Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2025 Jul 11;147(29):25478–25488. doi: 10.1021/jacs.5c05637

Carboranes without Cage Carbons: closo-Dodecaborate Mimics of Neutral closo-Carboranes

Austin D Ready †, Varun Tej Raviprolu †, Tyler A Kerr †, Joseph W Treacy †, Mei L Matsumoto †, Prairie E Hammer †, Ellen M Sletten †,‡, K N Houk †, Alexander M Spokoyny †,‡,*
PMCID: PMC12291439  PMID: 40643954

Abstract

Substituted two-dimensional aromatic systems, such as arenes, exhibit well-established reactivity patterns at specific sites, largely due to the pronounced electronic directing effects of attached substituents. In contrast, the regioselectivity of three-dimensional aromatic molecules as a function of substituents remains less understood and documented. In this work, we demonstrate that a series of closo-dodecaborate ([B12H12]2–) cluster isomers containing two -NMe3 + moieties exhibit unprecedented regioselective reactivity at boron vertices farthest from the charged substituents. Through a combination of theoretical and experimental studies, we reveal that these boron clusters display near-perfect regioselectivity with multiple electrophiles, ultimately enabling vertex differentiation chemistry within these systems. This observed phenomenon closely parallels the reactivity patterns typically associated with icosahedral closo-carboranes, where a carbon-based vertex induces a strong electronic dipole, leading to pronounced vertex-specific reactivity differences at boron sites. Our findings suggest that these modified closo-dodecaborates serve as electronic analogs of neutral closo-carboranes, achieving similar electronic directing effects without the need for cage-based carbon atoms. Instead, exopolyhedral substituents alone govern the regioselective behavior, expanding the potential for tailored functionalization in boron cluster chemistry.

graphic file with name ja5c05637_0012.jpg

graphic file with name ja5c05637_0010.jpg

Introduction

The electronic effects of different functional groups in two-dimensional aromatic systems, such as substituted arenes, are well established to exert a regiochemical directing influence (ortho, meta, or para) in electrophilic aromatic substitution (SEAr) reactions (Scheme A). However, the control of regiochemistry by exopolyhedral functional groups in three-dimensional aromatic cluster systems is less well established. A notable recent example by Velian and co-workers examines the selective reactivity of metal sites (M = Fe, Co, Zn, Sn) in M3Co6Se8-based molecular clusters (Scheme B). Additionally, some metal carbonyl clusters are known to undergo ligand exchange preferentially at specific metal vertices. Interestingly, among the studied inorganic clusters with three-dimensional electron delocalization, icosahedral carboranes represent a well-established platform where researchers have observed highly regioselective reactivity patterns since the inception of the field in the 1950s (Scheme C).

1. Electronic Directing Group Effects in Two- and Three-Dimensional Aromatic Systems .

1

Open in a new tab

a (A) Meta-, and ortho/para-directors in SEAr reactions. (B) Site-selective reactivity in M3Co6Se8 clusters and metal carbonyl clusters. (C) Isomers of icosahedral neutral closo-carboranes and di-functionalized closo-dodecaborates. (D) Regioselective reactivity of the boron clusters discussed in this work.

In these systems, the relative location of carbon atoms in isomers of neutral ortho-, meta- and para-carborane clusters induces regioselectivity due to the net dipole formed by the electron-withdrawing ability of C–H vertices relative to B–H (electronegativities of C = 2.5, B = 2.0, H = 2.2). Besides carboranes, there exists a large class of polyhedral cluster molecules containing only boron and hydrogen atoms. A quintessential cluster in this category is the closo-dodecaborate ([B12H12]2–) species. Similar to the carborane clusters mentioned above, closo-dodecaborate exhibits an icosahedral shape, but unlike neutral carboranes carries an overall 2– charge. Studies have shown that the placement of cationic substituents on the dianionic dodecaborate core can result in “charge-compensated” neutral clusters. Importantly, disubstituted closo-dodecaborate clusters can be formed as a mixture of “ortho”, “meta”, and “para” isomers, in a manner reminiscent of neutral icosahedral carboranes (Scheme C). However, there is no unified understanding of how the strength and location of exopolyhedral directing groups on closo-dodecaborate affect further regiochemistry as compared to carboranes, which inherently have endopolyhedral C–H directing groups. In this work, we set out to explore charge-compensated cluster isomers of closo-dodecaborate by incorporating two strongly electron-withdrawing -NMe3 + groups (σp = 0.82). These modified clusters demonstrate unprecedented and enhanced regioselective reactivity compared to neutral closo-carboranes, drawing an intriguing conceptual parallel between the electronic directing effects of functional groups in classical two-dimensional aromatic molecules and their three-dimensional aromatic counterparts.

Results and Discussion

Upon refluxing the dipotassium salt of [B12H12]2– (1) in the presence of hydroxylamine-O-sulfonic acid (HOSA; 8 equiv), a mixture of functionalized clusters is obtained (see Supporting Information for complete synthetic information and full characterization, Figures S1–S67), consisting of the monosubstituted [B12H11NH3]− cluster and the disubstituted [B12H10(NH3)2]0 cluster isomers, 2a–c (Figure ). Notably, the attachment of positively charged -NH3 + moieties to the dianionic dodecaborate core results in the partially charge-compensated, monoanionic ([B12H11NH3]−) as well as the fully charge-compensated, neutral [B12H10(NH3)2]0. The disubstituted cluster forms as a mixture of “ortho” (1,2), “meta” (1,7), and “para” (1,12) isomers in a distribution of roughly 1:2:2, respectively. Each individual isomer can be isolated by silica gel column chromatography. This is in contrast to many anionic boron clusters which require extensive ion-exchange protocols for isolation and purification, which sometimes serves as an impediment to the practitioners.

1.

1

Open in a new tab

(A) Synthesis of diammoniated boron clusters (8 equiv. HOSA) and subsequent methylation (46 equiv. Me2SO4) (B) X-ray crystal structures of the three purified isomers of B12H10(NMe3)2 (50% probability ellipsoids for all non-hydrogen atoms). All isomers are separable by silica gel column chromatography (ethyl acetate/hexanes gradient) as either the – (NH3)2 or – (NMe3)2 species and can even be methylated as a mixture of isomers and separated afterward.

