Rozprawy doktorskie na temat „Metal Mediated Catalysis”

Reduction of Ta(DIPP)₂Cl·OEt₂(DIPP= 2,6-OC₆H₃ⁱPr₂) with 2 equiv. of NaHg in the presence of 3,5-lutidine results in cyclometalation of DIPP to give TaCl(DIPP)-(OC₆H₃ⁱPr-η²(C,C)-CMe =CH₂)(3,5-lutidine)₂ (10) in moderate yield. Metallacycle 10 was also isolated from the reaction of (η⁶-C₆Me₆)Ta(DIPP)₂Cl with 3,5-lutidine. Examination of both crude reaction mixtures by ¹H NMR revealed 10 to be the major product without any indication of the formation of η²-lutidine species. These observations suggest that η²(N,C)-coordination of 3,5-lutidine is kinetically incompetitive with respect to the cyclometalation of DIPP by d² tantalum. Such undesired reactivity of DIPP can be potentially inhibited by the use of linked aryloxide ligands to prevent close approach of metalatable C-H bonds of DIPP to the metal center. An efficient route to a family of silane-linked aryloxides was developed. Tris(2-hydroxy-3-isopropylphenyl)methylsilane (H₃TIPSI, 59), bis(2-hydroxy-3-isopropyl-phenyl)diphenylsilane (H₂BIPSI, 61), and bis(2-hydroxy-3-isopropylphenyl)dimethyl-silane (H₂BIPSI, 60) were obtained via deprotection of the parent silane-linked anisoles. The anisoles were prepared in high yields by treating 2-methoxy-3-isopropyl-phenyllithium·0.5TMEDA (27·0.5TMEDA) with an appropriate amount of chloroalkylsilanes. The deprotection was carried out employing BBr₃ in CH₂Cl₂ followed by hydrolysis of the intermediate boron ethers in the presence of a non-nucleophilic base to avoid protiodesilylation. Additionally, a significantly improved synthesis of 1,2-bis(3-isopropyl-2-hydroxyphenyl)ethane (H₂BIPP, 40) employing 27·0.5TMEDA as a starting reagent is reported. 2-Methoxyphenyllithium 27·0.5TMEDA was prepared via catalytic ortho-directed metalation of 2-isopropylanisole, and the mechanistic aspects of such metalations are presented. Trinuclear complex (AlBr₂)₃TIPSI (55) was isolated from the reaction of Me₃TISPI with 3 equiv. of AlBr₃ in benzene at 60°C. Preliminary reactivity studies show that Me₃TIPSI (49) and Me₂BIPSI (51) can be reacted with TaBr₅ under similar conditions to give Br₃Ta(MeTIPSI)(THF)₂ (62) and Br₃Ta(BIPP)OEt₂ (63), respectively, after appropriate reaction work ups.

Computational methods were employed to investigate catalytic processes. First, DFT calculations predicted the important geometry metrics of a copper–nitrene complex. MCSCF calculations supported the open-shell singlet state as the ground state of a monomeric copper nitrene, which was consistent with the diamagnetic character deduced from experimental observations. The calculations predicted an elusive terminal copper nitrene intermediate. Second, DFT methods were carried out to investigate the mechanism of C–F bond activation by a low-coordinate cobalt(I) complex. The computational models suggested that oxidative addition, which is very rare for 3d metals, was preferred. A π–adduct of PhF was predicted to be a plausible intermediate via calculations. Third, DFT calculations were performed to study ancillary ligand effects on C(sp3)–N bond forming reductive elimination from alkylpalladium(II) amido complexes with different phosphine supporting ligands. The dimerization study of alkylpalladium(II) amido complexes indicated an unique arrangement of dative and covalent Pd-N bonds within the core four-membered ring of bimetallic complexes. In conclusion, computational methods enrich the arsenal of methods available to study catalytic processes in conjunction with experiments.

The factors that determine RNA structure formation, stability, and dynamics are inexorably linked to RNA function. The Hammerhead ribozyme (HHRz) has long served as a model for studying metal-dependent folding and catalysis in RNA. The HHRz consists of three helices meeting at a common junction of conserved nucleotides that form the active site of the ribozyme. Current models of metal-dependent HHRz function involve a requirement for divalent metals to globally fold the ribozyme at low metal concentrations, followed by a second metal-dependent process which activates the HHRz for catalysis. The exact role of metal ions in activating HHRz catalysis is still a subject of investigation. We used 2-aminopurine substitutions near the active site of the ribozyme to determine if this second metal-dependent process involves a conformational rearrangement in the core of the ribozyme. We find evidence for a conformational change beyond global folding in the core of the ribozyme that not only correlates with metal activated catalysis but is also sensitive to the identity of the metal ions used for folding. Though phosphorothioate substitutions indicate that a ground-state coordination of a catalytic metal to the scissile phosphate is required for efficient catalysis, our folding studies show that this coordination event is not absolutely required for folding of the HHRz core. To investigate possible roles for metal ions in general acid-base catalysis, we tested the pH dependence of the HHRz rate using a variety of metal ions. We find the pH dependent rate profile of the ribozyme is shifted by transition metal ions, whereas other group II metals show similar profiles to Mg

In this thesis will be described research towards the development of bioorthogonal bond-cleavage reactions, and their applications in targeted drug delivery (Figure 1). The first project relates to the development of a palladium mediated bond-cleavage or "decaging" reaction which can cause a propargyl carbamate to decompose and release an amine. This was further developed by the incorporation of a protein modification handle which allowed an amine-bearing drug to be covalently ligated to a protein by a palladium-cleavable linker. This chemistry was demonstrated by the conjugation of the anticancer drug doxorubicin to a tumour targeted anti-HER2 nanobody. The drug could then be delivered to cancer cells upon addition of a palladium complex. The second project relates to the development of a platinum mediated bond-cleavage reaction. This was developed with the aim of using platinum-containing anticancer drugs - such as cisplatin - as a catalyst to cause drug release reactions in tumours. In this reaction an alkyne-containing amide can decompose to release an amine upon addition of platinum complexes, and was applied to the release of prodrugs of the cytotoxins monomethylauristatin E and 5-fluorouracil in cancer cells. A cisplatin-cleavable antibody-drug conjugate was designed and synthesised, and progress towards its biological evaluation will be discussed.

