m-Carborane as a Novel Core for Periphery-Decorated Macromolecules

Closom-C2B10H12 can perform as a novel core of globular periphery-decorated macromolecules. To do this, a new class of di and tetrabranched m-carborane derivatives has been synthesized by a judicious choice of the synthetic procedure, starting with 9,10-I2-1,7-closo-C2B10H10. The 2a-NPA (sum of the natural charges of the two bonded atoms) value for a bond, which is defined as the sum of the NPA charges of the two bonded atoms, matches the order of electrophilic reaction at the different cluster bonds of the icosahedral o-and m- carboranes that lead to the formation of B-I bonds. As for m-carborane, most of the 2a-NPA values of B-H vertexes are positive, and their functionalization is more challenging. The synthesis and full characterization of dibranched 9,10-R2-1,7-closo-carborane (R = CH2CHCH2, HO(CH2)3, Cl(CH2)3, TsO(CH2)3, C6H5COO(CH2)3, C6H5COO(CH2)3, N3(CH2)3, CH3CHCH, and C6H5C2N3(CH2)3) compounds as well as the tetrabranched 9,10-R2-1,7-R2-closo-C2B10H8 (R = CH2CHCH2, HO(CH2)3) are presented. The X-ray diffraction of 9,10-(HO(CH2)3)2-1,7-closo-C2B10H10 and 9,10-(CH3CHCH)2-1,7-closo-C2B10H10, as well as their Hirshfeld surface analysis and decomposed fingerprint plots, are described. These new reported tetrabranched m-carborane derivatives provide a sort of novel core for the synthesis of 3D radially grown periphery-decorated macromolecules that are different to the 2D radially grown core of the tetrabranched o-carborane framework.


Introduction
Icosahedral carborane clusters with empirical formula C 2 B 10 H 12 can be in three different isomers: 1,2-closo-C 2 B 10 H 12 (o-carborane), 1,7-closo-C 2 B 10 H 12 (m-carborane; 1), and 1,12-closo-C 2 B 10 H 12 (p-carborane). Figure 1 displays a schematic representation of the isomers with their vertexes numbering. Despite their common icosahedral geometry, they display similarities, but also important differences. Among the similarities are the high stabilities and 3D geometrical properties, their very similar 3D aromatic character [1,2] that leads to display great inertia to keep the original scaffold upon electrophilic substitution, their dual-mode as electron-withdrawing through carbon or electron-donating through boron vertexes [3][4][5], their molecular volume that is high compared to rotating benzene [6], and high hydrophobicity [7][8][9]. Among the differences are the dipolar moment and their different reactivity towards boron elimination [8], and the lowest unoccupied molecular orbital (LUMO) geometrical disposition that is responsible for many of the physical properties of the isomers. Among the three of them, the most extensively studied is the o-carborane. Some tips to keep in mind between the three isomers when substitution is sought are: First, the weak acidic C c -H bond (C c = cluster C atom) [10] can be deprotonated using a strong base followed by an electrophilic reaction to form the C c -R bond [8,11]. Second, the B-H hydrogen atoms with the hydridic character on (B (9,12), B (8,10), and B (4,5,7,11)) are On the other hand, the reactivity of m-carborane is less studied but for the Cc-H vertexes, which are less acidic as compared to the Cc-H vertexes of the o-isomer [10,26]. Using a similar strategy as for o-carborane, a wide variety of 1-R-1,7-closo-C2B10H11 and 1,7-R2-1,7-closo-C2B10H10 derivatives has been developed [27][28][29][30][31][32][33][34][35]. To some extent, the current state of knowledge of the m-carborane functionalization through the B-H vertexes is in an odd situation. As compared to the o-carborane, a much-limited number of protocols leading to modify the B-H vertexes in the m-cluster have been reported [8,11]. In this context, very few derivatives of m-carborane with a functional group that is bonded to B(9) or B(9) and B(10) synchronously have been described [27][28][29][30][31][32][33][34][35]. The Pd-catalyzed crosscoupling reaction of 9-X-1,7-closo-C2B10H11 and 9,10-X2-1,7-closo-C2B10H10 (X= halogen atom) represents one of these examples of derivatization [34,36,37]. By contrast to the o-carborane, no multibranched m-carborane structures with a general formula 1,7-R2-9,10-R'2-1,7-closo-C2B10H8 have been reported despite the potential of its structure and the relatively high reactivity of the Cc-H bonds that should allow the reaction to a great extent. Notably, as shown in Figure 2, the m-carborane core provides a 3D radially growth core while o-carborane a 2D one.
The synthesis of 9,10-I2-1,7-closo-C2B10H10; (2) has been reported by using two different methodologies: i) the electrophilic iodination reaction of icosahedral closo m-carborane (1) by using a molar Equiv. Of iodine : monochloride, which acts as an electrophilic agent, in the presence of catalytic amounts of aluminum chloride, and ii) using iodine as an electrophilic agent in a very acidic media (HNO3:H2SO4 , 1:1). The target compound 2 was obtained in 60% and 87% yield, respectively [38], [39]. Our study focused on the synthesis of new Boron disubstituted closo m-carborane derivatives at the 9 and 10 vertexes began with the synthesis of 2 in 87% yield by combining the two reported methods: an equimolar ratio of m-carborane (1): iodine in acidic HNO3:H2SO4 (1:1) solution was left under reflux to react for 3 h (Scheme 1).

Figure 2.
Schematic view of the two types of radially expanded tetrabranched core for constructing dendritic structures. Circles colour: dark grey correspond to C c -H bonds, black to C atoms, pink to Boron atoms and grey to B-H vertexes in the tetra-branched clusters.