While the parent B12H10(NH3)2 isomers can be purified and isolated in individual isomeric form, , these molecules have limited solubility and can undergo facile deprotonation, thus limiting their practical use for functionalization. We therefore decided to modify the ammonio groups to improve their solubilities in organic solvents. N-methylation was chosen as a simple strategy to balance out the overall hydrophobicity of the resulting modified clusters. Two independent processes were developed to obtain individual isomers of B12H10(NMe3)2 (3a–c). In the first strategy, a mixture of 2a–c is cleanly permethylated by refluxing with dimethyl sulfate (46 equiv) in H2O/THF, followed by purification via flash column chromatography. Interestingly, these compounds follow the elution polarity trend normally observed with icosahedral carboranes, wherein the para- isomer elutes first, followed by meta- and then ortho-based congeners. Alternatively, individually purified isomers 2a–c can be subjected to the above methylation conditions, affording nearly quantitative conversion to the corresponding −(NMe3)2 derivatives 3a-c in good yields (49–74% isolated yields).

At this point, several key crystallographic features and spectroscopic similarities between 3a–c and their closo-carborane analogues can be elucidated. X-ray crystal structures of 3a–c show a slight increase in the average B–N bond lengths in the order 1, 2 > 1,7 > 1,12 (1.615 Å > 1.604 Å > 1.590 Å). Overall, these are slightly longer than the B–N bonds in exopolyhedral nitrogen-bound derivatives of ortho- and meta-carborane (∼1.50 Å). , Furthermore, the B–B bond between the NMe3 +-bound boron atoms in 3a is slightly elongated (1.822 Å) compared to the other B–B bonds within the same cluster (1.770–1.799 Å), possibly due to steric clash of the neighboring -NMe3 + groups. 3a, 3b, and 3c show similar features by 11B­{H} NMR spectroscopy to ortho-, meta-, and para-carborane, respectively, due to the identical cage symmetries, albeit the presence of one additional peak corresponding to the two nitrogen-bound boron vertices in these isomers (SI Figure S21). For example, the 1,7-(NMe3)2B12H10 isomer (3b) shows five peaks by 11B­{H} NMR spectroscopy, with the four resonances between −16 to −19 ppm corresponding to the ten unfunctionalized boron vertices (similar to meta-carborane) and the chemically identical B–N moieties appearing at +1 ppm. Similar observations can be made for 3a and ortho-carborane (SI Figure S17) as well as 3c and para-carborane (SI Figure S26), with the major differences being the lack of a B–N resonance in the closo-carboranes and changes in the chemical shifts of the B–H vertices.

We hypothesized that due to the net dipole induced by the positively charged -NMe3 + groups and the dinegative boron cluster, each isomer of these neutral dodecaborate-based clusters should demonstrate enhanced nucleophilic character at select B–H vertices due to the three-dimensional aromaticity inherent to these boron clusters. Conceptually, this directing group effect should lead to the same functionalization regioselectivity patterns at boron vertices as icosahedral carboranes, which arises due to the difference in electronegativity between carbon and boron. In carboranes, however, the induced dipole results from endopolyhedral electronic effects, whereas in this system the directing effects are induced by exopolyhedral functional groups. The electron density at different B–H vertices in carboranes has been previously studied theoretically as well as leveraged experimentally to develop numerous classes of regioselective reactions. − In their pioneering work, Shore and co-workers have previously demonstrated that placement of exopolyhedral sulfonium moieties onto closo-dodecaborate cluster results in a pronounced regioselectivity enhancement of the corresponding derivatives toward electrophilic substitution. − However, these clusters require arduous multistep synthesis and were shown to undergo facile dealkylation chemistry, limiting their overall stability and utility.

DFT studies calculated at the ωB97X-D/6–311+G­(d,p), CPCM­(acetonitrile) level of theory suggest a similar regioselective effect in our system (Figure A). The dipole moment of 3b was calculated to be 14.5 D, over three times greater than that of meta-carborane (4.0 D). Calculated CM5 partial charges indicate that when the boron and hydrogen partial charges are summed together, the B(9) vertex for both clusters has the most negative charge. 3b has a more negative overall partial charge at the B(9) position (−0.13) than meta-carborane (−0.08), further supporting the conclusion that the magnitude of the directing group effect is larger in 3b than in meta-carborane (Figure B) and that this position should be more reactive in 3b. The HOMO level for each cluster has similar phasing and distribution of the orbitals across the cage (Figure C). Further, the electrostatic potential at various sites of substituted benzenes have been shown in the so-called Wheeler-Houk model to be caused by direct through-space Coulombic interactions, and the same should be true of the substituted dodecaborates. This visualization for 3b and meta-carborane (Figure D) clearly shows the more negative potential corresponding to the B(9) vertex of 3b indicating the higher nucleophilicity and thus higher reactivity compared to the meta-carborane. Furthermore, DFT studies suggest that 3b features a significantly larger dipole moment than previously studied sulfonium-functionalized dodecaborate-based congeners potentially indicating a more pronounced reactivity (SI, Figure S68).

2.

2

Open in a new tab

Comparison between 1,7-(NMe3)2B12H10 (3b) and meta-carborane. (A) Calculated dipole moments of 3b (top) and meta-carborane (bottom) (B) CM5 partial charges of B(9)-H calculated at the ωB97X-D/6–311+G­(d,p), CPCM­(Acetonitrile) level of theory for 3b (top) and meta-carborane (bottom) (C) visualization of the HOMO level representations for the corresponding structures of 3b (top) and meta-carborane (bottom) (D) visualization of the electrostatic potentials of 3b (top) and meta-carborane (bottom).

