihydroxylation of carborane-derived alkenes, under mild conditions. The reaction showed a good substrate scope with 74-94% yields and 92->99% ee. This synthetic approach facilitated the creation of two adjacent stereocenters respectively located at the α,β-position of o-carborane cage carbon, with a single syn-diastereoisomer. In addition, the obtained chiral carborane-containing diol product can be transformed to cyclic sulfate and can subsequently undergo a nucleophilic substitution and reduction to obtain the unexpected nido-carboranyl derivatives of chiral amino alcohols in the form of zwitterions.

An iridium-catalyzed selective amination of B(4)-H via dehydrogenative cross-coupling of B-H/N-H bonds for the synthesis of o-carborane-fused indolines has been developed for the first time. Various types of unprecedented o-carborane-fused indolines have been synthesized, which would be potential candidates for applications in drug discovery, pharmaceutical chemistry and functional materials. This work offers a valuable reference for the designing and synthesis of o-carborane-fused heterocycles.

An efficient Ir-catalyzed cage boron alkenylation of 1-(2'-picolyl)-o-carboranes with diarylacetylenes has been developed, leading to a wide variety of B-H geminal addition products via 1,2-carbon migration of alkynes. The steric effect of cage carbon substituents has a great impact on the regioselectivity of such alkenylation reactions.

A facile halogenation method for highly selective synthesis of 9-X-o-carboranes, 9,12-X₂-o-carboranes, 9-X-12-X'-o-carboranes, 9-X-m-carboranes, 9,10-X₂-m-carboranes, and 9-X-10-X'-m-carboranes (X, X' = Cl, Br, I) has been developed on the basis of our previous work. The success of this transformation relies on the usage of trifluoromethanesulfonic acid (HOTf), the easily available strong Brønsted acid. The addition of HOTf greatly increases the electrophilicity of N-haloamides through hydrogen bonding interaction, resulting in the low loading of N-haloamides, short reaction time, and mild reaction conditions. Additionally, the solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is also essential to further increase the acidity of HOTf.

This work describes a general method for the efficient production of a class of cage B-centered carboranyl radicals at the B3, B4, and B9 sites via a visible-light-promoted palladium(0)/palladium(I) pathway using readily available iodo-o-carboranes as the starting materials. The electrophilicities of these hypervalent boron-centered radicals decrease in the following order: B3 > B4 > B9. They are useful intermediates for the preparation of a family of cage B-(hetero)arylated o-carboranes at ambient temperature.

In this work, two pathways of reactivity are investigated to generate site-specific substitutions at the B7 vertex of the luminescent boron cluster, anti-B₁₈H₂₂. First, a palladium-catalyzed cross-coupling reaction utilizing the precursor 7-I-B₁₈H₂₁ and a series of model nucleophiles was developed, ultimately producing several B-N- and B-O-substituted species. Interestingly, the B-I bond in this cluster can also be substituted in an uncatalyzed fashion, leading to the formation of various B-N, B-O, and B-S products. This work highlights intricate differences corresponding to these two reaction pathways and analyzes the role of solvents and additives on product distributions. As a result of our synthetic studies, seven new B₁₈-based clusters were synthesized, isolated, and characterized by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The photoluminescence properties of two structurally similar ether and thioether products were further investigated, with both exhibiting blue fluorescence in solution at 298 K and long-lived green or yellow phosphorescence at 77 K. Overall, this work shows, for the first time, the ability to perform substitution of a boron-halogen bond with nucleophiles in a B₁₈-based cluster, resulting in the formation of photoluminescent molecules.

Functionalization of carboranes in a vertex-specific manner is a perennial challenge. Here, we report a photocatalytic B-C coupling for the selective functionalization of carboranes at the boron site which is most distal to carbon. This reaction was achieved by the photo-induced decarboxylation of carborane carboxylic acids to generate boron vertex-centered carboranyl radicals. Theoretical calculations also demonstrate that the reaction more easily occurs at the boron site bearing higher electron density owing to the lower energy barrier for a single-electron transfer to generate a carboranyl radical. By using this strategy, a number of functionalized carboranes could be accessed through alkylation, alkenylation, and heteroarylation under mild conditions. Moreover, both a highly efficient blue emitter with a solid-state luminous efficiency of 42 % and a drug candidate for boron neutron capture therapy (BNCT) containing targeting and fluorine units were obtained.

The nucleophilic aromatic BH substitution reaction of carboranes is uncommon, compared to the electrophilic one. This work reported a pyridine-enabled transition-metal-free regioselective nucleophilic aromatic cage B(4)-H amination of 1,2-diaryl-o-carboranes with magnesium bisamides, giving a series of B(4)-aminated o-carboranes. DFT calculations showcased a stepwise B-N formation/B-H cleavage process, in which Mg-H formation/cage closure is the rate-determining step. Unprecedentedly, in the presence of 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy), a tandem B(4)-amination/cage isomerization reaction of o-carboranes was discovered for the facile preparation of B(2)-aminated m-carboranes. Control experiments indicated that magnesium complex, bidentate ligand (dtbpy) and reaction temperature were crucial in the cage isomerization process. This direct nucleophilic aromatic cage B-H amination reaction offers an alternative strategy for selective amination of o- and m-carboranes.