Powerful tools have emerged in the past few years to allow the sensing, imaging and modulation of biological processes in living systems. Bioorthogonal organometallic reactions are transformations catalysed by transition metals, which are compatible within a biological environment. Palladium-mediated cross-coupling and decaging reactions, for example, have been successfully applied to catalyse non-natural chemical transformations within a biological milieu. Up until now, copper-catalysed cycloaddition reactions have been used extensively for the conjugation, immobilisation, and purification of biomolecules, but their further application in vivo has been limited by the inherent toxicity of copper. Herein, different transition metal catalysts were designed and applied in cellular and in vivo manipulations. Polymeric solid supports were functionalised with palladium nanoparticles and used as biocompatible, heterogeneous catalysts in selective decaging and cross-coupling reactions to activate fluorescent probes and synthesise cytotoxic anticancer drugs in situ. In order to gain tumour selectively, targeting functionalities were incorporated into the particles to allow the spatial control of the selective activation of labelling probes. The simultaneous synthesis of two different anticancer agents intracellularly, by two totally different mechanisms (in situ synthesis and decaging), is reported. The cellular toxicity of copper was addressed by entrapping copper nanoparticles on a polymeric solid support, allowing the activation of labelling probes, as well as the synthesis of an anticancer agent from two benign components through the well-known copper catalysed azide-alkyne cycloaddition. The biocompatibility of the copper catalysts in vivo was shown by implantation in zebrafish embryos.

This thesis describes the investigation of thiadiazolidine 1-oxides and structurally related compounds as ligands in palladium catalysis. The introduction will provide background information on subjects related to the work of the main project. Palladium catalysed cross couplings, namely the Heck and Tsuji-Trost reactions, will feature prominently and will be discussed in basic detail. A general outline of different classes of ligands used in palladium catalysis will also be put forward. Extraneous factors which affect catalyst reactivity will also be discussed, including the use of microwave irradiation and the effect of additives. Special attention is paid towards sulfur containing ligands. As their use has been relatively limited this will also include other areas of catalysis. Investigations into the synthesis of esermethole prompt a general background of methods of synthesising oxindoles and also examples of previous syntheses of the compound. The second chapter begins by describing the initial exploratory work, the testing of a thiadiazolidine 1-oxide compound as a ligand for the Heck reaction. Aryl iodides are successfully coupled to a range of styrenes and α,β-unsaturated esters in excellent yields under microwave conditions. Aryl bromides are also successfully coupled after some optimisation. In many cases the presence of tetrabutylammonium bromide is required to prevent shattering of the sealed microwave vial. A range of differently substituted thiadiazolidine 1-oxides were synthesised in order to establish a pattern of reactivity based on steric and electronic factors. Structurally related chiral compounds were also synthesised, including the first reported enantiomerically pure thiadiazol-3-one 1-oxide and thiatriaza-indene 3-oxide systems chiral at the sulfur atom. The synthesis of oxindoles using palladium mediated and non-catalytic chemistry was also investigated. Investigations into the synthesis of esermethole were undertaken; the key stereoinducing reaction, the decarboxylative asymmetric allyic alkylation reaction, achieved a 46% ee. A formal synthesis of esermethole was outlined in 8 steps from commercially available material. The third chapter is the experimental section and is dedicated to the methods of synthesis and characterization of the compounds mentioned in the previous chapter. X-ray reports regarding the crystallographic representation of the structures presented in chapter two are provided in appendix A.

CO2 activation and conversion mediated by transition metal (TM) catalysts were investigated. Homogeneous catalysis of the reverse water gas shift reaction CO2+H2→H2O+CO was studied as a means to reduce CO2.  β-diketiminato metal models L'MI ( L' =C3N2H5-; M = first-row TMs) were considered as potential catalysts. The thermodynamics of prototypical reaction pathways were simulated using B3LYP/aug-cc-pVTZ. Results show that middle series metal complexes result in more thermodynamically favorable properties; therefore, more detailed thermodynamic and kinetic studies were carried out for Mn, Fe, and Co complexes. On the other hand, heterogeneous catalysis of the reduction of CO2 to CO was carried out on Fe, Co, Ni, and Cu surfaces, using the PBE functional. Reaction barriers were calculated using the climbing image nudged elastic band method. Late 3d and 4d transition metal ion (Fe, Co, Ni, Cu, Ru, Rh, Pd, and Ag) mediated activation of dimethyl ether was studied to investigate the intrinsic catalytic properties of metals for C-O bond cleavage. A set of density functional theory (DFT) methods (BLYP, B3LYP, M06, M06-L, B97-1, B97-D, TPSS, and PBE) with aug-cc-pVTZ basis sets was calibrated with CCSD(T)/CBS calculations on reaction energies and barriers.

