Charge-compensated nido-carborane derivatives in the synthesis of iron(II) bis(dicarbollide) complexes.

A series of stable iron(II) bis(dicarbollide) derivatives [8,8'-(RNHC(Et)HN)2-3,3'-Fe(1,2-C2B9H10)2] (R = Pr, R = Ph, (CH2)2OH, (CH2)3OH, (CH2)2NMe2) was prepared starting from FeCl2 or [FeCl2(dppe)] and the corresponding nido-carboranyl amidines [10-RNHC(Et)HN-7,8-C2B9H11]. In a similar way, the reactions of the oxonium derivatives of nido-carborane with FeCl2 in tetrahydrofuran in the presence of t-BuOK lead to the corresponding stable oxonium derivatives iron(II) bis(dicarbollide) [8,8'-(RR'O)2-3,3'-Fe(1,2-C2B9H10)2] (RR' = (CH2)4, (CH2)2O(CH2)2, (CH2)5; R = R' = Et), which can be alternatively prepared by the reaction of the parent iron(II) bis(dicarbollide) with tetrahydrofuran or 1,4-dioxane in the presence of Me2SO4. The cyclic voltammetry studies of the synthesized iron(II) bis(dicarbollide) derivatives revealed that the introduction of amidinium and oxonium substituents leads to a significant increase in the Fe2+/Fe3+ redox potential relative to the parent iron(II) bis(dicarbollide). The redox potentials of the oxonium derivatives are close to the redox potential of ferrocene and somewhat lower than redox potentials of sulfonium and phosphonium derivatives of iron(II) bis(dicarbollide).

Development of a Gadolinium-Boron-Conjugated Albumin for MRI-Guided Neutron Capture Therapy.

Noninvasive monitoring of boron agent biodistribution is required in advance of neutron capture therapy. In this study, we developed a gadolinium-boron-conjugated albumin (Gd-MID-BSA) for MRI-guided neutron capture therapy. Gd-MID-BSA was prepared by labeling bovine serum albumin with a maleimide-functionalized gadolinium complex and a maleimide-functionalized closo-dodecaborate orthogonally. The accumulation of Gd-MID-BSA in tumors in CT26 tumor-bearing mice reached a maximum at 24 h after the injection, as confirmed by T1-based MRI and biodistribution analysis using inductively coupled plasma optical emission spectrometry. The concentrations of boron and gadolinium in the tumors exceeded the thresholds required for boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT), respectively. The boron concentration ratios of tumor to blood and tumor to normal tissues satisfied the clinical criteria, indicating the reduction of undesired nuclear reactions of endogenous nuclei. The molar ratio of boron to gadolinium in the tumor was close to that of Gd-MID-BSA, demonstrating that the accumulation of Gd-MID-BSA in the tumor can be evaluated by MRI. Thermal neutron irradiation with Gd-MID-BSA resulted in significant suppression of tumor growth compared to the group injected with a boron-conjugated albumin without gadolinium (MID-BSA). The neutron irradiation with Gd-MID-BSA did not cause apparent side effects. These results demonstrate that the conjugation of gadolinium and boron within the albumin molecule offers a novel strategy for enhancing the therapeutic effect of BNCT and the potential of MRI-guided neutron capture therapy as a promising treatment for malignant tumors.

Nickel(II) and Palladium(II) Complexes with η5:κ1(N)-Coordinated Dicarbollide Ligands Containing Pendant Pyridine Group.

A series of C- and B-substituted nido-carborane derivatives with a pendant pyridyl group was prepared. The synthesized compounds were used as ligands in the complexation reactions with bis(triphenylphosphine)nickel(II) and palladium(II) chlorides to give six new metallacomplexes with unusual η5:κ1(N)-coordination of the metal center. The single crystal structures of 1-(NC5H4-2'-S)-1,2-C2B10H11, 1-(NC5H4-2'-CH2S)-1,2-C2B10H11, Cs [7-(NC5H4-2'-CH2S)-7,8-C2B9H11] closo- and nido-carboranes and 3-Ph3P-3-(4(7)-NC5H4-2'-S)-closo-3,1,2-NiC2B9H10 and 3-Ph3P-3-(4(7)-NC5H4-2'-CH2S)-closo-3,1,2-NiC2B9H10 metallacarboranes were determined using single crystal X-ray diffraction.

