Oxidative Generation of Boron-Centered Radicals in Carboranes

Abstract

We report the first indirect observation and use of boron vertex-centered carboranyl radicals generated by the oxidation of modified carboranyl precursors. These radical intermediates are formed by the direct oxidation of a B─B bond between a boron cluster cage and an exopolyhedral boron-based substituent (e.g., −BF₃K, −B(OH)₂). The in situ generated radical species are shown to be competent substrates in reactions with oxygen-based radicals, dichalcogenides, and N-heterocycles, yielding the corresponding substituted carboranes containing B─O, B─S, B─Se, B─Te, and B─C bonds. Remarkably, this chemistry tolerates various electronic environments, providing access to facile substitution chemistry at both electron-rich and electron-poor B─H vertices in carboranes.

Graphical Abstract

Carbon-centered radicals are ubiquitous in chemistry and have garnered significant interest due to their utility in building complex organic molecules.^1,2 Particularly, methods utilizing carbon-centered radical intermediates have made use of stable radical precursors containing cleavable C─X bonds (X: −COOH^3a, (−SO₂)₂Zn^3b,c, −B(OH)₂^3d-f, −BF₃K^3f-i) that undergo homolytic C─X bond scission in the presence of oxidants. These radical intermediates have subsequently been used to substitute various substrates including N-heterocycles^3a-d,f,g,i, extended aromatic systems^3e, and oxygen-based radical traps (Figure 1a).^3h

Figure 1.

(a) Literature examples of carbon-centered radicals generated by the oxidation of C─B bonds. (b) This work, oxidation of carboranes containing exopolyhedral B─[B] bonds.

Icosahedral carboranes (C₂B₁₀H₁₂)⁴ are molecular clusters that exist as three distinct isomers (ortho-, meta-, para-), featuring steric profiles similar to that of adamantane.⁵ Due to inherent asymmetry of the electronic structure, various vertices in these species feature orthogonal reactivity. For example, C─H vertices (pKa: 22-27)^4a exhibit nucleophilic reactivity after deprotonation with base. Conversely, B─H vertices in these molecules have been amenable to electrophilic substitution on the electron-rich boron vertices furthest away from the carbon sites.⁴ Most recently, new methods have enabled metal-catalyzed cross-coupling^6a, metal-catalyzed B─H activation^6b,c, and nucleophilic substitution^6d strategies at most B─H vertices in carboranes. While the majority of the above methods rely on two-electron transformations, one-electron chemistry has remained underexplored with these clusters.⁷

Recently, an example showcasing the possibility of efficiently generating boron vertex-centered radicals in carboranes was accomplished by Xie and coworkers.^7d In their elegant report, Xie et al. utilized the reduction of ortho-carboranyl diazonium salts to generate boron vertex-centered radical intermediates. Subsequently, the generated radical intermediates exhibited reactivity towards five-membered heterocycles and simple arenes. We hypothesized that, complimentary to the reductive approach for generating boron vertex-centered radicals, one could develop oxidative chemistry, akin to chemistry developed with borylated aryl and alkyl-based species (vide supra, Figure 1).