Treatment of the η(N,C)-pyridine complex [η²(N,C)-2,4,6-NC₅ᵗBU₃H₂]TA(DIPP)₂Cl (DIPP = 2,6-diisopropylphenoxide) with LiBEt₃H affords the C-N bond scission product (DIPP)₂Ta(=NCᵗBu=CHCᵗBu=CHCHᵗBu) (4). Reaction of [η²(N,C)-2,4,6-NC₅ᵗBU₃H₂]TA(DIPP)₂Cl with the appropriate alkyl lithium or Grignard reagent provides the alkyl derivatives [η²(N,C)-2,4,6-NC₅ᵗBU₃H₂]TA(DIPP)₂R [R = Me (5); Et (6); ⁿPr (7); ⁿBu (8); Ph (9); CH₂SiMe₃ (10)] in high yield. The molecular structure of the ethyl complex, [η²(N,C)-2,4,6-NC₅ᵗBU₃H₂]TA(DIPP)₂Et (6) has been determined. Upon thermolyzing complexes 5 - 9, a metal-ta-pyridine ligand alkyl migration is effected and the C-N bond cleavage products (DIPP)₂Ta(=NCᵗBu=CHCᵗBu=CHCHᵗBuR) [R = Ph (11); Me (12); Et (13); ⁿPr (14); ⁿBu (15)] are formed. Kinetic and mechanistic studies of the 5 → 12 conversion, indicate that methyl migration is strictly intramolecular; thus a formal endo attack on the η²(N,C)-pyridine ligand has occurred. While (DIPP)₂Ta(=NCᵗBu=CHCᵗBu=CHCHᵗBu) (4) and (DIPP)₂Ta(=NCᵗBu=CHCᵗBu=CHCᵗBuPh) (11) are indefinitely stable and are structurally characterized, the β-hydrogen containing alkyl derivatives, (DIPP)₂Ta(=NCᵗBu=CHCᵗBu=CHCᵗBuCHR') [R' = H (12); Me(13); Et (14); ⁿPr (15)] decompose to provide the metallapyridine complex, [(DIPP₂Ta(μ- NCᵗBu=CHCᵗBu=CH)₂ (16) and the t-butyl-substituted alkenes ᵗBuCH=CHR', respectively. The structure of 16 is reported. Labelling studies reveal the source of the ᵗBuCH=CH₂ in the 5 → 12 → 16 conversion and the decomposition of 12 to 16 and ᵗBuCH=CH₂ is proposed to proceed via the eight-membered, ring-expansion isomer, (DIPP₂)Ta(=NCᵗBu=CHCᵗBu=CHCᵗBuCH₂) (17). An acetonitrile adduct of this intermediate, (DIPP)Ta(=NCᵗBu=CHCᵗBu=CHCᵗBuCH₂)(MeCN)₂ (17-MeCN), has been trapped. An overall mechanism for the decomposition (DIPP)₂Ta(=NCᵗBu=CHCᵗBu=CHCᵗBuCH₂R') [R' = H (12); Me(13); Et (14); ⁿPr (15)] to [(DIPP)₂Ta(μ-NCtBu=CHCᵗBu=CH)₂ (16) and ᵗBuCH=CHR', based on these observations, is proposed. The heterocyclic complexes [η¹(N)-QUIN]Ta(Oar)₃Cl₂ (18) and [η ¹(N)-6MQ]- Ta(Oar)₃Cl₂ (19) (QUIN = quinoline, and 6MQ = 6-methylquinoline) are prepared from Ta(Oar)₃Cl₂(OEt₂) and QUIN or 6MQ. [η¹(N)-6MQ]Ta(OAr)₂Cl₃ (20) is prepared similarly from Ta(OAr)₂Cl₃(OEt₂). Upon rapid, two-electron reduction of these complexes, an η¹(N) → η²(N,C) bonding rearrangement is effected and the thermally sensitive, d² species [η²(N,C)-QUIN]Ta(Oar)₃ (21), [η²(N,C)-6MQ]Ta(Oar)₃ (22), and [η²(N,C)-6MQ]Ta(OAr)₂- Cl(OEt₂) (25) can be isolated. The PME₃ adducts [η²(N,C)-QUIN]Ta(Oar)₃(PMe₃) (23) and [η²(N,C)-6MQ]Ta(Oar)₃(PMe₃) (24) can be prepared by simple coordination of PMe₃ to the base-free compounds 21 and 22. The quinoline ligand of [η²(N,C)-QUIN]Ta(Oar)₃ (21) is readily hydrogenated under mild reaction conditions to afford 1,2,3,4- tetrahydroquionline. When Ta(Oar)₂Cl₃(OEt₂) is reduced by one electron in the presence of QUIN or 6MQ, the d¹ bis(ligand) complexes [η¹(N)-6MQ]₂Ta(Oar)₂Cl₂ (26) and [η¹(N)- QUIN]₂Ta(OAr)₂Cl₂ (27) can be isolated. The relevance of these studies with respect to industrial hydrodenitrogenation (HDN) catalysis is discussed.

The present thesis describes the development of heterogeneous catalytic methodologies using metal−organic frameworks (MOFs) as porous matrices for supporting transition metal catalysts. A wide spectrum of chemical reactions is covered. Following the introductory section (Chapter 1), the results are divided between one descriptive part (Chapter 2) and four experimental parts (Chapters 3–6). Chapter 2 provides a detailed account of MOFs and their role in heterogeneous catalysis. Specific synthesis methods and characterization techniques that may be unfamiliar to organic chemists are illustrated based on examples from this work. Pd-catalyzed heterogeneous C−C coupling and C−H functionalization reactions are studied in Chapter 3, with focus on their practical utility. A vast functional group tolerance is reported, allowing access to substrates of relevance for the pharmaceutical industry. Issues concerning the recyclability of MOF-supported catalysts, leaching and operation under continuous flow are discussed in detail. The following chapter explores puzzling questions regarding the nature of the catalytically active species and the pathways of deactivation for Pd@MOF catalysts. These questions are addressed through detailed mechanistic investigations which include in situ XRD and XAS data acquisition. For this purpose a custom reaction cell is also described in Chapter 4. The scope of Pd@MOF-catalyzed reactions is expanded in Chapter 5. A strategy for boosting the thermal and chemical robustness of MOF crystals is presented. Pd@MOF catalysts are coated with a protecting SiO2 layer, which improves their mechanical properties without impeding diffusion. The resulting nanocomposite is better suited to withstand the harsh conditions of aerobic oxidation reactions. In this chapter, the influence of the nanoparticles’ geometry over the catalyst’s selectivity is also investigated. While Chapters 3–5 dealt with Pd-catalyzed processes, Chapter 6 introduces hybrid materials based on first-row transition metals. Their reactivity is explored towards light-driven water splitting. The heterogenization process leads to stabilized active sites, facilitating the spectroscopic probing of intermediates in the catalytic cycle.

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Submitted. Paper 8: Submitted.

 

This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially p-carborane.

1-(1-p-carboranyl)-N-methyl-N-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate.

p-Carborane has been arylated on the 2-B-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-p-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C₆H₄-, 3-CH₃CONH-C₆H₄-, 4-NC-C₆H₄-, 3-NO₂-C₆H₄-], gave the corresponding 2-aryl-p-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd₂(dba)₃–dppb system. Under the same conditions, the boron-boron bond forming reaction of two p-carboranylboronic esters (2-[(pinacolato)boron]-p-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible.

p-Carborane has been vinylated on the 2-B-atom in high yields by use of the Heck reaction. The coupling between 2-I-p-carborane and various styrenes [4-H-, 4-C₆H₄-, 4-Cl , 4-Br-, 4-NO₂-, 4-CH3O- and 4 CH₃ ] resulted in the formation of the correspondingtrans-β-(2-B-p-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins.

The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-p-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [¹²⁵I]-iodide labelling could be improved and extended. 2-I-p- 9-I-m-, 9-I-o-, 3-I-o-carborane, 1-phenyl-3-I-o-carborane and 1,2-diphenyl-3-I-o-carborane could be [¹²⁵I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.