The synthesis of 9,10-I 2 -1,7-closo-C 2 B 10 H 10 ; (2) has been reported by using two different methodologies: i) the electrophilic iodination reaction of icosahedral closo m-carborane (1) by using a molar Equiv. Of iodine: monochloride, which acts as an electrophilic agent, in the presence of catalytic amounts of aluminum chloride, and ii) using iodine as an electrophilic agent in a very acidic media (HNO 3 :H 2 SO 4 , 1:1). The target compound 2 was obtained in 60% and 87% yield, respectively [38,39]. Our study focused on the synthesis of new Boron disubstituted closo m-carborane derivatives at the 9 and 10 vertexes began with the synthesis of 2 in 87% yield by combining the two reported methods: an equimolar ratio of m-carborane (1): iodine in acidic HNO 3 :H 2 SO 4 (1:1) solution was left under reflux to react for 3 h (Scheme 1).

Figure 2.
Schematic view of the two types of radially expanded tetrabranched core for constructing dendritic structures. Circles colour: dark grey correspond to Cc-H bonds, black to C atoms, pink to Boron atoms and grey to B-H vertexes in the tetra-branched clusters.
The synthesis of 9,10-I2-1,7-closo-C2B10H10; (2) has been reported by using two different methodologies: i) the electrophilic iodination reaction of icosahedral closo m-carborane (1) by using a molar Equiv. Of iodine : monochloride, which acts as an electrophilic agent, in the presence of catalytic amounts of aluminum chloride, and ii) using iodine as an electrophilic agent in a very acidic media (HNO3:H2SO4 , 1:1). The target compound 2 was obtained in 60% and 87% yield, respectively [38], [39]. Our study focused on the synthesis of new Boron disubstituted closo m-carborane derivatives at the 9 and 10 vertexes began with the synthesis of 2 in 87% yield by combining the two reported methods: an equimolar ratio of m-carborane (1): iodine in acidic HNO3:H2SO4 (1:1) solution was left under reflux to react for 3 h (Scheme 1). To produce the B-C bonds on 1, a useful and general method is the Kumada cross-coupling reaction on B-iodinated m-carborane 2 with Grignard reagents in the presence of Pd(II) and Cu(I) catalysts. To achieve the di-branched m-carborane derivatives at the 9, 10 vertexes, the cross-coupling reaction on 2 was studied using CH2CHCH2MgCl Grignard derivative in the presence of [PdCl2(PPh3)2] and CuI as catalysts to give the 9,10-(CH2CHCH2)2-1,7-closo-C2B10H10 (3) in 95% yield [40].
The terminal olefin groups in 3 are ready for further reactions on them, enabling the m-carborane cluster to become the template for a new type of macromolecules having a rigid head and two appended branches. As a first example of these molecules, compound 3 was converted to 9,10-(HOCH2CH2CH2)2-closo-1,7-C2B10H10, (4) following the hydroboration/oxidation reaction on 3 by using BH3·THF as hydroboration agent and subsequent oxidation with H2O2 in a basic aqueous solution. After workup, crystalline white pure solid, 4, was obtained in 93% yield. The 1 H NMR spectrum displays a new broad peak at 3.43 ppm, which supports the presence of the O-H group in 4. Also, the 1 H and 13 C{ 1 H} NMR spectra revealed that the reaction had proceeded by an anti-Scheme 1. Synthesis of 9,10-(CH 2 =CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 10 (3). Dark circles are C c -H vertexes, pink circles are boron atoms, and grey circles are B-H vertexes.
To produce the B-C bonds on 1, a useful and general method is the Kumada cross-coupling reaction on B-iodinated m-carborane 2 with Grignard reagents in the presence of Pd(II) and Cu(I) catalysts. To achieve the di-branched m-carborane derivatives at the 9, 10 vertexes, the cross-coupling reaction on 2 was studied using CH 2 CHCH 2 MgCl Grignard derivative in the presence of [PdCl 2 (PPh 3 ) 2 ] and CuI as catalysts to give the 9,10-(CH 2 CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 10 (3) in 95% yield [40].
The terminal olefin groups in 3 are ready for further reactions on them, enabling the m-carborane cluster to become the template for a new type of macromolecules having a rigid head and two appended branches. As a first example of these molecules, compound 3 was converted to 9,10-(HOCH 2 CH 2 CH 2 ) 2 -closo-1,7-C 2 B 10 H 10 , (4) following the hydroboration/oxidation reaction on 3 by using BH 3 ·THF as hydroboration agent and subsequent oxidation with H 2 O 2 in a basic aqueous solution. After workup, crystalline white pure solid, 4, was obtained in 93% yield. The 1 H NMR spectrum displays a new broad peak at 3.43 ppm, which supports the presence of the O-H group in 4. Also, the 1 H and 13 C{ 1 H} NMR spectra revealed that the reaction had proceeded by an anti-Markovnikov addition, therefore having the two hydroxyl groups at terminal positions. No hindered hydroboranes were thus needed for the control of the reaction's regioselectivity.
These terminal alcohol groups anticipate versatile chemistry for radial growth, given the availability of the terminal hydroxyl groups for further elongation of the chains. Moreover, the C c -H vertexes on the rigid m-carborane head are ready for derivatization or supramolecular assembly. Then, the m-carborane cluster, as o-carborane does, provides a singular platform for the construction of highly dense multibranched molecules with a wide range of possibilities. Therefore, derivatives of m-carborane with precise patterns of substitution, which are sterically different from the ones of o-carborane but complementary, can be prepared by a judicious choice of the synthetic procedure. Consequently, the substitution of the terminal hydroxyl units in 4 by chloro (5), ester (6), tosyl (7) or azide (8) groups, which enable the branches to grow by a subsequent coupling reaction with nucleophilic agents, was achieved (Scheme 2). hydroboranes were thus needed for the control of the reaction's regioselectivity.
