No description available.

<p> This thesis describes the synthesis and characterization of a series of carborane and metallocarborane-carbohydrate conjugates as model systems for developing a novel class of radiophannaceuticals. The role of the carborane group is to provide a site for binding radioactive elements while the carbohydrate moieties are present either as a targeting vector, or as a means by which to increase the hydrophilicity of the overall complex. In this research, the versatility of carboranes was demonstrated since it was shown that carbohydrate-nido-carborane derivatives could be labeled with both metals (Re/99Tc) and halogens (125I/127I). </p> <p> The initial synthetic target was compound 2.6, a simple nido-carboranyl glycoside of glucose. The syntheses of this model ligand and its Re-metallocarborane (2.1, 3.4) and iodinated (2.13) derivatives were carried out in order to determine the optimal methods and conditions for synthesis and purification of bifunctional ligands and the corresponding radioactive analogues. Microwave irradiation was found to greatly enhance the synthesis ofRe and 99mTc-metallocarborane complexes which were isolated in 31% and 58% yield respectively. Analysis of the Re complexes by 1H nOe NMR spectroscopy revealed that rearrangement of the carborane cage from the expected 3,1 ,2- ReC2B9 isomer to the 2,1 ,8- isomer occurred under the synthetic conditions employed. </p> <p> Iodination and radioiodination of model compound 2.6 was carried out using Na[1271] or Na[125I] in the presence of Chloramine-T or Iodogen as oxidants at room temperature. Reactions were complete in 5 min and the products isolated in 21% and 29% yield for 127I and 125I, respectively. </p> <p> Building on these results, bifunctional compounds 4.3 and 4.12 were prepared. Using microwave heating, these compounds were labeled with 99mTc in 62% and 44% yield, respectively. Compounds 4.3 and 4.12 contained a benzoic acid functionality through which conjugation to targeting vectors could be accomplished. To demonstrate this, benzamides 4.14 and 4.16 were synthesized using an active ester approach. The products were isolated in 41% and 35% yield and subsequently labeled with 1251 using the methods developed for the model system. Compounds [1251]-4.23 and [1251]-4.24 were obtained in 73% and 92% yield, respectively. The stability of these [1251]-labeled compounds was excellent, showing less than 1% degradation after 24 hours in solution. In order to assess the effect of the carbohydrate moiety upon lipophilicity, the log P of the radiolabeled benzamides was measured and found to be 1.53±0.01 for [125I]-4.23 and 0.82±0.04 for [1251]-4.24. This result confirmed the increase in hydrophilicity associated with the presence of the carbohydrate moiety. </p> <p> Progress was also made towards preparing a glucose-nido-carborane conjugate (5.9) whose Re and Tc complexes were pursued as metallocarborane analogues of the clinical PET tracer [18F]FDG. The key precursor was made in good overall yield and the product fully characterized. Future work should focus on preparing the radiolabeled analogues. </p> / Thesis / Doctor of Philosophy (PhD)

Malgrat que hi ha molta química descrita al voltant dels borans i dels carborans, la falta de mètodes sintètics fa palesa la manca de clústers substituïts en els àtoms de bor. Concretament en el cas de l'o-carborà, la substitució en els bors no és tant comú com sobre els carbonis donada la menor acidesa dels hidrògens units a ells. Per poder funcionalitzar-los generalment es duu a terme una substitució electrofílica que tant sols és efectiva sobre els àtoms de bor més llunyans dels àtoms de carboni, restant les posicions directament connectades a ambdós àtoms de carboni, B3 i B6 sense substituïr. Així doncs, l'objectiu del present treball és l'estudi de la reactivitat sobre els àtoms de bor, centrant-se