En el Capítol 2, coure(I) catalitza la ciclació borilativa de gamma-alquenil aldehids mitjançant una adició quimio- i regioselectiva de Cu-B sobre C=C, seguida d'una reacció intramolecular d'adició de Cu-C sobre C=O. Els productes s'han format amb diastereoselectivitat i un anàlisi computacional ha identificat els punts claus que determinen la quimio- i diastereoselectivitat observada. En el capítol 3, s'estudia la reactivitat dels compostos diborats amb diens 1,3 en un context lliure de metalls de transició. Unicament, l'addició de Na2CO3 sobre bis(pinacolat)diboro, en MeOH, permet la 1,4-hidroboració de 1,3-diens no cíclics i cíclics. La influencia electrònica del sustrat garanteix la hidroboración conjugada 1,4 versus la 1,2. Càlculs DFT mostran que la distribució de la càrrega en l'anió alílic intermedi governa la selectivitat en la 1,4-hidroboració, mentres que la configuració trans del diè determina la preferència pel producte alil-borilat E. En el capítol 4, s'estudia la química dels carbanions alpha-borilats, ja que mostren una gran diversitat i permeten la formació d'enllaços C-C eficients. La deficiència electrònica del centre borilat trisubstituit és responsable de l'estabilizació del carbanió, facilitant la seva formació i modelant la reactivitat. Es descriuen aspectes electrònics de la estructura i tendèncias reactives d'un conjunt ampli d'alpha-boril carbanions. Mitjançant estudis de DFT s'ha determinat un mapa de tendencies sobre la reactivitar nucleòfila dels carbanions alpha-borilats, variant la naturalesa del grup borilo, el número de grups borilo en el carbanió i la naturalesa del catió estabilizant. Aquest mapa de tendencies permet la selecció del sintó apropiat, en funció de la reactivitat objecte d'estudi.
egioselectiva de Cu-B sobre C=C, seguida de una reacción intramolecular de adición de Cu-C sobre C=O. Los productos se han formado con diastereoselectividad y un análisis computacional ha identificado los puntos clave que determinan la quimio- y diastereoselectividad observada. En el Capítulo 3, es estudia la reactividad de los compuestos diborados con 1,3-dienos en un contexto libre de metales de transición. La única adición de Na2CO3 sobre bis(pinacolato)diboro, en MeOH, permite la 1,4-hidroboración de 1,3-dienos no cíclicos y cíclicos. La influencia electrónica del sustrato garantiza la hidroboración conjugada 1,4 versus la 1,2. Cálculos DFT muestran que la distribución de la carga en el anión alílico intermedio gobierna la selectividad en la reacción de 1,4-hidroboración, mientras que la configuración trans del dieno determina la preferencia por el producto alil-borilado E. En el capítulo 4, se estudia la química de los carbaniones alpha-borilados, ya que muestran una gran diversidad y permiten la formación de enlaces C-C eficientes. La deficiencia electrónica del centro borilado trisustituido es responsable de la estabilización del carbanión, facilitando su formación y modelando su reactividad. Se describen aspectos electrónicos de la estructura y tendencias reactivas de un conjunto amplio de alpha-boryl carbanions. Mediante estudios de DFT se ha determinado un mapa de tendencias sobre la reactividad nucleófila de los carbaniones alpha-borilados, variando la naturaleza del grupo borilo, el número de grupos borilo en el carbanión y la naturaleza del catión estabilizante. Este mapa de tendencias permite la selección del sintón apropiado, en función de la reactividad objeto de estudio.
In Chapter 2, copper (I) catalyzes the borylative cyclization of gamma-alkenyl aldehydes through chemo- and regioselective addition of Cu-B to C=C and concomitant intramolecular 1,2-addition of Cu-C on the C=O. The products are formed in an exclusive diastereoselective manner and computational analysis identify the key points for the chemo- and diastereoselectivity observed. In Chapter 3, we study the reactivity of diboron reagents with 1,3-dienes in a transition-metal-free context. The sole addition of Na2CO3 to bis(pinacolato)diboron, in MeOH, allows the 1,4-hydroboration of cyclic and noncyclic 1,3- dienes. The electronic influence on the substrate guarantees the conjugated 1,4-hydroboration versus 1,2-diboration. DFTcalculations show that the distribution of charge in the allylic anion intermediate governs the selectivity toward 1,4- hydroboration, while the favored trans configuration in diene reagents determines the preference for the E allyl boronate products. In Chapter 4, we studied the chemistry of alpha-boryl carbanions since they show a remarkable diversity, and enable efficient C-C bond formation. The electron-deficient, trivalent boron center stabilizes the carbanion facilitating its generation and tunning its reactivity. We describe the electronic structure and the reactivity trends of a large dataset of apha-boryl carbanions. We use DFT-parameters for capturing their electronic and steric properties, computational reactivity towards model substrates, and crystallographic analysis within the Cambridge Structural Dataset. This study maps the reactivity space by systematically varying the nature of the boryl moiety, the substituents of the carbanionic carbon, the number of alpha-boryl motifs, and the metal countercation. Furthermore, we can classify the alpha-boryl alkylidene metal precursors into three classes directly related to their reactivity. This trend map aids the selection of the appropriate reactive synthon depending on the sought reactivity.

Iron-mediated oxidative cyclisation provides an efficient approach to pyrano[3,2-a]carbazole alkaloids. Thus, improved routes to girinimbine and murrayacine as well as the first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine are reported. Asymmetric epoxidation of girinimbine led to (−)-trans-dihydroxygirinimbine and the assignment of its absolute configuration
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Iron-mediated oxidative cyclisation provides an efficient approach to pyrano[3,2-a]carbazole alkaloids. Thus, improved routes to girinimbine and murrayacine as well as the first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine are reported. Asymmetric epoxidation of girinimbine led to (−)-trans-dihydroxygirinimbine and the assignment of its absolute configuration.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