In order to test our hypothesis, we set out to prepare potassium 9-meta-carboranyltrifluoroborate (3a, Figure 2a). Importantly, 3a would provide similar steric and electronic environments to alkyl trifluoroborates, which have been widely studied as radical precursors. ^3g-i To prepare 3a, we first developed borylation conditions to transform 9-iodo-meta-carboranyl (1a, Figure 2a) into the corresponding 9-meta-carboranyl boronic ester (2a, Figure 2a, SI sec. 4) while monitoring the progress of the reaction by HRGC-MS. After isolation of 2a, ¹¹B NMR spectroscopy of 2a revealed two diagnostic resonances corresponding to the substituted ¹¹B site of the boron cage and the ¹¹B of the boronic ester in a 1:1 ratio. The crystallographically derived structure of 2a (SI, sec. 12) was found to be consistent with its proposed structural formulation (Figure 2b), featuring an exopolyhedral B(9)─Bpin bond. The measured B(9)─Bpin bond length (1.684(3) Å) for 2a is consistent with the previously studied electron-poor, 3-ortho-carboranyl boronic ester obtained via direct B─H borylation (1.680(6) Å).⁸ Notably, similar to alkyl and aryl boronic esters⁹, 2a undergoes deprotection in the presence of fluoride or acid, yielding the corresponding trifluoroborate salt (3a) and boronic acid (4a) derivatives in 82% and 83% yields, respectively (Figure 2a, SI sec. 5). Additionally, it was possible to prepare the analogous 9-ortho-carboranyl boronic ester and acid, 2b and 4b, though the fluoride-sensitivity¹⁰ of ortho-carborane prevented the synthesis of the 9-ortho-carboranyltrifluoroborate derivative (see SI for full experimental details).

Figure 2.

(a) Synthesis of substituted carboranes containing exopolyhedral boron-based substituents (see SI for experimental details). (b) Single-crystal X-ray structure of 2a. (c) Oxidation 3a in the presence of TEMPO. (d) ¹¹B NMR spectrum of 5a. (e) Single-crystal X-ray structure of 5a. Thermal ellipsoids are drawn at 50% probability, hydrogens are omitted for clarity.

With a library of carborane-based reagents (3a and 4a-b), in hand, we commenced our studies to probe the propensity of these B─borylated carboranes to undergo oxidative B─[B] ([B]: −BF₃K, or −B(OH)₂) bond cleavage. We first performed the oxidation of 3a in acetic acid with manganese (III) acetate dihydrate (Mn(OAc)₃·2H₂O) in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO, Figure 2c, SI sec. 6,9) with the intent of trapping any radical intermediates formed in situ. During the course of the reaction, we observed the exclusive formation of a boron cluster-containing species corresponding to a TEMPO adduct of meta-carborane (5a) by HRGC-MS that could be isolated via silica gel column chromatography in 74% yield. ¹¹B NMR spectroscopy of purified 5a revealed a ¹¹B resonance within a chemical shift range indicative of an exopolyhedral ¹¹B─O bond (Figure 2d), which was subsequently confirmed by single-crystal X-ray crystallography (Figure 2e).

Isolation of 5a suggested the intermediacy of the boron vertex-centered radical, which could be trapped by other reagents besides TEMPO. To explore this generality, we evaluated a series of dichalcogenides as trapping agents under similar oxidizing conditions (Figure 3, SI sec. 10). First we performed the oxidation of 3a in the presence of diphenyl disulfide. This reaction generated a product mixture containing a species corresponding to 5b by HRGC-MS. Compound 5b was isolated from the product mixture as an air-stable solid via silica gel column chromatography in 56% yield and its identity was confirmed by ¹H, ¹³C, and ¹¹B NMR spectroscopy. The ¹¹B NMR spectrum of 5b featured a diagnostic ¹¹B resonance consistent with the formation of an exopolyhedral ¹¹B─S bond and is in agreement to the proposed structural formulation (Figure 3).

Figure 3.

Oxidation of 3a and reaction with TEMPO and dichalcogenides. ¹¹B NMR (and heteronuclear NMR, where relevant) spectra of compounds 5a-5e. Resonances highlighted in blue are attributed to the exopolyhedral ¹¹B─Y bond. Isolated yields are given as percentages and conversion by HRGC-MS in parenthesis. *No starting material was observed by HRGC-MS. **Conversion was determined by ¹¹B NMR spectroscopy. ^aReaction was performed under an atmosphere of argon.