These terminal alcohol groups anticipate versatile chemistry for radial growth, given the availability of the terminal hydroxyl groups for further elongation of the chains. Moreover, the Cc-H vertexes on the rigid m-carborane head are ready for derivatization or supramolecular assembly. Then, the m-carborane cluster, as o-carborane does, provides a singular platform for the construction of highly dense multibranched molecules with a wide range of possibilities. Therefore, derivatives of m-carborane with precise patterns of substitution, which are sterically different from the ones of ocarborane but complementary, can be prepared by a judicious choice of the synthetic procedure. Consequently, the substitution of the terminal hydroxyl units in 4 by chloro (5), ester (6), tosyl (7) or azide (8) groups, which enable the branches to grow by a subsequent coupling reaction with nucleophilic agents, was achieved (Scheme 2). Scheme 2. Derivatization reactions on 9,10-(CH2=CHCH2)2-1,7-closo-C2B10H10 3. Dark circles are Cc-H vertexes, pink circles are boron atoms, and grey circles are B-H vertexes.
As an example of the esterification of the terminal alcohol groups, compound 6 was obtained in 90% yield by Steglich esterification [41,42] with benzoic acid using N,N'-dicyclohexylcarbodiimide as a coupling reagent and the N,N-dimethylaminopyridine as a catalyst.
Overall, we have succeeded in the preparation of these new m-carborane derivatives 5-7 thanks to the primary alcohol groups, which undergo chain extension reactions. Owing to the formation of 5, a new way of functionalization is opened to prepare the azide derivative 8, which in turn opens the way to perform the Azide-Alkyne Huisgen Cycloaddition commonly known as the click reaction. Scheme 2. Derivatization reactions on 9,10-(CH 2 =CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 10 3. Dark circles are C c -H vertexes, pink circles are boron atoms, and grey circles are B-H vertexes.
As an example of the esterification of the terminal alcohol groups, compound 6 was obtained in 90% yield by Steglich esterification [41,42] with benzoic acid using N,N'-dicyclohexylcarbodiimide as a coupling reagent and the N,N-dimethylaminopyridine as a catalyst.
Overall, we have succeeded in the preparation of these new m-carborane derivatives 5-7 thanks to the primary alcohol groups, which undergo chain extension reactions. Owing to the formation of 5, a new way of functionalization is opened to prepare the azide derivative 8, which in turn opens the way to perform the Azide-Alkyne Huisgen Cycloaddition commonly known as the click reaction. Compound 8 was obtained in 81% yield by avigorous stirring of 5, with excess of NaN 3 and [Nbu 4 ]Cl in a mixture of toluene and water, at reflux for 24-48 h. An example of the click reaction on 8 was the compound 9 synthesis in 86% yield by simple reaction with phenylaceylene, sodium ascorbate, and hydrated CuSO 4 as a catalyst in a mixture of dioxane/water. Therefore, di-branched m-carborane derivatives (Scheme 2) with precise patterns of substitution are prepared by judicious choice of the synthetic procedure using similar conditions to the preparation of o-carborane derivatives present in previous work [14].
2.2. Synthesis of tetra-Branched m-carborane Derivatives at the 1,7,9,10 Vertexes The above described di-branched 9,10-(CH 2 =CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 10 (3) derivative, which still possesses its two C c -H vertexes are ready for derivatization, offers the possibility to obtain globular icosahedral m-carborane derivatives with four branches as a new dendritic structure ( Figure 2) by the incorporation of functional groups at the two carbon vertexes. Consequently, starting with 3 the four branched 1,7-(CH 2 =CHCH 2 ) 2 -9,10-(CH 2 =CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 8, 10, is obtained in two steps: i) removing the acidic hydrogen atoms with two equivalents of BuLi and ii) by electrophilic reaction with two equivalents of allylbromide (Scheme 3). From 10, the tetraalcohol 1,7-(OHCH 2 CH 2 CH 2 ) 2 -9,10-(OHCH 2 CH 2 CH 2 ) 2 -1,7-closo-C 2 B 10 H 8 , 11, can be achieved by hydroboration. In the same way, 11 is ready as a core for constructing a tetra-branched m-derivatives using the judicious choice of synthetic procedure (Scheme 3). Compound 8 was obtained in 81% yield by avigorous stirring of 5, with excess of NaN3 and [Nbu4]Cl in a mixture of toluene and water, at reflux for 24-48 h. An example of the click reaction on 8 was the compound 9 synthesis in 86% yield by simple reaction with phenylaceylene, sodium ascorbate, and hydrated CuSO4 as a catalyst in a mixture of dioxane/water. Therefore, di-branched m-carborane derivatives (Scheme 2) with precise patterns of substitution are prepared by judicious choice of the synthetic procedure using similar conditions to the preparation of o-carborane derivatives present in previous work [14].