en la dels àtoms B3 i B6.Per assolir l'objectiu, s'ha dissenyat un mètode simple i ràpid per a la síntesi amb alt rendiment de borats halogenats de fórmula [B6X6]2- (X = Br, I). També s'han sintetitzat i caracteritzat carborans halogenats (iodats i bromats) en la posició 3 del clúster d'o-carborà. Per a aquests clústers s'han dut a terme càlculs teòrics dels desplaçaments químics de 11B-RMN i s'ha estudiat la seva reactivitat davant reactius de Grignard obtenint derivats alquílics i arílics a la posició 3 del clúster d'o-carborà. Per a un d'aquests compostos, el 3-Iodo-1,2-dicarba-closo-dodecaborà, s'ha estudiat la reactivitat de l'enllaç B-I front a la reacció amb metalls. En el cas del magnesi s'ha desenvolupat un nou mètode de reducció de l'o-carborà. A més a més, per difracció de raigs X s'ha resolt l'estructura crista·lina del 3-Iodo-1,2-dicarba-closo-dodecaborà en la que s'ha evidenciat l'existència d'interaccions intermoleculars. Per degradació parcial dels clústers halogenats closo, s'han sintetitzat nido-carborans halogenats en la posició 3 del clúster. També s'ha sintetitzat i caracteritzat el 3,6-I2-1,2-dicarba-closo-dodecaborà. Per a aquest clúster, la reacció amb derivats de Grignard ha permès obtenir carborans substituïts en les posicions 3 i 6 amb restes alquílics i arílics i s'ha demostrat com el desplaçament químic i en alguns casos l'acidesa dels àtoms d'hidrogen units als àtoms de carboni del clúster, depèn del tipus de substituent que es troba en aquestes posicions, essent un efecte additiu.També s'han sintetitzat i caracteritzat derivats de l'o-carborà nona i deca-B-iodats. Les síntesis s'han dut a terme en globalment dues etapes. La primera es basa en la combinació de les reaccions de degradació parcial i inserció que permet obtenir el clúster iodat en posició 3 o bé 3 i 6 i la segona en un atac electrofílic amb ICl sobre el clúster mono o diiodat que porta a l'obtenció del clúster nonaiodat o decaiodat respectivament. S'ha estudiat l'acidesa dels àtoms d'hidrogen units als àtoms de carboni del derivat per-B-iodat de l'o-carborà front la desprotonació amb diferents bases i la protonació de la seva base conjugada amb diferents àcids. S'han sintetitzat i caracteritzat nido-carborans octa i nona-halogenats.També s'ha sintetitzat el carborà nonametilat en dues etapes. La primera es basa en la combinació de les reaccions de degradació parcial, inserció i acoblament creuat que permet obtenir el 3-metil-o-carborà i la segona en un atac electrofílic amb MeI sobre el clúster monosubstituït que porta a l'obtenció del clúster nonametilat. Intents de sintetitzar el clúster per-B-metilat, han portat a un carborà octametilat. Aquest fet experimental s'ha atribuït a l'efecte dels grups metil sobre els àtoms de bor del clúster que ha estat quantificat mitjançant càlculs teòrics. Així, a mesura que augmenta el nombre de grups metil, augmenta la càrrega total positiva en el clúster, disminuint la susceptibilitat a l'atac electrofílic. Finalment s'ha estudiat l'aplicació de closo-carborans halogenats en el camp del radiomarcatge. / Although the chemistry of borates and carboranes is already quite well developed, the lack of synthesis methods makes plausible the need of new boron substituted carboranes. In the case of o-carborane, boron substitution is not so common as carbon substitution due to the lower acidity of the hydrogen atoms bonded to boron atoms. Functionalization of boron atoms in o-carborane is usually achieved by electrophilic substitution. This is only effective on the boron atoms remote to carbon atoms, leaving B3 and B6, adjacent to carbon atoms, unsubstituted. For this reason, the aim of this work is the study of the reactivity on boron atoms, concretely on B3 and B6.To achieve this aim, an easy and fast method to synthesise halogenated borates [B6X6]2- (X = Br, I) in high yield has been