Similarly, oxidation of 3a in the presence of diphenyl diselenide and subsequent purification produced 5c in 57% isolated yield. Consistent with the presence of an exopolyhedral B─Se bonding interaction in 5c, one can observe a ⁷⁷S─¹¹B quartet resonance in the ⁷⁷Se NMR of 5c (Figure 3). When the oxidation of 3a is performed under inert atmosphere in the presence of diphenyl ditelluride, a species containing an exopolyhedral B─Te bond (5d) is formed, as suggested by HR-GCMS. This species could be isolated via a similar purification protocol (vide supra), albeit in a lower isolated yield (27%), likely due to the poor oxidative stability of telluroether compounds.¹¹ NMR spectroscopy experiments of 5d, including ¹¹B and ¹²⁵Te NMR spectra, are fully consistent with its proposed structural formulation. Finally, utilizing this approach, we were able to demonstrate the formation of a selenoether species (5e) containing two boron-connected substitutions, and the first example of a mixed-isomer dicarboranyl selenide (See SI for full experimental details). Interestingly, given the dramatic electron donating capabilities of the B(9) position of ortho- and meta-carboranes, 5e exhibits the most downfield ⁷⁷Se NMR chemical shift (Figure 3, δ = −284.0 ppm) for any known selenoether-type compound reported to date.¹¹ Overall, formation of products 5b-5e further reinforces our hypothesis of the intermediacy of the boron vertex-centered radicals during the course of 3a oxidation.

Carbon-centered radical intermediates have been known to undergo C─H activation processes with N-heterocycles, thereby allowing the formation of C─C bonds. We therefore hypothesized that the oxidatively generated boron vertex-centered radical intermediate could undergo a similar C─H activation mechanism, forming the desired exopolyhedral B─C bond (SI sec. 10). To investigate the potential for the carboranyl radical intermediate to participate in C─H activation mechanisms with N-heterocycles, we chose 4-methyl-quinoline^3g as a model substrate. 4-methyl-quinoline was treated with an excess of Mn(OAc)₃·2H₂O (3 eq) and 3a (1.5 eq) in acetic acid (1 mL). Monitoring of this reaction by HRGC-MS suggested partial conversion (17%) of 4-methyl-quinoline to a carborane-containing heterocyclic product. Increasing the stoichiometric ratio of Mn(OAc)₃·2H₂O and 3a, however, resulted in a substantial increase of the product formation (up to 32% conversion, SI sec. 7). When this reaction is performed on a larger scale (0.25 mmol), the product mixture can be subjected to purification via silica gel column chromatography to produce 5f as suggested by diagnostic ¹H, ¹³C, and ¹¹B NMR spectroscopy in 30% isolated yield. Notably, the efficiency of the carboranyl radical-heterocycle coupling is limited in this case, and is consistent with the sterically hindered nature of carborane. Similar reactions utilizing sterically hindered carbon-based substrates (e.g. tert-butyl radical synthons) usually exhibit conversions up to 58%.^3g Previous mechanistic studies into the C─H activation of N-heterocycles by carbon-centered radicals highlighted the innate reactivity of certain positions in pyridines that could, in theory, be extended to other heterocyclic systems.^3c To confirm the paralleled reactivity between boron vertex- and carbon-centered radicals further, we employed benzothiazole as a model five-membered heterocycle with innate reactivity towards carbon-centered radicals at C(2). When the oxidation of 3a is performed in a 1:1 mixture of acetic acid:water with benzothiazole as a trapping reagent, formation of a carborane-containing heterocyclic product was possible as indicated by HRGC-MS. Compound 5g was isolated from the product mixture via a similar purification protocol (vide supra) and obtained in 41% yield. ¹H, ¹³C, and ¹¹B NMR spectroscopy of 5g suggested likely C─H activation by the carboranyl radical at C(2) of benzothiazole, and single-crystals of 5g suitable for X-ray crystallography were subsequently grown from an acetone:pentane mixture.