How the Position of Substitution Affects Intermolecular Bonding in Halogen Derivatives of Carboranes: Crystal Structures of 1,2,3- and 8,9,12-Triiodo- and 8,9,12-Tribromo ortho-Carboranes.

The crystal structures of two isomeric triiodo derivatives of ortho-carborane containing substituents in the three most electron-withdrawing positions of the carborane cage, 1,2,3-I3-1,2-C2B10H9, and the three most electron-donating positions, 8,9,12-I3-1,2-C2B10H9, as well as the crystal structure of 8,9,12-Br3-1,2-C2B10H9, were determined by single-crystal X-ray diffraction. In the structure of 1,2,3-I3-1,2-C2B10H9, an iodine atom attached to the boron atom (position 3) donates its lone pairs simultaneously to the σ-holes of both iodine atoms attached to the carbon atoms (positions 1 and 2) with the I⋯I distance of 3.554(2) Å and the C-I⋯I and B-I⋯I angles of 169.2(2)° and 92.2(2)°, respectively. The structure is additionally stabilized by a few B-H⋯I-shortened contacts. In the structure of 8,9,12-I3-1,2-C2B10H9, the I⋯I contacts of type II are very weak (the I⋯I distance is 4.268(4) Å, the B8-I8⋯I12 and B12-I12⋯I8 angles are 130.2(3)° and 92.2(3)°) and can only be regarded as dihalogen bonds formally. In comparison with the latter, the structure of 8,9,12-Br3-1,2-C2B10H9 demonstrates both similarities and differences. No Br⋯Br contacts of type II are observed, while there are two Br⋯Br halogen bonds of type I.

New approaches to the functionalization of the 1-carba-closo-decaborate anion.

Two new approaches to the functionalization of the 1-carba-closo-decaborate anion [1-CB9H10]- at boron atoms via the ring-opening of its 1,4-dioxane derivative with various nucleophiles and Pd-catalysed cross-coupling of its iodo derivative with aromatic amines and heteroaromatics were developed.

Synthesis of 3-Aryl-ortho-carboranes with Sensitive Functional Groups.

A simple and efficient method was developed for the one-pot synthesis of 3-aryl derivatives of ortho-carborane with sensitive functional groups using 3-iodo-ortho-carborane and aryl zinc bromides that were generated in situ. A series of 3-aryl-ortho-carboranes, including those containing nitrile and ester groups, 3-RC6H4-1,2-C2B10H11 (R = p-Me, p-NMe2, p-OCH2OMe, p-OMe, o-CN, p-CN, o-COOEt, m-COOEt, p-COOEt) was synthesized using this approach. The solid-state structures of 3-RC6H4-1,2-C2B10H11 (R = p-OMe, o-CN, and p-CN) were determined by single crystal X-ray diffraction. The intramolecular hydrogen bonding involving the ortho-substituents of the aryl ring and the CH and BH groups of carborane was discussed.

Synthesis of Bis(Carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 (n = 0, 1) and Attempt of Synthesis of Gadolinium Bis(Dicarbollide).

Bis(carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 (n = 0, 1) were prepared by the reactions of the corresponding carboranyl acyl chlorides with ethylenediamine. Crystal molecular structure of 1,1'-µ-(CH2NH(O)C-1,2-C2B10H11)2 was determined by single crystal X-ray diffraction. Treatment of bis(carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 with ammonium or cesium fluoride results in partial deboronation of the ortho-carborane cages to the nido-carborane ones with formation of [7,7'(8')-µ-(CH2NH(O)C(CH2)n-7,8-C2B9H11)2]2-. The attempted reaction of [7,7'(8')-µ-(CH2NH(O)CCH2-7,8-C2B9H11)2]2- with GdCl3 in 1,2-dimethoxy- ethane did not give the expected metallacarborane. The stability of different conformations of Gd-containing metallacarboranes has been estimated by quantum-chemical calculations using [3,3-µ-DME-3,3'-Gd(1,2-C2B9H11)2]- as a model. It was found that in the most stable conformation the CH groups of the dicarbollide ligands are in anti,anti-orientation with respect to the DME ligand, while any rotation of the dicarbollide ligand reduces the stability of the system. This makes it possible to rationalize the design of carborane ligands for the synthesis of gadolinium metallacarboranes on their base.