In order to investigate these computational results, we set out to experimentally compare and benchmark the reactivity of the B12H10(NMe3)2 isomers with icosahedral carboranes by reaction with simple halogen electrophiles. We began our studies on the 1,7-(NMe3)2B12H10 cluster (3b), as it is the major isomer produced and the most symmetrically equivalent to meta-carborane. As suggested by our computational results, 3b reacted immediately with iodine monochloride to give 3b­[I], as confirmed by 11B NMR spectroscopy and X-ray crystallography (Figure ). The B–I bond on 3b­[I] manifests as a distinct upfield resonance at −26 ppm in the 11B NMR spectrum (SI, Figure S41), which is slightly more upfield than the structurally analogous 9-I-meta-carborane, for which the B–I bond appears at −24 ppm by 11B NMR spectroscopy. The iodination of 3b also proceeds quantitatively within 5 min at 0 °C without the need for a Lewis acid catalyst. This is in stark contrast to meta-carborane iodination, which requires refluxing conditions with I2/AlCl3 for 1 week to achieve monoiodination. Even recently improved conditions using hexafluoroisopropanol (HFIP) and N-iodo-succinimide (NIS) necessitate heating of meta-carborane at 50 °C. These differences in reactivity suggest that the exopolyhedral -NMe3 + groups can activate the B(9) position to a greater extent than the endopolyhedral C–H vertices in the analogous meta-carborane, which is consistent with our theoretical predictions (Figure ).

3.

3

Open in a new tab

Halogenation scheme of 1,7-(NMe3)2B12H10 (3b) and corresponding X-ray crystal structures (50% probability ellipsoids for all non-hydrogen atoms); (i) 1.0 eq. ICl, CH2Cl2, 0 °C, 5 min; (ii) r.t. Two h (iii) 1.0 eq. AlCl3, 0 °C, 2 h (iv) 2.5 equiv. Br2, 0 °C to r.t., 4 h (v) 2.5 eq. Br2, CH2Cl2, −78 °C, 36 h X-ray key: Boron = Pink, Carbon = Black, Nitrogen = Blue, Hydrogen = Gray, Chlorine = Green, Bromine = Brown, Iodine = Purple.

Upon heating with one equivalent of ICl in CH2Cl2, a mixture of both the mono- (3b­[I]) and di-iodinated (3b­[I 2 ]) products are obtained, as confirmed by 11B NMR spectroscopy and X-ray crystallography. After formation of the monosubstituted product (3b­[I]), the adjacent B(10) position is the most reactive, electron-rich vertex, further mimicking the regiochemistry of meta-carborane substitution.

Similar reactivity is observed for other halogen electrophiles. The addition of one equivalent of Br2 to a solution of 3b at −78 °C gradually forms the monobrominated product (3b­[Br]) upon warming to room temperature, as confirmed by 11B NMR spectroscopy (SI, Figure S48) and X-ray crystallography (Figure ). Additionally, we discovered that the cluster was chlorinated at the B(9) position to give 3b­[Cl] in the presence of AlCl3 at 0 °C, as confirmed by 11B NMR and X-ray crystallography. Even FeCl3, which is not typically considered a chlorinating reagent on its own, resulted in partial conversion of the starting material to 3b­[Cl] at 0 °C, as observed by 11B NMR spectroscopy (SI, Figure S71). Continued stirring overnight resulted in growth of a new peak on the 11B NMR spectrum which was attributed to a dichlorinated cluster. A mixed halogenated cluster 3b­[I, Br] can also be synthesized via reaction of 3b­[I] with Br2, as confirmed by 11B NMR spectroscopy and X-ray crystallography, analogous to mixed halogenated meta-carborane derivatives. Furthermore, when an equimolar ratio of 3b and meta-carborane were subjected to the bromination conditions, exclusive formation of 3b­[Br] was observed by 11B NMR spectroscopy with no apparent bromination of meta-carborane demonstrating the enhanced reactivity of 3b compared to its carborane-based analog.

To test the generality for the observed reactivity enhancement, the 1,12-(NMe3)2B12H10 isomer (3c) was subjected to the same conditions, resulting in facile monoiodination at 0 °C with ICl to give 3c­[I], as confirmed by 11B NMR spectroscopy and X-ray crystallography (Figure ). A diagnostic B–I peak arises at −28 ppm, along with the formation of two unique B–N peaks due to the desymmetrization of the cluster that occurs upon iodination at the B(2) position. In comparison, monoiodination of para-carborane typically requires I2/AlCl3 and several hours of reflux.

4.

4

Open in a new tab

(A) Synthesis of 3c­[I] (1.0 eq. ICl) and corresponding crystal structure. (B) 11B­{H} NMR spectra of the starting material (3c) and product (3c­[I]).

We next sought to compare the stability of 1,2- and 1,7-B12H10(NMe3)2 (3a and 3b, respectively) with the analogous ortho- and meta-carboranes. Neutral closo-carboranes are well-known to undergo cage rupture in the presence of Lewis bases via abstraction of a boron atom, resulting in the opened nido-carboranes (Figure ). Indeed, ortho- and meta-carborane show clean conversion to the deboronated products upon refluxing with tetrabutylammonium fluoride (TBAF) (Figure A, C).

5.

5

Open in a new tab

(A) 11B­{H} NMR spectra for the cage-opening of ortho-carborane. (B) 11B­{H} NMR spectra demonstrating the stability of 3a. (C) 11B­{H} NMR spectra for the cage-opening of meta-carborane. (D) 11B­{H} NMR spectra demonstrating stability of 3b.

Upon subjecting 3a and 3b to the same conditions, no deboronation or dealkylation was observed (Figure B, D). Clean starting material was obtained, even when refluxed for 24 h with excess TBAF (10 equiv).

We then investigated the electrochemical and thermal stability of 3a and 3b. No redox events were observed for both 3a and 3b over a roughly 6 V range ([0.1 M] TBAPF6 in CH3CN; vs Fc+/Fc) other than solvent/electrolyte decomposition, which is to be expected at the edges of the electrolyte stability window (Figure A). On the other hand, ortho- and meta-carborane undergo a two-electron reduction in the presence of strong chemical reductants to give cage-opened nido derivatives. , This has been observed electrochemically via cyclic voltammetry as reduction events between roughly −2.5 to −3.0 V vs Fc+/Fc − (converted from SCE; 0.1 M NBu4(ClO4) in DMF). Unlike ortho-carborane and meta-carborane, which contain C–C and C–B cluster moieties susceptible to reductive cleavage and electron storage, the dodecaborate-based core lacks such a feature and thus remains resistant to reduction under similar potentials.