The crystallographically derived structure of 5g (Figure 4a) is in agreement with the proposed structural formulation and definitively indicates substitution at C(2) position of the heterocycle leading to the formation of an exopolyhedral B(9)─C(2) bond. Furthermore, reactivity towards pyridines and quinoxalines was tested to further confirm that the regioselective substitution of the carboranyl radical onto the N-heterocycle is consistent with proposed radical-promoted C─H functionalization mechanisms.^3c Under identical oxidation conditions and following similar isolation procedures used in the synthesis of 5f, the radical-heterocycle coupling works comparably well with pyridines and quinoxalines, affording 5h and 5i in 44% and 34% isolated yields, respectively. Single-crystal X-ray crystallography of 5i (Figure 4a) confirms the anticipated regioselectivity of the C─H functionalization. Importantly, formation of products 5f-i are indicative of the paralleled reactivity between oxidatively generated boron vertex- and carbon-centered radicals when participating in analogous C─H functionalization mechanisms (Figure 4b). Interestingly, when highly activated N-heterocycles are used (e.g., 4-trifluoromethylpyridine), disubstitution is observed in significant quantities (SI sec. 9).

Figure 4.

(a) Oxidation of 3a and reaction with N-heterocycles. (b) ¹H NMR experiments of 4-methylquinoline and 5f. ^aReaction was performed in 1:1 AcOH:H₂O. Isolated yields are given as percentages and conversion by HRGC-MS in parenthesis. Thermal ellipsoids are drawn at 50% probability, hydrogens are omitted for clarity.

In order to determine the accessibility of other carboranyl radical intermediates, we probed the susceptibility of 4b and 3-ortho-carboranyl boronic acid (4c) to undergo homolytic B─B(OH)₂ bond scission in the presence of Mn(OAc)₃·2H₂O (Figure 5a, SI sec. 11). Initially, 4b was treated with identical oxidation conditions used in the preparation of 5a (Figure 5a), and the formation of 6a was monitored by HR-GCMS. After 18 hours, 6a was isolated from the reaction mixture via silica gel column chromatography in a similar yield to that of 5a (70%). Analogous to 5a, ¹¹B NMR spectroscopy of 6a revealed a diagnostic ¹¹B resonance typical of the formation of an exopolyhedral ¹¹B─O bond and can be crystallographically characterized. Likewise, when using 4c as a radical precursor, it was possible to synthesize and isolate 6b in 73% yield following the same procedure (vide supra). Carboranyl radical intermediates from the oxidation of 4b and 4c formed in the presence of 4-^tBu-pyridine also participate in the anticipated C─H functionalization pathway. As a result, products 6c and 6d were prepared and isolated in comparable yields to 5i (33% and 36%, respectively). Surprisingly, compounds 6c-d are the first known examples of substituted ortho-carboranes containing pyridyl groups at any boron vertex of the cluster. The synthesis of compounds 6a-d suggests that the reactivity of the carboranyl radical intermediates are independent of any perceivable difference in the electronic nature of the exopolyhedral boron-based substituent.

Figure 5.

(a) Oxidation of 4b-c. (b) Single-crystal X-ray structure of 6a. ^aReaction also included 1.25 eq of TFA. Isolated yields are given as percentages and conversion by HRGC-MS in parenthesis. Thermal ellipsoids are drawn at 50% probability, hydrogens are omitted for clarity.

In conclusion, we report the first example of boron vertex-centered carboranyl radicals generated via oxidative exopolyhedral B─[B] bond scission. Once generated, the carboranyl radical intermediates have been observed to participate in substitution chemistry similar to that of carbon-centered radicals, as manifested by both the chemoselectivity for chalcogen-based radical traps (TEMPO, dichalcogenides) and the regioselectivity of heterocycle substitution. The use of reactive, boron-centered carboranyl radical intermediates, has afforded new avenues to forge exopolyhedral B─X bonds with boron-rich clusters. Additionally, this new method for carboranyl radical generation expands upon the existing repertoire of reactive boron cluster species¹² and main group-centered radicals.¹³