The unexpected reactivity of 9-iodo-nido-carborane: from nucleophilic substitution reactions to the synthesis of tricobalt tris(dicarbollide) Na[4,4',4''-(MeOCH2CH2O)3-3,3',3''-Co3(µ3-O)(µ3-S)(1,2-C2B9H10)3].

An unusual reactivity of 9-iodo-nido-carborane [9-I-7,8-C2B9H11]- towards nucleophiles under strong basic conditions was revealed. The nucleophilic substitution of iodine with O- and N-nucleophiles results in [9-RO-7,8-C2B9H11]- (R = H, CH2CH2OMe) and [9-L-7,8-C2B9H11] (L = Py, NEt3, Me2NCH2CH2NMe2), respectively. Reaction of [9-I-7,8-C2B9H11]- with CoCl2 in 1,2-dimethoxyethane in the presence of t-BuOK, depending on the order of addition of the reagents, leads either to a diastereomeric mixture of diiodo derivatives cobalt bis(dicarbollide) rac-[4,4'-I2-3,3'-Co(1,2-C2B9H10)2]- and meso-[4,7'-I2-3,3'-Co(1,2-C2B9H10)2]- or to the corresponding mixture of 2-methoxyethoxy derivatives rac-[4,4'-(MeOCH2CH2O)2-3,3'-Co(1,2-C2B9H10)2]- and meso-[4,7'-(MeOCH2CH2O)2-3,3'-Co(1,2-C2B9H10)2]-. In the presence of accidental admixture of sodium thiosulfate, the reactions of 9-iodo-nido-carborane and 9-(2'-methoxyethoxy)-nido-carborane with CoCl2 in 1,2-dimethoxyethane were found to produce additionally unprecedented tricobalt tris(dicarbollide) cluster Na[4,4',4''-(MeOCH2CH2O)3-3,3',3''-Co3(µ3-O)(µ3-S)(1,2-C2B9H10)3], the central fragment of which is a trigonal bipyramid with apical oxygen and sulfur atoms, and the base is formed by the Co3 triangle flanked by three dicarbollide ligands. In addition, the 2-methoxyethoxy substituents of the dicarbollide ligands chelate the sodium cation in such a way that they form a helix whose rotation direction depends on the enantiomer of the parent ligand. Thus, in this case, induction of the helical chirality of the complex occurs due to the point chirality of the initial inorganic ligand. It is worth noting that in the case of symmetrically substituted 2-methoxyethoxy derivative of nido-carborane [10-MeOCH2CH2O-7,8-C2B9H11]- only formation of the corresponding cobalt bis(dicarbollide) complex [8,8'-(MeOCH2CH2O)2-3,3'-Co(1,2-C2B9H10)2]- was observed.

Bis(dicarbollide) Complexes of Transition Metals as a Platform for Molecular Switches. Study of Complexation of 8,8'-Bis(methylsulfanyl) Derivatives of Cobalt and Iron Bis(dicarbollides).

Complexation of the 8,8'-bis(methylsulfanyl) derivatives of cobalt and iron bis(dicarbollides) [8,8'-(MeS)2-3,3'-M(1,2-C2B9H10)2]- (M = Co, Fe) with copper, silver, palladium and rhodium leads to the formation of the corresponding chelate complexes, which is accompanied by a transition from the transoid to the cisoid conformation of the bis(dicarbollide) complex. This transition is reversible and can be used in design of coordination-driven molecular switches based on transition metal bis(dicarbollide) complexes. The solid-state structures of {(Ph3P)ClPd[8,8'- (MeS)2-3,3'-Co(1,2-C2B9H10)2-κ2-S,S']} and {(COD)Rh[8,8'-(MeS)2-3,3'-Co(1,2-C2B9H10)2-κ2-S,S']} were determined by single crystal X-ray diffraction.