The reason for this unexpected reaction can be the comparable acidity of the allyl groups and the C c -H of the m-carborane unit, which may allow a deprotonation/protonation isomerization of the allyl group as it is well known for allylbenzenes [45]. The pKa value of the unsubstituted carborane clusters, which are insoluble in water, have been determined by two methods [6,10]. The pKa by using Streitwieser's scale provides the 27.9 value for the isomers mcarborane, while the one obtained by polarography is 24 [46]. Both experimental techniques support that unsubstituted m-carborane is a very weak Brønsted acid [46]. The allyl isomerization of 3 to propenyl in 12, which takes place in THF, is supported by the formation of solvent separated ion pairs that prevent the carboranyl anion to act as a nucleophile. To verify this hypothesis, Density-functional theory (DFT) calculations were performed (details in the S.I.). The proton affinity (PA) of the cluster carbon atom is 332.8 kcal/mol (at B3LYP-D3/6-311+G**, PCM=tetrahydrofuran level of theory), while the proton affinity of allylic carbon atom has a somewhat higher value (342.3 kcal/mol). This moderate difference (∆PA = 9.5 kcal/mol) probably allows for the above-mentioned mechanism. The question arises whether the same process does not occur in the case of the analog o-carborane based compounds [44]. It is known that cluster carbon in m-carborane is more than 1000 times less acidic than its orto isomer [47,48] therefore the difference between the two positions (allylic vs carboranyl) is larger as it was verified by our calculations (∆PA = 18.6 kcal/mol) as well. It should be highlighted that Li + mediated isomerizations on allyl substituents bonded at the C c vertexes of the o-carborane cluster was previously demonstrated as well, as Et 2 O does not tend to induce isomerization, whereas THF or DME produces the propenyl isomer [49]. A similar mechanism should be considered as well.
Molecules 2019, 24, x FOR PEER REVIEW 6 of 24 performed (details in the S.I.). The proton affinity (PA) of the cluster carbon atom is 332.8 kcal/mol (at B3LYP-D3/6-311+G**, PCM=tetrahydrofuran level of theory), while the proton affinity of allylic carbon atom has a somewhat higher value (342.3 kcal/mol). This moderate difference (∆PA = 9.5 kcal/mol) probably allows for the above-mentioned mechanism. The question arises whether the same process does not occur in the case of the analog o-carborane based compounds [44]. It is known that cluster carbon in m-carborane is more than 1000 times less acidic than its orto isomer [47,48] therefore the difference between the two positions (allylic vs carboranyl) is larger as it was verified by our calculations (∆PA = 18.6 kcal/mol) as well. It should be highlighted that Li + mediated isomerizations on allyl substituents bonded at the Cc vertexes of the o-carborane cluster was previously demonstrated as well, as Et2O does not tend to induce isomerization, whereas THF or DME produces the propenyl isomer [49]. A similar mechanism should be considered as well.

Characterization of di-Branched m-carborane Derivatives at the 9,10 Vertexes
The electrophilic substitution of the o-carborane led to the formation of the tetrasubstituted 8,9,10,12-I4-1,2-closo-C2B10H8 compound [5,42,43] in which the B-I vertexes reside at the compacted adjacent positions antipodal to the two cluster carbon Cc atoms. Conversely, the iodination electrophilic substitution takes place only at the B(9) and B(10) vertexes of the m-isomer.
We reported that the 2a-NPA value for a bond, defined as the sum of the NPA charges of the two bonded atoms (e.g., B-H or C-H), matches the order of attack on the different cluster' bonds [50]. Calculated NPA charges of the two bonded atoms (2a-NPA, calculated at B3LYP-D3/6-311+G** level of theory) of ortho-and meta-closo-carborane (present in Table 1 Top: Designed a synthetic reaction to achieve the dianionic species. Bottom: Achieved reaction was the isomerization of 9,10-(CH 2 =CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 10 , to 9,10-(CH 3 CH=CH) 2 -1,7-closo-C 2 B 10 H 10 . Dark circles are C c -H vertexes, pink circles are boron atoms, and grey circles are B-H vertexes. 1 H-NMR spectrum of 12 supported the allyl branches isomerization to propenyl ones but, this process was unambiguously proven by X-ray diffraction of 12 from good crystals, which were grown from its acetone solution.

Characterization of di-Branched m-carborane Derivatives at the 9,10 Vertexes
The electrophilic substitution of the o-carborane led to the formation of the tetrasubstituted 8,9,10,12-I 4 -1,2-closo-C 2 B 10 H 8 compound [5,42,43] in which the B-I vertexes reside at the compacted adjacent positions antipodal to the two cluster carbon C c atoms. Conversely, the iodination electrophilic substitution takes place only at the B(9) and B(10) vertexes of the m-isomer.
We reported that the 2a-NPA value for a bond, defined as the sum of the NPA charges of the two bonded atoms (e.g., B-H or C-H), matches the order of attack on the different cluster' bonds [50]. Calculated NPA charges of the two bonded atoms (2a-NPA, calculated at B3LYP-D3/6-311+G** level of theory) of orthoand meta-closo-carborane (present in Table 1 [3,51]. Contrary to the o-carborane that contains two positive natural charges; the m-carborane presents four positive natural charges on BH vertex, which explain the difficulty of the substitution of the B-H vertexes. Figure 3 shows that LUMO in o-carborane is located between the C atoms, whereas it is not the case for m-carborane where it is more disperse. Therefore, the carbon cluster position in the carborane has an important role related to the substitution of the B-H vertexes. Using the electrophilic iodination, it is possible to derivatize only B(9) and B(10) because these boron atoms do not have any connection with the C c in the meta isomer. On the contrary, for the oisomer the same procedure allows the attack to all B-H vertexes except B(3) and B(6) that are adjacent to both carbon clusters [52]. Table 1. Theoretical calculations of natural charges, 2a-NPA charges, and cumulative build-up of the cluster-only total charge (CTC) of ortho-closo and meta-closo carborane. See Figure 1 for the numbering of the clusters' vertexes.  Figure 3 shows that LUMO in o-carborane is located between the C atoms, whereas it is not the case for m-carborane where it is more disperse. Therefore, the carbon cluster position in the carborane has an important role related to the substitution of the B-H vertexes. Using the electrophilic iodination, it is possible to derivatize only B(9) and B(10) because these boron atoms do not have any connection with the Cc in the meta isomer. On the contrary, for the o-isomer the same procedure allows the attack to all B-H vertexes except B(3) and B(6) that are adjacent to both carbon clusters [52]. Table 1. Theoretical calculations of natural charges, 2a-NPA charges, and cumulative build-up of the cluster-only total charge (CTC) of ortho-closo and meta-closo carborane. See Figure 1 for the numbering of the clusters' vertexes. The starting (2 and 3) and new compounds (4-9) were fully characterized by 1 H, 1 H{ 11 B}, 11 B, 11 B { 1 H}, 13 C{ 1 H}, and 2D COSY 11 B { 1 H}-11 B { 1 H} NMR spectroscopic techniques to be taken as inputs for the discussion of the influence of the substituents at the 9,10 vertexes on the Boron disubstituted closo m-carborane derivatives.