6.

6

Open in a new tab

(A) Cyclic voltammogram of 3a versus electrolyte blank. (B) Thermogravimetric curve for 3a. (C) Cyclic voltammogram of 3b versus electrolyte blank. (D) Thermogravimetric curve for 3b.

Compounds 3a and 3b are also thermally stable up to nearly 350 °C in a N2 atmosphere (Figure B). 3b and 3a lose roughly 45% relative weight upon thermal decomposition, which agrees well with the calculated weight loss from the cleavage of both -NMe3 + groups. In terms of thermal stability, both ortho- and meta-carborane sublime even with gentle heating, and eventually isomerize to the para-isomer at temperatures upward of 600 °C.

The distinctively different chemical and electrochemical stability profile of the B12H10(NMe3)2 family (3a–c) as compared to icosahedral neutral closo-carboranes makes these clusters an appealing substitute for reactions in which carborane deboronation is a concern. Importantly, compounds 3a and 3b also show superior stability to the previously developed charge-compensated -SMe2 + clusters, which undergo facile S-demethylation chemistry. − Furthermore, high binding affinities of the cucurbit[7]­uril host with the isomers 3a–c (e.g., K a = 2.6 × 105 M–1 for 3a) are consistent with the strong binding affinities previously reported for neutral closo-carborane guests.

Having established the general reactivity of 3b toward electrophiles, we next sought to subject the iodinated derivative (3b­[I]) to further functionalization. Upon reaction of 3b­[I] with the corresponding Grignard reagents and catalytic Pd­(PPh3)2Cl2, the methyl- and phenyl-substituted clusters (3b­[Me] and 3b­[Ph], respectively) were readily obtained (Figure A). The conversion is evident by 11B NMR spectroscopy as the complete loss of the B–I peak at −26 ppm and concomitant formation of a new B–C peak at 6 ppm (Figure C). Structures were confirmed by X-ray crystallography (Figure B). Interestingly, the plane of the phenyl ring in the crystal structure of 3b­[Ph] intersects the midpoint of the two -NMe3 + groups, presumably to reduce steric clash. Likewise, the 4-chlorophenyl derivative (3b­[PhCl]) was also synthesized by cross coupling 3b­[I] with the corresponding aryl Grignard reagent (SI, Figure S73).

7.

7

Open in a new tab

(A) Kumada coupling of monoiodo derivative (3b­[I]) to give B–C bound products (isolated yields in parentheses) (8 eq. MeMgBr and 8 eq. PhMgBr). (B)11B­{H} NMR spectra of the starting material (3b­[I]) and product 3b­[Ph]. (C) Crystal structure of 3b­[Me] (left); crystal structure of 3b­[Ph] from the side and down the plane of the phenyl ring (right). (D) 19F­{H} NMR chemical shift values (in CD3CN) of various fluoroaryl compounds; 19F­{H} NMR spectra of 3b­[PhF] and its meta-carborane analogue in CD3CN (inset).

In order to probe the electronic environment of the cluster-bound aryl substituents, we synthesized a derivative with a 4-fluorophenyl group at the B(9) position (3b­[PhF]) and compared it to the meta-carborane analogues, along with several other fluoroaryl compounds for benchmarking (Figure D). 3b­[PhF] has a 19F NMR resonance at −121 ppm, which is upfield of both the B-bound (−117 ppm) and C-bound (−114 ppm) meta-carborane analogues, which are known to contain electron-donating and electron-withdrawing cluster vertices, respectively. The 4 ppm upfield shift from boron-bound PhF-meta-carborane to 3b­[PhF] suggests an increase in the electron-donating ability of our system compared to meta-carborane, further corroborating the experimental and theoretical results. Additionally, 3b­[PhF] is downfield of the dodecaborate analog (−124 ppm), which is electron-rich due to the pronounced dianionic charge on the cluster. This suggests that the boron cluster attached through the B(9) vertex in 3b is a strong electron donor group (stronger than classical carbon-based substituents), despite the overall neutral charge on the cluster.

In our previous work, , we employed boron–selenium (B–Se) carborane-based compounds as sensitive probes to investigate the electronic properties of parent carborane clusters as a function of specific vertex attachment, with a particular focus on quantifying inductive effects exerted by C- and B-bound substituents. These exopolyhedral B–Se motifs, due to their well-defined electronic signatures and responsiveness to local electronic environments by 77Se NMR spectroscopy, enabled a nuanced understanding of electron-donating and -withdrawing influences within the carborane framework. , Building on this strategy, we have extended the use of these B–Se probes to the cluster system described in the present study, allowing us to further evaluate how new structural modifications influence the electronic character of the cage. When cluster 3b was reacted with PhSeCl under microwave conditions, the selenated derivative 3b­[PhSe] was obtained, as confirmed by multinuclear NMR spectroscopy and X-ray crystallography (Figure C). Importantly, electrophilic selenylation proceeds in an uncatalyzed fashion regioselectively at the B(9) vertex of the cluster, further reinforcing the findings from halogenation studies and highlighting the broader applicability of the demonstrated chemistry. In the 11B­{1H} NMR spectrum (Figure B), the boron site functionalized with selenium clearly appears at −10 ppm. Additionally, the 77Se NMR spectrum shows a resonance at 113 ppm (SI, Figure S82), corresponding to the selenium atom bonded to B(9) position of the cage. This chemical shift is comparable to that observed for B-functionalized selenoether species containing a single carborane cage and an aryl group (ca. 80 ppm), further underscoring the electronic and structural similarity between B(9)-functionalized cluster 3b and B(9)-functionalized meta-carborane (for comparison, C-bound carborane selenol appears at ca. 340 ppm) and the extremely electron-donating nature of these B(9)-bound substituents.

8.

8

Open in a new tab

(A) Regioselective electrophilic selenylation of 3b with PhSeCl (1.0 equiv). (B)11B­{1H} NMR spectrum of 3b­[PhSe]. (C) X-ray crystal structure of 3b­[PhSe].