One of the more formidable challenges in the synthesis of complex organic molecules remains the efficient formation of carbon-carbon bonds. The development of a broad class of reactions to achieve this goal involves the addition of carbon based nucleophiles to carbonyl and imine compounds. Until recently, classical approaches to carbon-carbon bond formation generally required the use of stoichiometric pre-formed organometallic reagents to serve as nucleophiles, which translate into stoichiometric organometallic byproducts. In an effort to minimize nucleophile pre-activation and byproduct formation, our lab has developed efficient methods for carbonyl and imine additions via in situ formation of alkyl metal nucleophiles from π-unsaturates. The research reported herein describes our advances in an assortment of transition metal-catalyzed carbon-carbon bond forming reactions mediated by transfer hydrogenation, including regioselective hydrohydroxymethylation, hydrohydroxyfluoroalkylation, and hydroaminomethylation. Additionally, the investigation of regioselective carbonyl vinylation is reported.
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Several organic transformations are mediated by group(IV) metal alkoxides. The reactivity is based on the basic nature of alkoxide group, Lewis acidic nature of the group(IV) metals, insertion of unsaturated molecules into the M-OR bond and the reduction of M(OR)4 to low valent species. The thesis deals with insertion reactions and the reductive and metathetic coupling reactions mediated by group(IV) metal alkoxides. Titanium(IV) alkoxides and zirconium(IV) alkoxides promote insertion and metathesis of aryl isocyanates. It was observed that aryl isocyanates underwent double insertion in addition to mono insertion. At room temperature, head to tail double insertion is observed whereas at elevated temperatures, head to head double insertion occurred leading to metathesis. The reaction has also been extended to metathesis between heterocumulenes and heteroalkenes. Titanium and zirconium carry out these reactions with different efficiencies. The reasons for these differences have been sought through computational methods. New organic transformations promoted by group(IV) metal alkoxides that are reduced with Grignard reagents and silanes have been explored. Grignard reagents do show reactivity towards imines in the presence of group(IV) metal alkoxides. The reactions have been studied with stoichiometric and catalytic amounts of titanium(IV) isopropoxide and are shown to follow different pathways. Isotope labeling studies indicate that alkylated products formed in stoichiometric reactions arise due to metal-olefin intermediates. However in catalytic reactions, a metal-alkyl complex is responsible for alkylation. Titanium(IV) alkoxides when used in combination with silanes such as phenylsilane bring about the reductive coupling of imines. One of the interesting features is that this pinacol type coupling is diastereospecific.

Several organic transformations are mediated by group(IV) metal alkoxides. The reactivity is based on the basic nature of alkoxide group, Lewis acidic nature of the group(IV) metals, insertion of unsaturated molecules into the M-OR bond and the reduction of M(OR)4 to low valent species. The thesis deals with insertion reactions and the reductive and metathetic coupling reactions mediated by group(IV) metal alkoxides. Titanium(IV) alkoxides and zirconium(IV) alkoxides promote insertion and metathesis of aryl isocyanates. It was observed that aryl isocyanates underwent double insertion in addition to mono insertion. At room temperature, head to tail double insertion is observed whereas at elevated temperatures, head to head double insertion occurred leading to metathesis. The reaction has also been extended to metathesis between heterocumulenes and heteroalkenes. Titanium and zirconium carry out these reactions with different efficiencies. The reasons for these differences have been sought through computational methods. New organic transformations promoted by group(IV) metal alkoxides that are reduced with Grignard reagents and silanes have been explored. Grignard reagents do show reactivity towards imines in the presence of group(IV) metal alkoxides. The reactions have been studied with stoichiometric and catalytic amounts of titanium(IV) isopropoxide and are shown to follow different pathways. Isotope labeling studies indicate that alkylated products formed in stoichiometric reactions arise due to metal-olefin intermediates. However in catalytic reactions, a metal-alkyl complex is responsible for alkylation. Titanium(IV) alkoxides when used in combination with silanes such as phenylsilane bring about the reductive coupling of imines. One of the interesting features is that this pinacol type coupling is diastereospecific.

Ph.D.
The work described in this thesis was directed at advancing the applications of Al(OTf)3, a metal triflate, in organic synthesis. Lewis acids play an important role in catalysis and catalyse reactions with high selectivities, unique reactivities under mild conditions. Metal triflates have become the Lewis acids of choice for acid catalysed organic transformations. A detailed literature study of metal triflates provided numerous examples of their use in organic transformations. Al(OTf)3 has been widely neglected as a Lewis acid which is contrasting to the attention the other metal triflates have received. Previous work in our laboratories had established Al(OTf)3 as an effective Lewis acid catalyst for the ring-opening of epoxides with simple alcohols and amines. The alcoholysis of epoxides provides a ready access to β-alkoxy alcohols. Whilst this reaction has been shown to occur with Al(OTf)3 as a catalyst, the established protocol calls for the use of the nucleophilic alcohol in an excess amount. Whilst this proves no problem when simple alcohols are employed as nucleophiles in the ring-opening reaction, it is a problem when more complex and expensive alcoholic nucleophiles are utilised. A modified procedure utilising Al(OTf)3 as a catalyst was developed which tolerates the use of only 1 equivalent of the nucleophilic alcohol for the ring opening reaction. The desymmetrisation of a meso-epoxide with chiral alcoholic nucleophiles was also investigated and the outcome of the diastereoselectivity of the reaction reported. The aminolysis of epoxides has been established utilising Al(OTf)3 as the Lewis acid catalyst. However, this has only been demonstrated for the ring opening of simple epoxides with simple amines. Piperazine derived β-amino alcohols with known biological activity were chosen as substrates with which to test the Al(OTf)3 catalysed aminolysis of epoxides in the synthesis of more complex β-amino alcohols. The various starting epoxides and amine nucleophiles were synthesised. During which a new approach towards the synthesis of - glycidyl amines was developed utilising a two step approach with the first step being catalysed by Al(OTf)3. It was also found that the optimal method for forming the β-amino alcohol bond was one in which the glycidyl motif was placed on the less basic heteroatom and ring opened by the more nucleophilic piperazine amine.