The 11 B{ 1 H} NMR spectrum of the parent cluster 1 displays four signals with intensities 2:2:4:2 from low to high field −5.6, −9.5, −12,0 and −15.4 ppm, which corresponds to a weighted average Molecules 2020, 25, 2814 8 of 24 11 B{ 1 H} NMR chemical shift, <δ( 11 B)> ≈ −10.9 ppm [53]. Conversely, the 11 B { 1 H} NMR spectrum of 2 displays four signals with intensities 2:4:2:2 from low to high field at -3.0, -10.4, -17.0, and -19.5 ppm, which corresponds to a weighted average <δ( 11 B)> ≈ −12 ppm. The presence of the two iodo groups bonded to the B(9,10) in 2 produces a <δ( 11 B)> upfield of −1.1 ppm in the 11 B NMR. The upfield resonance of the 11 B { 1 H} NMR spectrum of 2 at −19.5 ppm does not split into a doublet in the 11 B-NMR spectrum supporting that it corresponds to the B-I at the 9 and 10 vertexes. 11 B { 1 H}-11 B { 1 H} 2D COSY NMR is of enormous use and potential in polyhedral boron chemistry because it provides a way of rapidly assigning 1l B resonances [54,55]. To assign the resonances of compounds 1 and 2 to the different cluster's vertexes by NMR spectroscopy, the two-dimensional 11 B { 1 H}-11 B { 1 H} COSY NMR spectra of compounds 1 and 2 were run (See Supplementary Information).
Once the B(9,10) has been unambiguously assigned in compounds 1 and 2, it is possible to confirm that the substitution of hydrogen by iodo causes significant shielding (−10 ppm) on the boron atoms that support the iodo units. 11   The 11 B{ 1 H} NMR spectrum of 3 displays four signals with intensities 2:2:4:2 from low to high field at 0.6, −5.4, −12.5, and −19.1 ppm, which corresponds to a weighted average <δ( 11 B)> of ca. −9.8 ppm. The peak at +0.6 ppm does not split into a doublet in the 11 B-NMR spectrum, which supports the substitution of an iodo by carbon from the allyl group, which causes a downfield shift on the boron vertexes. On the other hand, the 1 H and 1 H{ 11 B} NMR spectra are useful to identify the presence of the organic fragments linked to the carborane cluster. Figure  Compounds 4, 5, 6, and 7 were also characterized by 1 H, 1 H{ 11 B}, 11 B, 11 B { 1 H} and 13 C{ 1 H} NMR spectroscopy. Table 3 lists the 11 B{ 1 H} NMR chemical shifts for the B(9,10) disubstituted m-carborane derivatives while Table 4 summarizes the 1 H, 13 C{ 1 H } NMR spectra and the stretching frequency of Cc-H in the IR spectra for the B(9,10) disubstituted m-carborane derivatives. The presence of organic branches connected to B(9) and B(10) causes a resonance downfield shift about +11 ppm on these boron atoms. Therefore, the average chemical shift value <δ( 11 B)> = -10.9 ppm of parent 1 is around -9.6 ppm for 9,10-R2-1,7-closo-C2B10H12 derivatives (R=CH₂=CH-CH₂, HO(CH2)3, Cl(CH2)3, PhCOO(CH2)3, CH3-C6H4-SO3(CH2)3). There is no difference in these two features between the two isomers, ortho and meta.  Compounds 4, 5, 6, and 7 were also characterized by 1 H, 1 H{ 11 B}, 11 B, 11 B{ 1 H} and 13 C{ 1 H} NMR spectroscopy. Table 3 lists the 11 B{ 1 H} NMR chemical shifts for the B(9,10) disubstituted m-carborane derivatives while Table 4 summarizes the 1 H, 13 C{ 1 H } NMR spectra and the stretching frequency of C c -H in the IR spectra for the B(9,10) disubstituted m-carborane derivatives. The presence of organic branches connected to B(9) and B(10) causes a resonance downfield shift about +11 ppm on these boron atoms. Therefore, the average chemical shift value <δ( 11 B)> = -10.9 ppm of parent 1 is around -9.6 ppm for 9,10-R 2 -1,7-closo-C 2 B 10 H 12 derivatives (R=CH 2 =CH-CH 2 , HO(CH 2 ) 3 , Cl(CH 2 ) 3 , PhCOO(CH 2 ) 3 , CH 3 -C 6 H 4 -SO 3 (CH 2 ) 3 ). There is no difference in these two features between the two isomers, ortho and meta.   Table 3 shows a downfield shift (∆δ = +10.1 ppm) of the B(9,10) resonances of 9,10-(allyl) 2 -1,7-closo-C 2 B 10 H 10 (3) vs the corresponding B(9,10)-H ones in the parent m-carborane. A similar downfield (∆δ = +10.6 ppm) is reported for the B(9,12) vertexes of 9,12-(allyl) 2 -1,2-closo-C 2 B 10 H 10 with respect to the B(9,12)-H vertexes of the parent o-carborane [14]. The 11 B{ 1 H} NMR spectrum provides information on the electron density surrounding B atoms in the cluster vertexes, so it can be concluded that the effect of a B-allyl vertex concerning to the former B-H in the 11 B{ 1 H} NMR of both isomers is almost the same, ∆δ +10.6 ppm and +10.1 ppm, for oand m-, respectively. However, there is a major difference in the chemical shifts of the B-allyl nuclei of the two isomers: δ = +7.75 pm for 9,12-(allyl) 2 -1,2-closo-C 2 B 10 H 10 and δ = +0.6 pm for 9,10-(allyl) 2 -1,7-closo-C 2 B 10 H 10 . We should remember that B-allyl vertexes are located antipodal to the C c vertexes in the oisomer but antipodal to B vertexes in the m-isomer. This fact indicates a quite relevant different electronic surrounding in the B-allyl sites in both isomers, which depends on the atoms' nature at the antipodal vertexes. Table 4 summarizes the 1 H and 13 C{ 1 H } NMR spectra and stretching frequencies of C c -H bonds in the IR spectra for the reported 9,10-R 2 -1,7-closo-C 2 B 10 H 10 derivatives; the presence of the allyl branches at the B(9,10) vertexes produces an upfield of the carbon and hydrogen atoms resonances of the C c -H concerning to the parent m-carborane in their 1 H and 13 C{ 1 H } NMR spectra.