Conclusions

While substitution chemistry of benzene and similar two-dimensional aromatic molecules is a well-established conceptual framework taught in introductory university chemistry, analogous concepts for three-dimensional aromatic systems are still largely absent. In our work, we have demonstrated that a quintessential three-dimensional aromatic cluster [B12H12]2– can be derivatized with two exopolyhedral charged NMe3 + functional groups which collectively exhibit a strong electronic directing effect rendering antipodal B–H vertices most nucleophilic and thus extremely reactive toward electrophiles. These cluster isomers are chemically more robust than some of their closo-carborane analogs and are amenable to a wide range of single and multiple substitutions with electrophiles. Notably, spectroscopic analysis of B(9) arylated meta-B12H10(NMe3)2 species indicates that the [B12H10(NMe3)2] substituent exhibits one of the strongest observable electron-donating inductive effects among classical carbon-based substituents and neutral boron clusters including neutral closo-carboranes. Overall, our work introduces an exciting new class of neutral closo-dodecaborate derivatives that exhibit reactivity patterns reminiscent of icosahedral neutral closo-carboranes. However, unlike neutral closo-carboranes, these systems lack dipole-inducing carbon-based vertices, relying solely on exopolyhedral substituents to achieve precise electronic directing effects. This discovery expands the scope of boron cluster chemistry by demonstrating how the strategic placement of multiple substituents around the cage can enable intricate control over vertex differentiation. This approach offers a complementary strategy to existing directed functionalization methods, paving the way for new advancements in boron cluster reactivity and design. It is also clear from this study that more work is warranted in studying the effect of boron cluster polysubstitution on the resulting regioselectivity with several already existing systems demonstrating promising outcomes. In general, the closo-dodecaborate cluster offers a distinct advantage over its carborane counterpart in terms of both stability and boron content. Unlike described neutral closo-carboranes, which contain two carbon atoms within the cage, the dodecaborate-based framework is composed entirely of 12 boron atoms. This all-boron composition contributes to its exceptional chemical and thermal stability, making it highly robust under a wide range of conditions. Moreover, the presence of two additional boron atoms per cage compared to carboranes results in a higher boron density per molecule. This feature is particularly advantageous for applications such as boron neutron capture therapy (BNCT), where maximizing the delivery of boron atoms to tumor cells is critical for therapeutic efficacy. Thus, the dodecaborate-based scaffold not only enhances molecular stability but also offers a strategic benefit in achieving higher boron payloads in biomedical contexts. Lastly, this work showcases a close conceptual parallel between the electronic directing effects of functional groups appended onto classical two-dimensional aromatic molecules and three-dimensional aromatic congeners.

Supplementary Material

ja5c05637_si_001.pdf (10.1MB, pdf)

Acknowledgments

A.M.S. thanks NIGMS (R35GM124746) for funding. A.M.S. thanks Dreyfus Foundation for the Camille Dreyfus Teacher-Scholar Award. E.M.S. thanks NIH DP2GM132680 for support. This work used computational and storage services associated with the Hoffman2 Shared Cluster provided by the UCLA Institute for Digital Research and Education’s Research Technology Group.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c05637.

  • Details about instruments, materials, methods, chemical synthesis, NMR spectroscopy characterization, computational information and crystallographic information (PDF)

§.

A.D.R and V.T.R. contributed equally to this work. The manuscript was written through contribution of all authors. All authors have given approval to the final version of the manuscript.

The authors declare the following competing financial interest(s): A.M.S., A. D. R. and V. T. R. are co-inventors on a patent application from UCLA associated with the work described.