Carboranes are boron-carbon molecular clusters that possess unique properties, such as their icosahedron geometry, high boron content, and delocalized three-dimensional aromaticity. These features render carboranes valuable building blocks for applications in supramolecular design, nanomaterials, optoelectronics, organometallic coordination chemistry, and as boron neutron capture therapy (BNCT) agents. Despite tremendous progress in this field, stoichiometric chemical redox reagents are largely required for the oxidative activation of carborane cages. In this context, electrosyntheses represent an alternative strategy for more sustainable molecular syntheses. It is only in recent few years that considerable progress has been made in electrochemical cage functionalization of carboranes, which are summarized in this Minireview. We anticipate that electrocatalysis will serve as an increasingly powerful stimulus within the current renaissance of carborane electrochemistry.

Transition-metal-free synthetic method for o-carborane-fused pyrazoles as a new scaffold has been developed from the reaction of B(4)-acylmethyl or B(3,5)-diacylmethyl o-carborane with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) in the presence of DBU in acetonitrile through sequential diazotization and cyclization reaction in one pot, consequently allowing twofold C-N bond formation under extremely mild conditions and high functional group tolerance.

Carboranes represent a class of compounds with increasing therapeutic potential. However, few general approaches to readily embed carboranes into small molecules, peptides, and proteins are available. We report a strategy based on palladium-mediated C-X (X = C, S, and N) bond formation for the installation of carborane-containing moieties onto small molecules and peptides. We demonstrate the ability of Pd-based reagents with appropriate ligands to overcome the high hydrophobicity of the carborane group and enable chemoselective conjugation of cysteine residues at room temperature in aqueous buffer. Accordingly, carboranes can be efficiently installed on proteins by employing a combination of a bis-sulfonated biarylphosphine-ligated Pd reagent in an aqueous histidine buffer. This method is successfully employed on nanobodies, a fully synthetic affibody, and the antibody therapeutics trastuzumab and cetuximab. The conjugates of the affibody Z_HER2 and the trastuzumab antibody retained binding to their target antigens. Conjugated proteins maintain their activity in cell-based functional assays in HER2-positive BT-474 cell lines. This approach enables the rapid incorporation of carborane moieties into small molecules, peptides, and proteins for further exploration in boron neutron capture therapy, which requires the targeted delivery of boron-dense groups.

Amination of carboranes has a good application prospect in organic and pharmaceutical synthesis. However, the current methods used for this transformation suffer from limitations. Herein, we report a practical method for a highly regioselective formation of a B-N bond by Pd(II)-catalyzed B(9)-H amination of o- and m-carboranes in hexafluoroisopropanol (HFIP) with different nitrogen sources under air atmosphere. The silver salt and HFIP solvent play critical roles in the present protocol. The mechanistic study reveals that the silver salt acts as a Lewis acid to promote the electrophilic palladation step by forming a heterobimetallic active catalyst PdAg(OAc)₃; the strong hydrogen-bond-donating ability and low nucleophilicity of HFIP enhance the electrophilic ability of Pd(II). It is believed that these N-containing carboranes are potentially of great importance in the synthesis of new pharmaceuticals.

A general strategy for the generation of hypervalent boron-centered carboranyl radicals at the B(3), B(4), and B(9) positions has been developed for the first time via visible-light-promoted iodine atom abstraction from iodo-o-carboranes by low-valent nickel complex. These radicals react with various (hetero)arenes to afford a wide range of cage B-arylated carborane derivatives at room temperature in very good to excellent yields with a broad substrate scope. Their electrophilicities are dependent on the vertex charges of the cage and follow the order B(3) > B(4) > B(9). Both visible light and nickel catalyst are proved critical to the generation of boron-centered carboranyl radicals. The involvement of boron radicals is supported by control experiments. A reaction mechanism associated with these reactions is also proposed. This strategy offers a new protocol for the generation of boron-centered carboranyl radicals at the selected boron vertex, leading to a facile synthesis of a large class of cage boron substituted carborane molecules.

The B(9)-H halogenation of o-carborane and m-carborane was achieved with excellent selectivities in hexafluoroisopropanol (HFIP) under simple reaction conditions: single reagent [trichloroisocyanuric acid (TCCA), tribromoisocyanuric acid (TBCA) or N-iodosuccinimide (NIS)], catalyst-free, air-/moisture-tolerant, and convenient work-up. With this method, a variety of 9-halogenated o-carboranes and m-carboranes were obtained in good to excellent yields with broad tolerance of functional groups.