Radical cyclizations are important reactions in organic chemistry. However, they are seldom used industrially due to their reliance on neurotoxic trialkyltin hydride. Many substitutes for tin hydrides have been developed but none have provided a general solution to the problem. Transition metal hydrides with weak M-H bonds can generate carbon centered radicals by hydrogen atom transfer (HAT) to olefins. This metal to olefin hydrogen atom transfer (MOHAT) reaction has been postulated as the initial step in many hydrogenation and hydroformylation reactions. The Norton group has shown MOHAT can mediate radical cyclizations of ɑ,ω dienes to form five and six membered rings. The reaction can be done catalytically if 1) the product metalloradical reacts with hydrogen gas to reform the hydride and 2) the hydride can perform MOHAT reactions. The Norton group has shown that both CpCr(CO)₃H and Co(dmgBF₂)₂(H₂O)₂ can catalyze radical cyclizations. However, both have significant draw backs. In an effort to improve the catalytic efficiency of these reactions we have studied several potential catalyst candidates to test their viability as radical cyclization catalysts. I investigate the hydride CpFe(CO)₂H (FpH). FpH has been shown to transfer hydrogen atoms to dienes and styrenes. I measured the Fe-H bond dissociation free energy (BDFE) to be 63 kcal/mol (much higher than previously thought) and showed that this hydride is not a good candidate for catalytic radical cyclizations. I have investigated the dynamics of Co(dmgBF₂)₂(H₂O)₂ under hydrogen gas to attempt to observe its hypothesized cobalt hydride. Under large pressures up to 70 atm we see two species one which we assign as the cobalt hydride and one which we assign as a ligand protonated Co(I) complex. These are supported by high pressure NMR studies of the same complexes. By varying the H₂ pressure, we can calculate the hydrogen atom donor ability of the mixture formed under H₂ as 50 kcal/mol. This makes this mixture a very good H• donor. The Norton group has shown that vanadium hydrides have very weak V-H bonds that donate H* rapidly. However, they cannot be made catalytic under hydrogen gas. I have attempted to regenerate these vanadium hydrides by a sequential reduction then protonation of the metalloradical. With HV(CO)₄dppe this only produced hydrogen gas, presumably by one electron reduction of HV(CO)₄dppe. However, with HV(CO)₄dppf this does not readily occur and this hydride could potentially be a catalyst for radical cyclizations. Many radical cyclizations involve vinyl (sp²) radicals. I have shown that both the CpCr(CO)₃H and the Co(dmgBF₂)₂(H₂O)₂ systems can catalytically perform metal to alkyne hydrogen atom transfers (MAHAT's) and that these reactions can be used to perform radical cyclizations very efficiently.

Dottorato Scienza e Tecnica "Bernardino Telesio", Metodologie Inorganiche, Ciclo XXVIII, a.a. 2015-2016
Una delle principali sfide nel mondo scientifico è superare la linea di confine tra la natura e il mondo inanimato. La Chimica Biomimetica e la Biologia Sintetica collaborano al raggiungimento di questo obiettivo. Lo sviluppo della Chimica Biomimetica è stato ispirato dall’elevata efficacia catalitica degli enzimi naturali, che giocano un ruolo chiave nella maggior parte delle reazioni chimiche che avvengono nell’organismo. Essa può essere definita come una branca della chimica che cerca di imitare le reazioni naturali e i processi enzimatici allo scopo di accrescere il potere della chimica stessa. La Biologia Sintetica, invece, è una nuova area di ricerca che rappresenta la convergenza di nuovi sviluppi in chimica, in biologia e in scienza computazionale al fine di progettare e creare nuovi sistemi biologici, partendo da materiale biologico già esistente e modificato mediante l’applicazione di processi chimici, da utilizzare in ambito industriale, energetico, medico e ambientale. La presente tesi pone l’attenzione sul meccanismo di azione seguito da alcuni catalizzatori biomimetici, per i quali sono state investigate sia la regioselettività, sia l’attività riscontrata sperimentalmente, e sullo studio delle proprietà energetiche e strutturali relative a nuovi sistemi bio-ispirati. I catalizzatori biomimetici e i nuovi sistemi biologici il cui comportamento è stato studiato e razionalizzato come scopo di questo lavoro di tesi possono essere suddivisi in tre categorie: i- Alcuni composti del naftalene caratterizzati dalla presenza di atomi di selenio, zolfo o tellurio, come mimici degli enzimi iodotironine deiodinase (ID), coinvolti nell’attivazione e inattivazione degli ormoni tiroidei. ii- Una serie di complessi di monooxomolibdeno(IV) come biomimetici dell’enzima trimetilammina-N-ossidoreduttase (TMAOR). iii- Alcuni modelli di DNA duplex, contenenti coppie di nucleobasi non complementari mediate da metalli di transizione. Lo studio teorico dei sistemi sopra elencati è stato effettuato utilizzando l’approccio quantomeccanici (QM) basato sulla teoria del funzionale della densità (DFT).
Università della Calabria

The hydrolysis of 4-Nitrophenylphosphate (NPP) as model substrate in the presence of several cobalt (III) amine [N4Co(OH)(H2O)]2+ and copper bipyridyl [Cu(bpy)(H2O)2]2+ complexes in oil in water microemulsion media was investigated. The reaction was monitored by measuring the absorbance of the nitrophenolate ion produced in the reaction aliquots with time under the experimental conditions. The order of effectiveness of the microemulsion systems towards the hydrolysis of NPP in the presence of these metal ions were found to be cationic > anionic > aqueous at neutral pH. The results of the present investigation exhibits stoichiometric turnovers for the 1:1, 2:1 and 3:1 cobalt to NPP ratio and catalytic turnovers for the [Cu(bpy)2+ to NPP ratio of 1:20. Catalysis in the microemulsion mediated reaction solutions was evident even in low concentrations of the metal ions in 1:2000 metal to NPP ratio. An explanation for the enhanced catalytic activity of the [Cu(bpy)(OH)(H2O)]2+ complex for the hydrolysis of NPP is afforded and the application of the above model systems for possible environmental decontamination of toxic organophosphates is anticipated.
Chemistry
M.Sc. (Chemistry)

碩士
國立交通大學
應用化學系碩博士班
100
The first part of the thesis presents silver trifluoroacetate-mediated reactions of [60]Fullerene with ketonic compounds to afford different structures of C60 derivatives. 4-Alkylcyclohexanone reacted with C60 to afford methanofullerene derivatives. At the same time, dihydrofuran-fused C60 was found as a side product. Fortunately, the intermediate was found and identified as C60-fused 1,3-dioxolanes. Althought 3-alkylcyclohexanone or 2-alkylcyclohexanone could be reacted with C60, the reactivity wasn’t obvious. Then α-tetralone was applied in the reaction to afford dihydrofuran-fused C60 product. The second part of the thesis is kinetics study about the hydrogen released from a H2-encapsulating open-cage Fullerenes.