References

  1. a Mitchell B. S., Krajewski S. M., Kephart J. A., Rogers D., Kaminsky W., Velian A.. Redox-Switchable Allosteric Effects in Molecular Clusters. JACS Au. 2022;2:92–96. doi: 10.1021/jacsau.1c00491. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Kephart J. A., Zhou D. Y., Sandwisch J., Cajiao N., Krajewski S. M., Malinowski P., Chu J., Neidig M. L., Kaminsky W., Velian A.. Caught in the Act of Substitution: Interadsorbate Effects on an Atomically Precise Fe/Co/Se Nanocluster. ACS Cent. Sci. 2024;10(6):1276–1282. doi: 10.1021/acscentsci.4c00210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Wang W., Einstein F. W. B., Pomeroy R. K.. Site Preference of the tert-Butyl Isocyanide Ligand in Pentaosmium Carbonyl Clusters. Crystal Structures of Os5(CO)18(CNBut) and Os5(CO)15(CNBut) Organometallics. 1994;13:1114–1119. doi: 10.1021/om00016a015. [DOI] [Google Scholar]
  3. Grimes, R. N. Carboranes, 2nd ed.; Academic Press, 2011. [Google Scholar]
  4. Teixidor F., Barberà G., Vaca A., Kivekäs R., Sillanpää R., Oliva J., Vinas C.. Are Methyl Groups Electron-Donating or Electron-Withdrawing in Boron Clusters? Permethylation of o-Carborane. J. Am. Chem. Soc. 2005;127:10158–10159. doi: 10.1021/ja052981r. [DOI] [PubMed] [Google Scholar]
  5. Sivaev I. B., Bregadze V., Sjöberg S.. Chemistry of closo-Dodecaborate Anion [B12H12]2‑: A Review. Collect. Czech. Chem. Commun. 2002;67:679–727. doi: 10.1135/cccc20020679. [DOI] [Google Scholar]
  6. Hansch C., Leo A., Taft R. W.. A Survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 1991;91(2):165–195. doi: 10.1021/cr00002a004. [DOI] [Google Scholar]
  7. Tolpin E. I., Wellum G. R., Berley S. A.. Synthesis and Chemistry of Mercaptoundecahydro-closo-dodecaborate­(2-) Inorg. Chem. 1978;17:2867–2873. doi: 10.1021/ic50188a037. [DOI] [Google Scholar]
  8. Hertler W. R., Raasch M. S.. Chemistry of Boranes. XIV. Amination of B10H10 –2 and B12H12 –2 with Hydroxylamine-O-sulfonic Acid. J. Am. Chem. Soc. 1964;86:3661–3668. doi: 10.1021/ja01072a014. [DOI] [Google Scholar]
  9. Pluntze A. M., Bukovsky E. V., Lacroix M. R., Newell B. S., Rithner C. D., Strauss S. H.. Deca-B-fluorination of Diammonioboranes. Structures and NMR cCharacterization of 1,2-, 1,7-, and 1,12-B12H10(NH3)2 and 1,2-, 1,7-, and 1,12-B12F10(NH3)2 . J. Fluor. Chem. 2018;209:33–42. doi: 10.1016/j.jfluchem.2018.01.014. [DOI] [Google Scholar]
  10. Mu X., Hopp M., Dziedzic R. M., Waddington M. A., Rheingold A. L., Sletten E. M., Axtell J. C., Spokoyny A. M.. Expanding the Scope of Palladium-Catalyzed B–N Cross-Coupling Chemistry in Carboranes. Organometallics. 2020;39:4380–4386. doi: 10.1021/acs.organomet.0c00576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kataki-Anastasakou A., Axtell J. C., Hernandez S., Dziedzic R. M., Balaich G. J., Rheingold A. L., Spokoyny A. M., Sletten E. M.. Carborane Guests for Cucurbit[7]­uril Facilitate Strong Binding and On-Demand Removal. J. Am. Chem. Soc. 2020;142:20513–20518. doi: 10.1021/jacs.0c09361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Alexandrova A. N., Boldyrev A. I., Zhai H.-J., Wang L.-S.. All-boron aromatic clusters as potential new inorganic ligands and building blocks in chemistry. Coord. Chem. Rev. 2006;250:2811–2866. doi: 10.1016/j.ccr.2006.03.032. [DOI] [Google Scholar]
  13. a Spokoyny A. M., Machan C. W., Clingerman D. J., Rosen M. S., Wiester M. J., Kennedy R. D., Stern C. L., Sarjeant A. A., Mirkin, C A.. A Coordination Chemistry Dichotomy for Icosahedral Carborane-based Ligands. Nat. Chem. 2011;3:590–596. doi: 10.1038/nchem.1088. [DOI] [PubMed] [Google Scholar]; b Mills H. A., Alsarhan F., Ong T.-C., Gembicky M., Rheingold A. L., Spokoyny A. M.. Icosahedral Meta-Carboranes Containing Exopolyhedral B-Se and B-Te Bonds. Inorg. Chem. 2021;60:19165–19174. doi: 10.1021/acs.inorgchem.1c02981. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Lee K., Harper J. L., Kim T. H., Noh H. C., Kim D., Cheong P. H.-Y., Lee P. H.. Regiodivergent Metal-Catalyzed B(4)- and C(1)-Selenylation of o-Carboranes. Chem. Sci. 2023;14:643–649. doi: 10.1039/D2SC05590B. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Schulz J., Clauss R., Kazimir A., Holzknecht S., Hey-Hawkins E.. On the Edge of the Known: Extremely Electron-Rich (Di)­Carboranyl Phosphines. Angew. Chem., Int. Ed. 2023;62:e202218648. doi: 10.1002/anie.20221864. [DOI] [PubMed] [Google Scholar]
  14. Zhang, J. ; Xie, Z. . Advances in Transition Metal Catalyzed Selective BH Functionalization of O-Carboranes. In Advances in Catalysis; Diéguez, M. ; Núñez, R. , Eds.; Academic Press, 2022, Vol. 71, Chapter 3, pp 91–167. [Google Scholar]
  15. Raviprolu V. T., Farias P., Carta V., Harman H., Lavallo V.. When the Ferrocene Analogy Breaks Down: Metallocene Transmetallation Chemistry. Angew. Chem., Int. Ed. 2023;62:e202308359. doi: 10.1002/anie.202308359. [DOI] [PubMed] [Google Scholar]
  16. Kleinsasser J. F., Fisher S. P., Tham F. S., Lavallo V.. On the Reactivity of the Carba-closo-dodecaborate Anion with the Trityl Cation. Eur. J. Inorg. Chem. 2017;2017:4417–4419. doi: 10.1002/ejic.201700614. [DOI] [Google Scholar]
  17. Jaiswal K., Malik N., Tumanskii B., Ménard G., Dobrovetsky R.. Carborane Stabilized “19-Electron” Molybdenum Metalloradical. J. Am. Chem. Soc. 2021;143:9842–9848. doi: 10.1021/jacs.1c03568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nussbaum B. C., Humphries A. L., Gange G. B., Peryshkov D. V.. Redox-active carborane clusters in bond activation chemistry and ligand design. Chem. Commun. 2023;59:9918–9928. doi: 10.1039/D3CC03011C. [DOI] [PubMed] [Google Scholar]