developed. B3-halogenated (iodinated and brominated) carboranes have also been synthesised. For these clusters, theoretical 11B-NMR chemical shifts has been calculated and through cross coupling with Grignard reagents alkyl and aryl B3-substituted carboranes have been obtained. For the 3-Iodo-1,2-dicarba-closo-dodecaborane, the reactivity of the B-I bond in front of different metals has been studied. In the case of magnesium, a new o-carborane reduction method has been developed. Furthermore, through X-Ray diffraction, the existence of intermolecular interactions in the crystal structure of 3-Iodo-1,2-dicarba-closo-dodecaborane has been evidenced. Through partial deboronation of halogenated closo clusters, halogenated nido-carborane has been obtained. The synthesis of 3,6-I2-1,2-dicarba-closo-dodecaborane has also been substituted. For this cluster, the cross coupling reaction with alkyl and aryl magnesium salts led to the obtaining of B3 and B6 disubstituted carboranes. The chemical shift, and in some cases the acidity of the hydrogen atoms bonded to cluster carbon atoms, depends on the type of substituent at B3 and B6, with additive effects.Nona and deca iodinated carboranes have been synthesised and characterized. In both cases the synthesis procedure has two main steps. One step is based on the combination of partial degradation and insertion of a new vertex that allows the obtaining of the iodinated cluster at B3 or B3 and B6. The second step consists in an electrophilic attack with ICl on the nona or decaiodinated clusters respectively. The acidity of the hydrogen atoms bonded to cluster carbon atoms of the per-B-iodinated carborane has been studied through the deprotonation with different bases and the protonation of its conjugated base with different acids. Octa and nona-halogenated nido carboranes have also been synthesised and characterized.A nonamethylated carborane has also been synthesised by two steps. One step is based on the combination of the partial degradation reaction, insertion and cross coupling reaction to obtain 3-methyl-o-carborane and the second step consists in an electrophilic attack with MeI on the monosubstituted cluster to lead the nonamethylated cluster. Attempts to synthesise the per-B-methylated cluster, led an octamethylated carborane. This experimental fact has been attributed to the methyl groups effect on the boron atoms. This effect has been quantified by theoretical calculations. The higher is the number of methyl groups, the higher the total cluster positive charge, decreasing thent the electrophilic attack susceptibility. Finally, the application of halogenated closo-carboranes in radiolabelling has been studied.

Heidelberg, Univ., Diss., 2000.

University, Diss., 2005--Heidelberg.

Yes / We report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] (1 and 2) in Pluronic® triblock copolymer P123 core–shell micelles. The spherical nanoparticles RuMs and OsMs, dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively). Complexes 1 and 2 were highly active towards A2780 human ovarian cancer cells (IC50 0.17 and 2.50 μM, respectively) and the encapsulated complexes, as RuMs and OsMs nanoparticles, were less potent (IC50 6.69 μM and 117.5 μM, respectively), but more selective towards cancer cells compared to normal cells. / We thank the Leverhulme Trust (Early Career Fellowship no. ECF-2013-414 to NPEB), the University of Warwick (Grant no. RDF 2013-14 to NPEB), the Swiss National Science Foundation (Grant no. PA00P2_145308 to NPEB and PBNEP2_142949 to APB), the ERC (Grant no. 247450 to PJS), EPSRC (EP/G004897/ 1 to APB, and EP/F034210/1 to PJS), Institute of Advanced Study (IAS) – University of Warwick (Fellowship to JJSB), and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (055663/Z/98/Z) for funding to the Electron Microscopy Facility, School of Life Sciences, University of Warwick.