In Table 5, the comparison of the influence of the substituents at the B(9,12) in the o-carborane and the B(9,10) in the m-carborane is listed. To notice is that the influence on the chemical shift of the B-halogen (halogen = Cl, Br, I) vertexes in both isomers is the same: iodo is larger than bromo and bromo is larger than chloro. This is due to the i) electronegativity of halogen atoms, which follows the trend Cl > Br > I and ii) π back donation of halogen is I > Br > Cl. Table 5. 1 H-and 13 C{ 1 H} NMR chemical shift values (in ppm) of C c -H vertexes for several 9,12-R 2 -1,2-closo-C 2 B 10 H 10 and 9,10-R 2 -1,7-closo-C 2 B 10 H 10 derivatives. NMR spectra were run in *(CD 3 ) 2 CO or # CDCl 3 .    Table 3). Consequently, the incorporation of organic branches at the cluster vertexes produces a downfield of <δ( 11 B)> in the 11 B NMR while the iodo groups have the opposite effect, supporting that cluster-only total charge is dissimilarly affected by electron-withdrawing substituents than electron-donating ones.
To get information in such a family of compounds, good crystals of 9,10-(HOCH 2 CH 2 CH 2 ) 2 -1,7-closo-C 2 B 10 H 10 (4) and 9,10-(CH 3 CH=CH) 2 -1,7-closo-C 2 B 10 H 10 (12) suitable for X-ray-diffraction were grown from an acetone solution at low temperature. Compound 4 was solved in the triclinic system, with a P 1 space group with four molecules in the asymmetric unit (Z = 4) and all atoms laid on the 1(a) Wyckoff positions. Compound (12) also solved in the triclinic system, but in a different space group (P-1) with two molecules in the asymmetric unit (Z = 2) and all atoms laid in 1(i) Wyckoff position. Figure 5 shows the crystal structures of 4 and 12 with the corresponding atom labels. Table 6 displays all crystallographic data and selected bond distances and angles are in the Supplementary Information.  Molecules 2019, 24, x FOR PEER REVIEW 12 of 24 Figure 5. ORTEP presentation of 9,10-(HOCH2CH2CH2)2-1,7-closo-C2B10H10 (4) and 9,10-(CH3CH=CH)2-1,7-closo-C2B10H10 (12) showing the atom numbering and displacement. Ellipsoids are at 30% and 50% probability level, respectively. Compound 4 is the first example of a B(9,10) disubstituted closo 1,7-carborane derivative with a terminal O-H group. Furthermore, compound 12 is the first example of closo m-carborane with branches containing double bonds. For this, the behaviour of the two branches in the crystal network has been studied in detail. Exploring the crystal self-assembly, the presence of H … H short contacts in ORTEP presentation of 9,10-(HOCH 2 CH 2 CH 2 ) 2 -1,7-closo-C 2 B 10 H 10 (4) and 9,10-(CH 3 CH=CH) 2 -1,7-closo-C 2 B 10 H 10 (12) showing the atom numbering and displacement. Ellipsoids are at 30% and 50% probability level, respectively. Compound 4 is the first example of a B(9,10) disubstituted closo 1,7-carborane derivative with a terminal O-H group. Furthermore, compound 12 is the first example of closo m-carborane with branches containing double bonds. For this, the behaviour of the two branches in the crystal network has been studied in detail. Exploring the crystal self-assembly, the presence of H . . . H short contacts in the range from 1.207 Å to 2.240 Å for compound 4 and equal to 2.252 Å for compound 12 are noticed, which are presented in Figures 6 and 7, respectively. In carborane chemistry, the dihydrogen H . . . H short contacts are related to the presence of two types of H atoms: the acidic C c -H and the hydride B-H [58]. The supramolecular structure of 4 has an extensive network of hydrogen bonding due to the presence of the terminal OH groups (Figure 6a the range from 1.207 Å to 2.240 Å for compound 4 and equal to 2.252 Å for compound 12 are noticed, which are presented in Figures 6 and 7, respectively. In carborane chemistry, the dihydrogen H … H short contacts are related to the presence of two types of H atoms: the acidic Cc-H and the hydride B-H [58]. The supramolecular structure of 4 has an extensive network of hydrogen bonding due to the presence of the terminal OH groups (Figures 6a,b) Figure 6c. Accordingly, three different types of H … H short contacts were observed for 4: C7-H7 … H16-O16, O20-H20 … H16-O16, and B3-H3 … H14-C14. As expected, the presence of double bonds in 12 has a noticeable role in the stabilization of the supramolecular network (Figure 7). The π electronic effect of the double bond leads to the formation of the π … H-Cc contacts (brown dashed lines), which are substantially shorter than 2.90 Å corresponding to the sum of the van der Waals radii (∑vdW) [60]. The layers of 12 are connected into

Hirshfeld Surface Analysis
The Hirshfeld surface analysis, which is a very valuable method for the analysis of intermolecular contacts that offers a whole-of-the-molecule approach [61], presents three different colours to study the intermolecular interactions in crystal structures. The red colour means the presence of an intermolecular distance shorter that ∑vdW, white colour indicates the presence of intermolecular distances close to ∑vdW and blue colour designates the contacts longer than ∑vdW. Moreover, the shape index on the Hirshfeld surface identify hollows (with shape index < 0) and bumps (with shape index > 0), which are related to the character of each atom; the presence of an acceptor atom is marked by a concavity and the presence of a donor one is marked by a convexity. Therefore, the previous results were corroborated by studying the Hirshfeld surface of both structures using the crystal explorer program [62]. In this respect, Figure 8 presents the dnorm of 4 and 12 to visualize the intermolecular interactions and their contribution towards the supramolecular network. The two-dimensional fingerprint plots, which provide information about the percentage of intermolecular contacts present in the Hirshfeld surface is present in the S.I.