碩士
國立中正大學
化學工程研究所
106
In our prior research, we have demonstrated that the combination of stereoregular isotactic poly(2-vinylpyridine) (iP2VP) with chiral acid can lead to the generation of self-assembled nanohelices both in liquid and in the solid state. As the handiness of helicity can be controlled by the chirality of the added chiral dopants, the resulting helical structure offers a chiral supermolecular environment similar to the DNA systems adopted by Feringa who used the DNA to combine trantition metal for mediating enantioselective reactions. Accordingly, this research aims to investigate the possibility of forming chiral catalysts by the combination of different transition metals, chiral ligands and P2VP with different tacticity. Attempt to use the chiral catalysts generated by molecular self-assembly has been investigated to mediate the enantioslective Diels-Alder reaction. Results of this bio-mimicking catalysts applied in the inducement of enantioslective Diels-Alder reaction are reported herein.

Hydrogen gas is the cleanest and most cost-effective reductant available to mankind, and the use of hydrogen gas in catalytic hydrogenation reactions is one of the oldest and most utilized organic reactions. Although catalytic hydrogenation has been practiced in industry on enormous scale, the use of hydrogen gas as a terminal reductant in C-C bond forming reactions has been limited to processes involving the migratory insertion of carbon monoxide such as: alkene hydroformylation and the Fischer-Tropsch reaction. A significant advance to the field of synthetic organic chemistry would be the expansion of C-C bond forming reactions beyond reductive coupling via carbon monoxide insertion. Herein, related metal catalyzed reductive couplings to [alpha],[beta]-unsaturated compounds in the presence of reducing agents such as: silane, borane, and hydrogen are reviewed. The following chapters discuss the development of hydrogen-mediated reductive aldol and Mannich reactions. The results from this body of work clearly demonstrate that hydrogen-mediated C-C bond forming reactions are emerging as a powerful tool for synthetic chemists.

博士
國立中正大學
化學所
93
Abstract This thesis involves the synthesis, characterization of a new class of aza-based bidentate phosphinic amide ligands, the study of catalytic applicability of the phosphinic amido palladium complexes to various Heck-type C-C formation reactions, and the kinetic and theoratic study of organotungsten Lweis acid catalyzed Diels-Alder reactions. The thesis also includes discussions of a new path for P-C cleavage which is induced by the basicity of the reaction system. The results and discussion will be categorized into four independent chapters. In the first chapter, we mainly focused our research efforts on the syntheses, structural characterization of a series of gold nanosurface-immobilized palladium(II) complex catalysts, and their catalytic reactivity towards various Heck-type C-C coupling reactions. Spherical gold nanoparticles of a diameter of 2.7 ± 0.5 nm in size were used as support for molecular palladium complex catalysts. These gold nanoparticles were obtained by the chemical reduction method using NaBH4 as the reducing agent to reduce HAuCl4・3H2O in the presence of CH3(CH2)7SH stabilizer. The compound [HS(CH2)11N(H)(O)P(2-py)2] (4), which was derived from Br(CH2)11OH, with both ends having coordination capability was specially designed as the linker between molecular metal catalysts and metal nanosurfaces. The thiol end (HS) of the anchoring linker can be put onto gold nanoparticles’ surfaces by ligand exchange at elevated temperature. Four types of “soluble” or “dispersible” gold nanoparticle-supported ligands, Au−L-A~D (Au−L = Au−S(CH2)11N(H)P(O)(2-py)2), anchored with different amounts of spacing linkers with diameters of 3-5 nm in size were synthesized by design. Again, these gold nanoparticle-supported ligands can be dispersed (or dissolved) in various organic solvents, such as CH3Cl, DMSO, MeOH, EtOH and CH3CN, etc. The direct reaction of the above-mentioned four types of ligands, Au−L-A~D, with palladium (II) complex, Pd(CH3CN)2Cl2, resulted in the formation of “soluble” gold nanosurface-immobilized palladium complexes, Au−L−Pd-A~D (Au−L−Pd = Au−S(CH2)11N(H)P(O)(2-py)2PdCl2). The diameters of the gold cores remain unchanged after palladation, and these gold nanoparticles dissolve in DMSO and MeOH fairly easily. Taking the advantage of the high solubility, A rapid and precise method to structurally characterize these systems (Au−L−Pd-A~D) using solution 1H, 13C and 31P probe NMR spectroscopy becomes accessible. In addition to the NMR technique, the atomic absorption spectroscopy (AA) was also used to determine the amount of Pd catalysts anchored on gold nanoparticle’s surface. By performing a size-and-particle calculation based on the TEM image, one can obtain the average number of Pd catalysts and stabilizers on each gold nanoparticle’s surface. These gold nanoparticle-supported palladium complexes, Au−L−Pd-A~D, were demonstrated to be highly effective catalysts for various Heck C-C coupling reactions. The turnnover frequencies (TOF) of 35000-45000 h-1 were obtained for the A-D systems. The controlled experiment of the molecular palladium complex catalyst HO(CH2)11N(H)(O)P(2-py)2PdCl2) (6) promoted Heck reactions gave TOF values of 10,000-17,000 h-1, which are 3~4 times less than those obtained for the Au−L−Pd-A~D catalytic systems. The kinetic studies revealed that a second order kinetic behavior was found for all the homogeneous 6-catalyzed Heck C-C coupling reactions. However, the kinetic studies showed that the gold nanoparticle-supported catalytic systems deviated dramatically from a normal second order kinetic behavior. In the second chapter, A new class of bidentate, aza-based phosphinic amide ligands, RNHP(O)(2-py)2, where R = CH2CH(CH2)9, HOCH2(CH2)10, (O)3Si(CH2)11, was efficiently synthesized via a one-pot Staudinger reaction of organic azides and 2-pyridylphosphines followed by in situ hydrolyses. The complex CH2CH(CH2)9NHP(O)(2-py)2 was structurally characterized, and its ORTEP drawing showed a pentavalent, trigonal pyramidal arrangement around the P center. The intermediate iminophosphoranes, CH2CH(CH2)9N=P(2-py)3, CH2CH(CH2)9N=P(Ph)- (2-py)2, CH2CH(CH2)9N=P(Ph)2(2-py) and CH2CH(CH2)9N=PPh3 were isolated by design and their hydrolyses in both acidic and basic environments were carefully studied. While all four compounds followed the expected route of a P=N cleavage to give CH2CH(CH2)9NH3+ and phosphine oxides in acidic environments. Hydrolyses of the iminopyridlphosphoranes CH2CH(CH2)9N=P(Ph)n(2-py)2-n (n = 0, 1, 2) under basic conditions produced an N-substituted phosphinic amide, CH2CH(CH2)9NHP(O)(Ph)n(2-py)2-n and a free pyridine via a P-C cleavage. The pyridylphosphorane with e-donating OMe-substituent, CH2CH(CH2)9N=PPh(2-py-4-OMe)2, hydrolyzed in a much slower rate as compared to its parent pyridylphosphoranes. On the contrary, the phenylphosphoranes with e-withdrawing halide-substituents, CH2CH(CH2)9N=P(4-X-Ph)3 (X = F, Cl), hydrolyzed in a noticeably faster rate with reference to their nonsubstituted counterpart. Three different palladium catalysts with a stable metallahexacycle formed around the Pd center were synthesized by the complexation of phosphinic amide ligand with Pd(CH3CN)2Cl2. The soluble, molecular HOCH2(CH2)10NHP(O)(2-py)2PdCl2 catalyzed Heck-type reactions of iodobenzene and acrylates and/or styrene very efficiently to give TOF values of 10,000-17,000 h-1. Both SiO2-supported homogeneous and heterogeneous, (O)3Si−(CH2)11NHP(O)(2-py)2PdCl2, are effective and regioselective catalysts for [2+2+2] alkyne cyclotrimerization reactions and can be successfully reused up to the sixth cycle without the problem of losing activity. In the third chapter, the based-catalyzed hydrolysis of two different phosphine oxides O=PX3 (X = 2-pyridy, phenyl) were carefully studied. The mixed phenyl/pyridyl phosphine oxides O=PPhn(2-py-X)3-n, where X = H, n= 1, 2； X= Me, OMe, n = 1, were hydrolyzed in the presence of base to give [HO(O)PPhn(2-py-X)2-n] and pyridine as products. The results of kinetic study showed that the rate of hydrolysis would decrease while the number of phenyl group increases as follows: O=P(2-py)3> O=PPh(2-py)2> O=PPh2(2-py). However, the measured reaction barriers for hydrolyses were found to be increased when the H atom at the para-position on the pyridyl group of O=PPh(2-py)2 replaced with the e-donating groups, OMe or Me. The rates of hydrolyses were in the following order: O=PPh(2-py)2> O=PPh(2-py-4-Me)2 > O=PPh(2-py-4-OMe)2. For phenyphosphine oxides O=P(4-Ph-X)3, where X = F and Cl, the hydrolyses can be carried out to give [HO(O)P(Ph-X)2-n] and halogenated benzene as products. The hydrolysis rates for this series of phenylphosphine oxides were found in the following order: O=P(Ph-F)3> O=P(Ph-Cl)3> O=PPh3. The parent triphenylphosphine oxide, however, would not undergo hydrolysis even at temperature of 190 oC for days. The energy barriers of the based-catalyzed hydrolysis were calculated by using HF/6-31+G* and B3LYP/6-31+G* level of theory, and the results were consistent with the experimental observation. We found that the energy barriers for the hydrolyses followed the similar trend shown below in its decreasing order: O=P(2-py)3> O=PPh(2-py)2> O=PPh(2-py-4-Me)2 > O=PPh(2-py-4-OMe)2 > O=PPh2(2-py)> O=P(Ph-F)3> O=P(Ph-Cl)3> O=PPh3. In the last chapter, the catalytic reactivity of tungsten Lewis acid [P(2-py)3W(CO)(NO)2]2+ toward Diels-Alder reaction of cyclopentadiene and methyl vinyl kentone and/or 1,3-cyclohexadiene and methyl vinyl kentone were discussed. Comprehensive kinetic measurements of both the uncatalyzed and the corresponding 1-catalyzed Diels-Alder reaction of cyclopentadiene and methyl vinyl kentone as well as cyclohexadiene and methyl vinyl kentone were conducted at various temperatures. Based on the results of these kinetic works, we were able to obtain lavish information to quantify the catalyst efficiencies. For example, the activation energies, preexponetial factors, entropies of the transition state, the reaction rate constants, and reaction order were determined. According to these results, a reasonable mechanism and the reaction rate determining step of the 1-catalyzed Diels-Alder reactions of cyclopentadiene and methyl vinyl kentone as well as cyclohexadiene and methyl vinyl kentone were therefore suggested. The experiment of this chapter is research of continuing the laboratory schoolmate, so does not do the detailed discussion in this thesis, only publish it the thesis and examine and enclose it in the appendix.

Membrane transport processes underlie many purification technologies. The efficiency of a membrane separation process depends upon material throughput (flux), and the degree to which the membrane discriminates amongst species in the feed stock (selectivity). In a supported liquid membrane, flux may be enhanced by carrier molecules, which act as catalysts of translocation. Carrier molecules also confer selectivity, via differential molecular recognition of the substances in the feed stock. The effect of electrical potential on the flux and selectivity of carrier-containing supported liquid membranes is not well documented. We elected to study the effect of electrical potential on supported liquid membranes containing valinomycin, a potassium ionophore, and a calixarene ester, a sodium ionophore. In these systems, the open circuit membrane potential could be made positive or negative by the choice of anion. With both of these carriers, we observed that selectivity for potassium or sodium salts was dependent on the open circuit membrane potential. To confirm that electrical potential was responsible for the observed selectivity variance, we applied a potential across the membrane using a potentiostat. The applied potential created conditions for carrier-mediated electrodialysis, where oxidation and reduction reactions on either side of the membrane act as the driving force for transmembrane flux of charged species. In chronoamperometry experiments, we found that selectivity for potassium or sodium ion was dependent on the applied electrical potential. Subject to some constraints, selectivity and flux could be controlled by the application of positive or negative electrical potentials. Linear sweep voltammetry experiments allowed for the rapid prediction of the potential that must be applied to achieve optimal selectivity. We also found that membrane potential measurements, as well as the magnitude of current that flows in chronoamperometry experiments, could be interpreted to predict Eisenman and Hofmeister sequences. These results are novel, and await a convincing theoretical justification. The results also suggest that a separation technology could be developed around the idea of modulating selectivity with electrical potential. In this regard, carrier-mediated electrodialysis may be suitable for the sequestration of toxic or radioactive heavy metals, and a large number of carrier molecules for metal ions are currently known. The technique may also be suitable for separating organic molecules, such as high-value chiral pharmaceuticals. Supported liquid membranes are a useful research tool, but industrial applications may require a more stable membrane architecture.
Graduate