Les importants aplicacions pràctiques que presenta el cobaltobis(dicarballur), [3,3'-Co(1,2-C2B9H11)2]-, ja sigui com a extractant de radionúclids procedents d'aïgues residuals de centrals nuclears o com a agent dopant de polímers conductors de polipirrol, ens han encoratjat en la recerca d'aquest clúster de bor. Així l'objectiu primordial d'aquest treball és la síntesi i caracterització de nous cobaltocarborans que incorporin substituents tant dels vèrtexs de carboni com en els de bor, per tal d'ésser destinats a aquestes aplicacions. La incorporació de fosfines en els vèrtexs de carboni del cobaltobis(dicarballur) ha estat possible per metal·lació directa d'aquest amb n-BuLi seguida de la reacció amb una clorofosfina (ClPR2: R=Ph, Et, iPr o Cl2PPh). Aquesta reacció ha conduït a la síntesi i separació d'espècies C-difosfinosubstituïdes. La caracterització d'aquestes difosfines per RMN (1H, 13C, 31P i 11B) i difracció de raigs X ha revelat que l'isòmer generat és la mescla racèmica. Únicament s'ha format l'isòmer meso si es duu a terme la mateixa reacció sobre el compost [8,8'-m-C6H4-3,3'-Co(1,2-C2B9H10)2]-. També l'únic cas de mono-C-substitució s'ha observat partint d'aquest compost. Un cop sintetizada tota aquesta nova família de C-fosfino derivats s'han preparat els respectius anàlegs òxids de fosfina per tractament amb H2O2 en acetona. Aquest mètode d'oxidació també s'ha aplicat a closo-carboranildifosfines, en aquests casos però, un cop a tingut lloc l'oxidació dels àtoms de fòsfor té lloc la degradació parcial del clúster closo a nido. Són els òxids de fosfina els que s'han utilitzat en els assaigs d'extracció de radionúclids, en tècniques d'extracció líquid-líquid i en experiments de transport en membranes líquides suportades.La semblança estructural de la cobaltocarboranildifosfina aniònica [3,3'-Co(1-PPh2-1,2-C2B9H10)2]- aquí sintetitzada amb els coneguts lligands BINAP i dppf ens ha motivat a determinar com es comporta aquest cobaltocarborà com a lligand. Per això s'ha complexat amb metalls tals com la Ag, l'Au, el Rh i el Pd. També s'ha dut a terme un anàlisi detallat dels trets geomètrics que diferencien aquests tres lligands tant semblants.Pel que fa a la funcionalització dels vèrtexs de bor, s'ha optimitzat el mètode de síntesi dels derivats iodats [3,3'-Co(8-I-1,2-C2B9H10)(1',2'-C2B9H11)]- i [3,3'-Co(8-I-1,2-C2B9H10)2]- i se n'ha estudiat la seva reactivitat amb reactius de Grignard. La reacció del derivat monoiodat amb magnesians ha permès generar derivats monoalquílics i monoarílics en la posició B8. S'ha estudiat l'efecte del substituent alquil o aril tant experimentalment mitjançant les tècniques de RMN, UV-Visible, voltamperometria cíclica i difracció de raigs X com per càlculs teòrics Extended Hückel i ab initio. D'aquest estudi en resulta el caràcter electroatraient d'un grup alquil quan està enllaçat a bor, i la menor participació dels orbitals d del metall en els orbitals frontera. La reactivitat del derivat diiodat amb magnesians ha generat compostos tant B8,B8'-dialquilsubstituïts com B8-alquil-B8'-hidroxilsubstituïts. A partir del derivat [3,3'-Co(8-Me-1,2-C2B9H10)(8-OH-1',2'-C2B9H10)]- s'ha observat per primer cop en la química dels clústers de bor un procés d'oxodesmetilació. De la reactivitat dels derivats mono i diiodats amb alquins en destaca la reacció del derivat monoiodat amb trimetilsililacetilè la qual ha permès aïllar i caracteritzar els anàlegs en tres dimensions al fenantrè i al 9-vinilfenantrè: [8,8'-m-C2H2-3,3'-Co(1,2-C2B9H10)2]- i [8,8'-m-C4H2(SiMe3)2-3,3'-Co(1,2-C2B9H10)2]-. S'ha proposat un mecanisme basat en etapes d'acoblament B-C, d'hidroboració intramolecular o intermolecular, d'hidrodesililació i "enyne" metàtesis per a explicar la generació d'aquests nous compostos. També