The darkest red area in the dnorm surface of 4 is observed at the end of the molecule, arising from the O … H short contact as presented in Figure 8 and confirmed in the fingerprint plots (See Supplementary Information). Furthermore, the dnorm surface has shown the presence of bright red areas related to the presence of the O … O and H … H short contacts. Because of this packing arrangement, the O atoms at the molecular extremity present an important behaviour on the stability of this molecule by showing close contact values with H atoms of adjacent molecules shorter than ∑vdW.
The dnorm presentation of compound 12 (Figures 8 and S.I.) shows the presence of dark red points related to the classic H … H bonds. The existence of π … H short contacts is observed as a bright red point. The presence of the π acceptor interactions is indicated by the appearance of red concave triangles surrounded by blue ones in the shape index surface (Figure 9a) [63] while the Cc-H donor is confirmed by the blue convex area (Figure 9b) [64].
Despite the presence of many strong intermolecular interactions with contacts shorter than the sum of the van der Waals radii minus 0.  As expected, the presence of double bonds in 12 has a noticeable role in the stabilization of the supramolecular network ( Figure 7). The π electronic effect of the double bond leads to the formation of the π . . . H-C c contacts (brown dashed lines), which are substantially shorter than 2.90 Å corresponding to the sum of the van der Waals radii ( vdW) [60]. The layers of 12 are connected into the final 3D structure through the B3-H3 . . . H15A-C15 bonds due to the acceptor character of the hydrogen-bonded to the boron and the donor character of the hydrogen atoms of the -CH 3 group.

Hirshfeld Surface Analysis
The Hirshfeld surface analysis, which is a very valuable method for the analysis of intermolecular contacts that offers a whole-of-the-molecule approach [61], presents three different colours to study the intermolecular interactions in crystal structures. The red colour means the presence of an intermolecular distance shorter that vdW, white colour indicates the presence of intermolecular distances close to vdW and blue colour designates the contacts longer than vdW. Moreover, the shape index on the Hirshfeld surface identify hollows (with shape index < 0) and bumps (with shape index > 0), which are related to the character of each atom; the presence of an acceptor atom is marked by a concavity and the presence of a donor one is marked by a convexity. Therefore, the previous results were corroborated by studying the Hirshfeld surface of both structures using the crystal explorer program [62]. In this respect, Figure 8 presents the d norm of 4 and 12 to visualize the intermolecular interactions and their contribution towards the supramolecular network. The two-dimensional fingerprint plots, which provide information about the percentage of intermolecular contacts present in the Hirshfeld surface is present in the S.I.  The darkest red area in the d norm surface of 4 is observed at the end of the molecule, arising from the O . . . H short contact as presented in Figure 8 and confirmed in the fingerprint plots (See Supplementary Information). Furthermore, the d norm surface has shown the presence of bright red areas related to the presence of the O . . . O and H . . . H short contacts. Because of this packing arrangement, the O atoms at the molecular extremity present an important behaviour on the stability of this molecule by showing close contact values with H atoms of adjacent molecules shorter than vdW.
The d norm presentation of compound 12 (Figure 8 and S.I.) shows the presence of dark red points related to the classic H . . . H bonds. The existence of π . . . H short contacts is observed as a bright red point. The presence of the π acceptor interactions is indicated by the appearance of red concave triangles surrounded by blue ones in the shape index surface (Figure 9a) [63] while the C c -H donor is confirmed by the blue convex area (Figure 9b) [64].

Experimental Section
Materials and instrumentation: All m-carborane clusters prepared are air-stable. All manipulations were carried out under nitrogen atmosphere. THF and DMF were distilled from sodium benzophenone before use. Reagents were obtained commercially and used as purchased without purification. 1,7-closo-C2B10H12 was obtained from Katchem.

Experimental Section
Materials and instrumentation: All m-carborane clusters prepared are air-stable. All manipulations were carried out under nitrogen atmosphere. THF and DMF were distilled from sodium benzophenone before use. Reagents were obtained commercially and used as purchased without purification. 1,7-closo-C 2 B 10 H 12 was obtained from Katchem. ATR-IR spectra (ν, cm −1 ) were obtained using the a JASCO FT/IR-4700 spectrometer on a high-resolution (Madrid, Spain). The 1 H and 1 H{ 11 B} NMR (300.13 MHz), 13 C{ 1 H} NMR (75.47 MHz), and 11 B and 11 B{ 1 H} NMR (96.29 MHz) spectra were recorded on a Bruker ARX300 instrument equipped with the appropriate decoupling accessories (Bruker Biospin, Rheinstetten, Germany)). All NMR spectra were performed in the indicated deuterated solvent at 22 • C. The 11 B and 11 B{ 1 H} NMR chemical shifts were referenced to external BF 3 ·OEt 2 , while the 1 H, 1 H{ 11 B}, and 13 C{ 1 H} NMR shifts were referenced to SiMe 4 . Chemical shifts are reported in units of parts per million downfield from reference, and all coupling constants in Hz.

Synthesis and Characterization of 3
The procedure for the synthesis of 3 was similar to that previously reported [40]. To a stirred solution of 9,10-I 2 -1,7-closo-C 2 B 10 H 10 2, (300 mg, 1.34 mmol) in THF (15 mL) cooled to 0 • C in an ice-water bath was added, drop wise, a solution of allylmagnesium chloride in THF (6.06 mL, 1 M, 6.06 mmol). After stirring at room temperature for 30 min, [PdCl 2 (PPh 3 ) 2 ] (21.28 mg, 4% equiv.) and CuI (5.77 mg, 4% equiv.) were added in a single portion, following which the reaction was heated to reflux overnight. The solvent was removed, and 20 mL of diethyl ether were added to the residue. The excess of Grignard reagent was destroyed by slow addition of dilute HCl. The organic layer was separated from the mixture, and the aqueous layer was extracted with diethyl ether (3 × 10 mL). The combined organic phase was dried over MgSO 4 , filtered and the solvent removed under reduced pressure. The crude product was dissolved in hexane/chloroform mixture (1:1 by volume, ca. 5 mL) and passed rapidly through a bed of silica. The solvent was removed in a vacuum to give 9,10-(CH 2 =CHCH 2 ) 2 -1,7-closo-C 2 B 10 H 10 3 as a yellowish oil (161.2 mg, 95%). Elemental analysis: calc: %C 42.

Synthesis and Characterization of 5
To a stirred solution of 9,10-(HOCH 2 CH 2 CH 2 ) 2 -1,7-closo-C 2 B 10 H 10 , 4, (300 mg, 1.14 mmol) and [NBu 4 ]Cl (132.59 mg, 0.478mmol) in dry THF (10mL) at 0 • C, was added SOCl 2 dropwise (0.52 mL, 7.076 mmol). The resulting solution was stirred at 0 • C for 1 h and at room temperature overnight. The solvent was removed under reduced pressure, and 8 mL of diethyl ether were added. A solution of Na 2 CO 3 (8 mL, 2 M) was slowly added with stirring. The mixture was thoroughly shaken, and the two layers separated. The aqueous layer was extracted with diethyl ether (3 × 5 mL). Then, the combined organic phase was separated and a solution of HCl (8 mL, 0.1 M) was added, the mixture was thoroughly shaken again. The upper organic layer was separated from the mixture, and the aqueous layer was washed with diethyl ether (3 × 5 mL). Finally, the combined organic phase was dried over MgSO 4 , filtered and the solvent removed in vacuo to give 9,10-(ClCH 2 CH 2 CH 2 ) 2 -1,7-closo-C 2 B 10 H 10

Hirshfield Surface Analysis
The Hirshfeld surface analyses were run using the CIF format by the CrystalExplorer program [62]. Hirshfeld surface analysis help to recognize the strong and weak intermolecular interactions area and the nature of these interactions from the electron distribution. The d norm (normalized contact distance) is given by the Equation (1) where d i is from the Hirshfeld surface to the nearest atom outside-external, d e from the Hirshfeld surface to the nearest internal atom, and r vdw is the Van Der Walls radii of the atom

Conclusions
All allyl di and tetrabranched derivatives of the m-carborane framework have been synthesized. The starting 9,10-(allyl) 2 -1,7-closo-carborane compound was made by Kumada cross-coupling reaction on 9,10-I 2 -1,7-closo-carborane with allyl Grignard reagent in the presence of Pd(II) and Cu(I) as catalysts. These olefin groups have led to a variety of functional groups, alcohol, chloro, tosyl, and azide that have permitted to produce esters and 1,2,3-triazoles by the azide-alkyne cycloaddition, as examples of reactions that show the wide possibilities of this globular icosahedral m-carborane to act as a novel core for periphery-decorated macromolecules. Importantly, the four branches in the tetrabranched m-carborane derivatives are located in two perpendicular planes and are coplanar in the o-carborane isomer. This difference provides novel cores for 3D and 2D radially grown periphery-decorated macromolecules, respectively. Unexpectedly, the isomerization of B-allyl to B-propenyl vertexes in 9,10-(allyl) 2 -1,7-closo-C 2 B 10 H 10 was observed in THF. DFT calculation studies conclude that the comparable acidity of the allyl groups and the C c -H of the m-carborane unit allows a deprotonation/protonation isomerization of the allyl group as it is well known for allylbenzenes. X-ray crystal structures of 9,10-(OHCH 2 CH 2 CH 2 ) 2 -1,7-closo-C 2 B 10 H 10 and 9,10-(CH 3 CHCH) 2 -1,7-closo-C 2 B 10 H 10 compounds show an extensive network of hydrogen bonding and π···H-C c contacts, respectively, due to the presence of alcohol and olefin groups that have been analyzed by Hirshfeld surfaces and decomposed fingerprint plots.
Supplementary Materials: The following are available online, Spectroscopic characterization of compounds 1-12. Figures S1-S78 with IR and NMR spectra and crystal packing of 4 and 12. Table S1-S4 containing the bond lengths and bond angles of crystals 4 and 12; S5-S11 with XYZ coordinates and total energies of the investigated systems.