  19. Dziedzic R. M., Spokoyny A. M.. Metal-catalyzed cross-coupling chemistry with polyhedral boranes. Chem. Commun. 2019;55:430–442. doi: 10.1039/C8CC08693A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hamilton E. J. M., Leung H. T., Kultyshev R. G., Chen X., Meyers E. A., Shore S. G.. Unusual Cationic Tris­(Dimethylsulfide)-Substituted closo-Boranes: Preparation and Characterization of [1,7,9-(Me2S)3-B12H9]­BF4 and [1,2,10-(Me2S)3-B10H7]­BF4 . Inorg. Chem. 2012;51:2374–2380. doi: 10.1021/ic2023709. [DOI] [PubMed] [Google Scholar]
  21. Kultyshev R. G., Liu J., Liu S., Tjarks W., Soloway A. H., Shore S. G.. S-Alkylation and S-Amination of Methyl Thioethers – Derivatives of closo-[B12H12]2‑. Synthesis of a Boronated Phosphonate, gem-Bisphosphonates, and Dodecaborane-ortho-carborane Oligomers. J. Am. Chem. Soc. 2002;124:2614–2624. doi: 10.1021/ja0123857. [DOI] [PubMed] [Google Scholar]
  22. Kultyshev R. G., Liu S., Leung H. T., Liu J., Shore S. G.. Synthesis of Mono- and Dihalogenated Derivatives of (Me2S)2B12H10 and Palladium-Catalyzed Boron–Carbon Cross-Coupling Reactions of the Iodides with Grignard Reagents. Inorg. Chem. 2003;42:3199–3207. doi: 10.1021/ic020600u. [DOI] [PubMed] [Google Scholar]
  23. Wheeler S. E.. Understanding Substituent Effects in Noncovalent Interactions Involving Aromatic Rings. Acc. Chem. Res. 2013;46(4):1029–1038. doi: 10.1021/ar300109n. [DOI] [PubMed] [Google Scholar]
  24. Guo W., Guo C., Ma Y.-N., Chen X.. Practical Synthesis of B(9)-Halogenated Carboranes with N-Haloamides in Hexafluoroisopropanol. Inorg. Chem. 2022;61:5326–5334. doi: 10.1021/acs.inorgchem.2c00074. [DOI] [PubMed] [Google Scholar]
  25. Zheng Z., Jiang W., Zinn A. A., Knobler C. B., Hawthorne M. F.. Facile Electrophilic Iodination of Icosahedral Carboranes. Synthesis of Carborane Derivatives with Boron-Carbon Bonds via the Palladium-Catalyzed Reaction of Diiodocarboranes with Grignard Reagents. Inorg. Chem. 1995;34:2095–2100. doi: 10.1021/ic00112a023. [DOI] [Google Scholar]
  26. Sieckhaus J. F., Semenuk N. S., Knowles T. A., Schroeder H.. Icosahedral Carboranes. XIII. Halogenation of p-carborane. Inorg. Chem. 1969;8:2452–2457. doi: 10.1021/ic50081a041. [DOI] [Google Scholar]
  27. Fox M. A., Wade K.. Deboronation of 9-substituted-ortho- and -meta-carboranes. J. Organomet. Chem. 1999;573:279–291. doi: 10.1016/S0022-328X(98)00881-X. [DOI] [Google Scholar]
  28. Dunks G. B., Wiersema R. J., Hawthorne M. F.. Chemical and Structural Studies of the Dodecahydrodicarba-closo-dodecarborate­(2-) Ions Produced from Icosahedral Dicarbacloso-dodecarborane(12) J. Am. Chem. Soc. 1973;95:3174–3179. doi: 10.1021/ja00791a018. [DOI] [Google Scholar]
  29. McKay D., Macgregor S. A., Welch A. J.. Isomerisation of nido-[C2B10H12]2– Dianions: Unprecedented Rearrangements and New Structural Motifs in Carborane Cluster Chemistry. Chem. Sci. 2015;6:3117–3128. doi: 10.1039/C5SC00726G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Núñez R., Tarrés M., Ferrer-Ugalde A., de Biani F. F., Teixidor F.. Electrochemistry and Photoluminescence of Icosahedral Carboranes, Boranes, Metallacarboranes, and Their Derivatives. Chem. Rev. 2016;116:14307–14378. doi: 10.1021/acs.chemrev.6b00198. [DOI] [PubMed] [Google Scholar]
  31. Morris J. H., Gysling H. J., Reed D.. Electrochemistry of Boron Compounds. Chem. Rev. 1985;85(1):51–76. doi: 10.1021/cr00065a003. [DOI] [Google Scholar]
  32. a Miller J. R., Cook A. R., Šimková L., Pospíšil L., Ludvík J., Michl J.. The Impact of Huge Structural Changes on Electron Transfer and Measurement of Redox Potentials: Reduction of ortho-12-Carborane. J. Phys. Chem. B. 2019;123:9668–9676. doi: 10.1021/acs.jpcb.9b08151. [DOI] [PubMed] [Google Scholar]; b Mattejat M., Ménard G.. Selective Heterogeneous Capture and Release of Actinides Using Carborane-Functionalized Electrodes. Chem. Commun. 2023;59:9710–9713. doi: 10.1039/D3CC02135A. [DOI] [PubMed] [Google Scholar]
  33. Connelly N. G., Geiger W. E.. Chemical Redox Agents for Organometallic Chemistry. Chem. Rev. 1996;96:877–910. doi: 10.1021/cr940053x. [DOI] [PubMed] [Google Scholar]
  34. Spokoyny A. M.. New ligand platforms featuring boron-rich clusters as organomimetic substituents. Pure Appl. Chem. 2013;85:903–919. doi: 10.1351/PAC-CON-13-01-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Blanch R. J., Sleeman A. J., White T. J., Arnold A. P., Day A. I.. Cucurbit­[7]­uril and o-Carborane Self Assemble to Form a Molecular Ball Bearing. Nano Lett. 2002;2:147–149. doi: 10.1021/nl015655s. [DOI] [Google Scholar]
  36. a Hawthorne M. F., Adler R. G.. Determination of the Electronic Properties of Carboranes, Carborane Anions, and Metallocarboranes from Fluorine-19 Nuclear Magnetic Resonance Studies. J. Am. Chem. Soc. 1970;92:6174–6182. doi: 10.1021/ja00724a012. [DOI] [Google Scholar]; b Gabel, D. ; Al-Joumhawy, M. ; Assaf, K. A. . The Hammett Substituent Constant of the Dodecaborate Dianion Inaugurates a Non-coordinating, Non-basic, and Strongly Inductively Electron-donating Group for Organic Chemistry 10.21203/rs.3.rs-3930485/v1. [DOI]