s'han sintetitzat nous cobaltocarborans que incorporen cadenes de polièter en la posició B8 per reacció de l'espècie dioxanada [3,3'-Co(8-C4H8O2-1,2-C2B9H10)(1',2'-C2B9H11)] amb alcòxids sòdics. A més a més, per difracció de raigs X s'ha resolt l'estructura cristal·lina de Na[3,3'-Co(8-O(CH2CH2O)2Et-1,2-C2B9H10)(1',2'-C2B9H11)] en la que s'evidencia l'existència d'interaccions B-H&#9674;&#9674;&#9674;Na.Finalment, s'ha polimeritzat electroquímicament el polipirrol amb alguns dels cobaltocarborans B8-substituïts per a avaluar la resistencia a la sobreoxidació del nou material polimèric. / The practical application of cobaltobis(dicarbollide), [3,3'-Co(1,2-C2B9H11)2]-, either as an extractant of radionuclides from nuclear wastes or as a doping agent on conducting organic polymers in particular polypyrrole, has encouraged to research on this boron cluster. The aim of this work has been to synthesize and characterize new cobaltocarborane derivatives with substituents on the carbon vertexes and on the boron vertexes to be used as extractant or doping agents. The incorporation of phosphines in the carbon vertexes of the cobaltobis(dicarbollide) has been possible through direct metallation of the cluster with n-BuLi, followed by reaction with chlorophosphines (ClPR2: R=Ph, Et, iPr or Cl2PPh). This reaction has led to the synthesis and separation of C-diphosphinosubstituted species. Their characterization by NMR spectroscopy (1H, 13C, 31P i 11B) and X-ray diffraction has revealed that among all possible isomers, only the racemic mixture is formed. The meso isomer is only generated if the same reaction is applied to the compound [8,8'-m-C6H4-3,3'-Co(1,2-C2B9H10)2]-. Also the unique case of mono-C-substitution has been observed starting from this compound. After synthesizing all this new family of C-phosphino derivatives, the phosphine oxides analogous has been prepared by treatment with H2O2 in acetone. This oxidation methode has also been applied to closo-carboranyldiphosphines. In this cases, upon oxidation of the phosphorous atoms takes place the partial cluster degradation from closo to nido. The phosphine oxides have been used in radionuclides extraction experiments, liquid-liquid extraction techniques and transport experiments using supporting liquid membranes.The structural similarity of the anionic cobaltocarboranyldiphosphine [3,3'-Co(1-PPh2-1,2-C2B9H10)2]- synthesized here with the well-known BINAP and dppf ligands has motivated to determine how the cobaltocarborane acts as a ligand. In this sense, this has been complexed with metals such as Ag, Au, Rh and Pd. A detailed analysis of the geometrical differences between the three ligands has also been explored.Concerning the functionalization of the boron atoms, the synthetic procedure for the iodated derivatives [3,3'-Co(8-I-1,2-C2B9H10)(1',2'-C2B9H11)]- and [3,3'-Co(8-I-1,2-C2B9H10)2]- as well as their reactivity with Grignard reagents has been studied. The cross-coupling reaction between the monoiodated compound and a Grignard reagent has allowed to generate monoalkylated and monoarylated derivatives on B8 position. The effect of alkyl and aryl substituents has been studied experimentally by NMR, UV/Vis, cyclic voltammetry and X-ray diffraction. Theoretically Extended Hückel and ab initio methods have also been carried out. Experimental and theoretical data agree with the electronwithdrawing character of alkyl groups when bonded to boron, and the less contribution of the metal d orbitals to the frontier orbitals. On the other hand, the reactivity of the diiodated compound with magnesium salts has generated homo-B8,B8'-dialkylsubstituted and hetero-B8-alkyl-B8'-hydroxilsubstituted derivatives. An oxodemethylation process has been observed for the first time in