The First Nickelacarborane with closo-nido Structure.

The first nickelacarborane with closo-nido structure [10',11'-(Py)2-3,9'-Ni(1,2-C2B9H11)(7',8'-C2B8H8)] was isolated from the reaction of nickel(IV) bis(dicarbollide) with pyridine. The molecular structure of this complex was determined by single crystal X-ray diffraction. The nickel atom is a common vertex for the closo-NiC2B9 cluster and the nido-NC2B8 cluster where it is located together with carbon atoms in the open NiC2B2 pentagonal face. It is assumed that its formation proceeds through the nucleophile-induced removal of the B(6)H vertex followed by rearrangement of the forming 11-vertex cluster, which most likely proceeds through a sequence of closing and opening reactions.

Synthesis and Structure of Methylsulfanyl Derivatives of Nickel Bis(Dicarbollide).

Symmetrically and unsymmetrically substituted methylsulfanyl derivatives of nickel(III) bis(dicarbollide) (Bu4N)[8,8'-(MeS)2-3,3'-Ni(1,2-C2B9H10)2], (Bu4N)[4,4'-(MeS)2-3,3'-Ni(1,2-C2B9H10)2], and (Bu4N)[4,7'-(MeS)2-3,3'-Ni(1,2-C2B9H10)2] were synthesized, starting from [Ni(acac)2]3 and the corresponding methylsulfanyl derivatives of nido-carborane (Bu4N)[10-MeS-7,8-C2B9H11] and (Bu4N)[10-MeS-7,8-C2B9H11]. Structures of the synthesized metallacarboranes were studied by single-crystal X-ray diffraction and quantum chemical calculations. The symmetrically substituted 8,8'-isomer adopts transoid conformation stabilized by two pairs of intramolecular C-H···S hydrogen bonds between the dicarbollide ligands. The unsymmetrically substituted 4,7'-isomer adopts gauche conformation, which is stabilized by two nonequivalent C-H···S hydrogen bonds and one short chalcogen B-H···S bond (2.53 Å, -1.4 kcal/mol). The gauche conformation was found to be also preferred for the 4,7'-isomer.

Cyanide free contraction of disclosed 1,4-dioxane ring as a route to cobalt bis(dicarbollide) derivatives with short spacer between the boron cage and terminal functional group.

The 1,4-dioxane derivative of cobalt bis(dicarbollide) reacts with dialkylsulfides and triphenylphosphine to give the corresponding sulfonium and phosphonium derivatives [8-L(CH2CH2O)2-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)] (L = SMe2, S(CH2CH2)2O, PPh3). The treatment of the triphenylphosphonium derivative with sodium hydroxide results in contraction of the side chain with formation of [8-HOCH2CH2O-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)](-). The same product was obtained by treatment of the dimethylsulfonium derivative with the poorly nucleophilic base t-BuOK, whereas the stronger nucleophiles induce the sulfur demethylation to give [8-MeS(CH2CH2O)2-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)](-). The alcohol was used for the synthesis of a series of other short-spacer functional derivatives [8-XOCH2CH2O-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)](-) (X = NH2, SH, N3). A similar contraction of the disclosed 1,4-dioxane ring via the reactions with SMe2 and PPh3 can be used for the synthesis of short-spacer functional derivatives of nido-carborane, whereas the 1,4-dioxane derivatives of closo-decaborate and closo-dodecaborate anions, being stronger electron donors, are more stable and do not react with dimethylsulfide and triphenylphosphine.

A new approach to the synthesis of functional derivatives of nido-carborane: alkylation of [9-MeS-nido-7,8-C2B9H11]⁻.

A series of asymmetrically substituted sulfonium derivatives of nido-carborane [9-R(Me)S-nido-7,8-C2B9H11] (R = Et, Pr, Bu, Bn, CH=CH2, CH2CH=CH2, CH2C≡CH, CH=C=CH2) were prepared by alkylation of the 9-methylthio-nido-7,8-carborane. The synthesized compounds are the first examples of diastereomers combining nido-carborane and sulfonium chiral centers.