  37. a Modro T. A., Ridd J. H.. Substituent Effects of Positive Poles in Aromatic substitution. Part III. Nature of the Deactivating Effect of the Trimethylammonio-Group. J. Chem. Soc. B. 1968:528–534. doi: 10.1039/j29680000528. [DOI] [Google Scholar]; b Brown H. C., Okamoto Y.. Electrophilic Substituent Constants. J. Am. Chem. Soc. 1958;80(18):4979–4987. doi: 10.1021/ja01551a055. [DOI] [Google Scholar]; c Roberts J. D., Clement R. A., Drysdale J. J.. The Electrical Effect of the Trimethylammonium [-N­(CH3)3 +] Group. J. Am. Chem. Soc. 1951;73(5):2181–2183. doi: 10.1021/ja01149a077. [DOI] [Google Scholar]
  38. a Quan Y., Xie Z.. Controlled Functionalization of o-carborane via Transition Metal Catalyzed B-H Activation. Chem. Soc. Rev. 2019;48:3660–3673. doi: 10.1039/C9CS00169G. [DOI] [PubMed] [Google Scholar]; b Quan Y., Xie Z.. Iridium Catalyzed Regioselective Cage Boron Alkenylation of o-carboranes via Direct Cage B-H Activation. J. Am. Chem. Soc. 2014;136(44):15513–15516. doi: 10.1021/ja509557j. [DOI] [PubMed] [Google Scholar]; c Zhang Y., Wang T., Wang L., Sun Y., Lin F., Liu J., Duttwyler S.. RhIII -Catalyzed Functionalization of closo-Dodecaborates by Selective B-H Activation: Bypassing Competitive C-H Activation. Chem. - Eur. J. 2018;24:15812–15817. doi: 10.1002/chem.201803455. [DOI] [PubMed] [Google Scholar]; d Zhu T.-C., Xing Y., Sun Y., Duttwyler S., Hong X.. Directed B-H Functionalization of the closo-Dodecaborate Cluster via Concerted Iodination-Deprotonation: Reaction Mechanism and Origins of Regioselectivity. Org. Chem. Front. 2020;7:3648–3655. doi: 10.1039/D0QO01019G. [DOI] [Google Scholar]; e Qiu Z., Xie Z.. A Strategy for Selective Catalytic B-H Functionalization of o-Carboranes. Acc. Chem. Res. 2021;54(21):4065–4079. doi: 10.1021/acs.accounts.1c00460. [DOI] [PubMed] [Google Scholar]; f Chen M., Xu J., Zhao D., Sun F., Tian S., Tu D., Lu C., Yan H.. Site-Selective Functionalization of Carboranes at the Electron-Rich Boron Vertex: Photocatalytic B-C Coupling via a Carboranyl Cage Radical. Angew. Chem., Int. Ed. 2022;61:e202205672. doi: 10.1002/anie.202205672. [DOI] [PubMed] [Google Scholar]
  39. a Kaszyński P., Ringstrand B.. Functionalization of closo-Borates via Iodonium Zwitterions. Angew. Chem., Int. Ed. 2015;54:6576–6581. doi: 10.1002/anie.201411858. [DOI] [PubMed] [Google Scholar]; b Kleinsasser J. F., Fisher S. P., Tham F. S., Lavallo V.. On the Reactivity of the Carba-closo-dodecaborate Anion with the Trityl Cation. Eur. J. Inorg. Chem. 2017;2017:4417–4419. doi: 10.1002/ejic.201700614. [DOI] [Google Scholar]; c Vrána J., Holub J., Samsonov M. A.. et al. Access to Cationic Polyhedral Carboranes via Dynamic Cage Surgery with N-heterocyclic Carbenes. Nat. Commun. 2021;12:4971. doi: 10.1038/s41467-021-25277-0. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Xu S., Zhang H., Xu J., Suo W., Lu C.-S., Tu D., Guo X., Poater J., Sola M., Yan H.. Photoinduced Selective B–H Activation of nido-Carboranes. J. Am. Chem. Soc. 2024;146:7791–7802. doi: 10.1021/jacs.4c00550. [DOI] [PubMed] [Google Scholar]; e Mu X., Axtell J. C., Bernier N. A., Kirlikovali K. O., Jung D., Umanzor A., Qian K., Chen X., Bay K. L., Kirollos M., Rheingold A. L., Houk K. N., Spokoyny A. M.. Sterically Unprotected Nucleophilic Boron Cluster Reagents. Chem. 2019;5:2461–2469. doi: 10.1016/j.chempr.2019.07.018. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Varkhedkar R., Yang F., Dontha R., Zhang J., Liu J., Spingler B., van der Veen S., Duttwyler S.. Natural-Product-Directed Catalytic Stereoselective Synthesis of Functionalized Fused Borane Cluster–Oxazoles for the Discovery of Bactericidal Agents. ACS Cent. Sci. 2022;8:322–331. doi: 10.1021/acscentsci.1c01132. [DOI] [PMC free article] [PubMed] [Google Scholar]; g Jayaweera H. D. A. C., Rahman M. M., Pellechia P. J., Smith M. D., Peryshkov D. V.. Free Three-dimensional Carborane Carbanions. Chem. Sci. 2021;12:10441–10447. doi: 10.1039/D1SC02252K. [DOI] [PMC free article] [PubMed] [Google Scholar]; h Sun F., Tan S., Cao H.-J., Lu C.-S., Tu D., Poater J., Sola M., Yan H.. Facile Construction of New Hybrid Conjugation via Boron Cage Extension. J. Am. Chem. Soc. 2023;145:3577–3587. doi: 10.1021/jacs.2c12526. [DOI] [PubMed] [Google Scholar]; i Lovera S. O., Gregory A., Espinoza Morelos K., Farias P., Carta V., Musgrave C. B. III, Lavallo V.. Noncatalyzed Intramolecular B–N and B–O Cross-Coupling of “Inert” Carboranes Lead to the Formation of an Unusual Oxoborane, via Reversible Cluster C–B Bond Scission. J. Am. Chem. Soc. 2025;147:17764–17771. doi: 10.1021/jacs.5c01106. [DOI] [PMC free article] [PubMed] [Google Scholar]; j Huang J.-H., Zhang H., Wang Z.-Y., Hu J.-H., Li J., Cai J., Zang S.-Q.. Atomic-Precise Active Site Surgery on Carboranylthiolate-Protected Silver Nanocluster Catalysts. J. Am. Chem. Soc. 2025;147:16593–16601. doi: 10.1021/jacs.5c03721. [DOI] [PubMed] [Google Scholar]
  40. Recent representative example (and references within):; Hattori Y., Ishimura M., Ohta Y., Takenaka H., Kawabata S., Kirihata M.. Dodecaborate Conjugates Targeting Tumor Cells Overexpressing Translocator Protein for Boron Neutron Capture Therapy. ACS Med. Chem. Lett. 2022;13:50–54. doi: 10.1021/acsmedchemlett.1c00377. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ja5c05637_si_001.pdf (10.1MB, pdf)

Articles from Journal of the American Chemical Society are provided here courtesy of American Chemical Society

RESOURCES