boron cluster chemistry when using [3,3'-Co(8-Me-1,2-C2B9H10)(8-OH-1',2'-C2B9H10)]- in the presence of I2.Remarkable is the reaction between the monoiodated derivative with trimethylsilylacetylene which has permitted the isolation and characterization of the three-dimensional analogous of phenantrene and 9-vinylphenantrene: [8,8'-m-C2H2-3,3'-Co(1,2-C2B9H10)2]- and [8,8'-m-C4H2(SiMe3)2-3,3'-Co(1,2-C2B9H10)2]-. A mechanism based on B-C coupling, intramolecular or intermolecular hydroboration, hydrodesilylation and enyne metathesis reactions has been proposed to explain the formation of these compounds. The synthesis of new cobaltocarboranes that incorporates polyethers chains in B8 vertex has been possible by reaction of the dioxanate species [3,3'-Co(8-C4H8O2-1,2-C2B9H10)(1',2'-C2B9H11)] with sodium alkoxides. Furthermore, through X-ray diffraction has been solved the crystal structure of Na[3,3'-Co(8-O(CH2CH2O)2Et-1,2-C2B9H10)(1',2'-C2B9H11)] that evidenciates the existence of B-H&#9674;&#9674;&#9674;Na interactions. These B8-substituted cobaltocarborane derivatives have been used as doping agents in the electrochemical polymerization of polypyrrol in order to evaluate the overoxidation resistance of the new polymeric materials.

In this dissertation, catalytic C-F bond activation mediated by alumenium and silylium species, improved methods for the synthesis of highly chlorinated carboranes and dodecaborates, new type of P2Si= pincer silylene Pt complexes and PBP pincer Rh complexes are presented. In Chapter II, the design and synthesis of P2Si= and PBP ligand precursors is described. BrC6H4PR2 is shown to be a useful building block for PXP type of ligands with o-arylene backbone. RLi reagents displayed high chemoselectivity towards electrophiles, such as Si(OEt)4 and BX3 (X = Hal). In Chapter III, new chlorination methods to synthesize [HCB11Cl11]- and [B12Cl12]2- are presented. [HCB11Cl11]- was obtained via reactions of Cs[HCB11H11] with SbCl5 or via reactions of Cs[HCB11H11] with Cl2 in acetic acid and triflic acid. Heating Cs2[B12H12] in mixtures of SO2Cl2 and MeCN led to the isolation of Cs2[B12Cl12] in high yield. In Chapter IV, Et2Al[HCB11H5Br6] or Ph3C[HCB11H5Br6] were shown to be robust catalysts for sp3 C-F bond activation with trialkylaluminum as the stoichiometric reagent. Trialkylaluminum compounds were also shown to be able to be used as “clean-up” reagent for the C-F bond activation reactions, which led to ultra high TON for the catalytic reactions. In Chapter V, a series of (TPB)M complexes (M = Ni, Pd, Pt) were synthesized and characterized by multinuclear NMR spectroscopy and X-ray crystallography. The resulting metal complexes displayed strong dative M→B interaction and unusual tetrahedral geometry for four-coordinate 16ē species, due to the cage structure of the ligand. In Chapter VI, (PSiHP)PtCl was synthesized via the reaction of the ligand precursor and Pt(COD)Cl2, which was used to obtain a series of (PSiHP)PtX complexes(X= I, OTf, Me, Ph, Mes). After hydride abstraction by Ph3C[HCB11Cl11], the X ligand (X= I, OTf, Me, Ph) migrated from the Pt center to silicon center to give a cationic pincer silyl species. The migration was not observed when mesityl was used as the X ligand, which resulted in the first known pincer complex with central silylene donor. Our approaches towards PNP pincer boryl Rh complexes were summarized in Chapter VII. (PBPhP)Rh pivalate complex underwent C-Ph bond activation to yield the pivalate-bridging Rh borane complex.

Universiẗat, Diss., 2003--Dortmund.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18292号 / 工博第3884号 / 新制||工||1596(附属図書館) / 31150 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 中條 善樹, 教授 澤本 光男, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM