Degree: Master of Science Department: Science / Metal-ligand models and complex stability constants of newly synthesised chelating ligands, N,N’-bis(2-hydroxycyclopentyl)-ethylenediamine (Cyp2EN) and N,N’-bis(2-hydroxycyclohexyl)-ethylenediamine (Cy2EN), with metal ions Cd2+, Cu2+, Ni2+, Pb2+ and Zn2+ were established in this work. Stability constants were determined by Glass Electrode Potentiometry (GEP) and polarography as electrochemical techniques. A new concept, termed Virtual Potentiometry (VP), was also used for the evaluation of stability constants. In this concept, polarographic or polarographic + potentiometric data were evaluated using potentiometric computer software (ESTA). This concept assisted in obtaining a final model for Cd–Cyp2EN and Pb–Cyp2EN systems. It could refine M(HL) complex inaccessible via polarographic study of Pb–Cyp2EN system and refined the hydroxo–complex ML2(OH) that in turn was inaccessible using GEP for Cd– Cyp2EN system. For all metals studied, the complexes ML formed with the ligand Cy2EN were found more stable than the complexes ML formed with the ligand Cyp2EN. The complex M(HL) was obtained for all systems studied, but it seemed to be a minor species. The complex ML2 was obtained in different systems studied with the ligand Cy2EN while this complex was only found in Cd–Cyp2EN system. In several systems potentiometric (ESTA) and voltammetric (3D–CFC) software could not distinguish which hydroxo–complexes were present as these species were formed in the pH range where the ligand was fully deprotonated. Selectivity trends for Cyp2EN and Cy2EN were compared and related to DHEEN as a function of metal ion radius. It was observed that the large metal ions were favoured by the addition of cyclopentyl bridges in DHEEN while the small metal ions were favoured when cyclohexyl bridges were added.

Metal-Ligand Cooperation (MLC) has been under study over the past two decades as a powerful tool for small molecule activation and functionalization. However, more mechanistic details are needed in order to understand the detailed steps that are enabled by the bifunctional cooperation between ligand and metal. In this regard, the hydroboration reaction offers a useful platform through which to assess the details of bifunctional reaction pathways and catalyst speciation. This dissertation focuses on the synthesis, characterization, and catalytic activity of base-metal complexes with cooperative N-, S-, and O-donor ligands to explore reaction pathways that are a consequence of diverging from traditional phosphine-based ligands. In Chapter 1 concepts and examples of MLC, especially as applied to hydroboration catalysis, are presented. In Chapter 2, three new Zn(II)-(κ²-SNS)₂ complexes were synthesized to directly compare the bifunctional catalytic activity rendered by amido and thiolate SNS ligands. Although all three complexes catalyzed carbonyl hydroboration, a detailed catalyst speciation study showed that the Zn amido complex reacts with pinacolborane (HBpin) to generate Zn-H and an unbound borylamido ligand. Subsequent substrate-derived zinc alkoxide formation followed by a second equiv of HBpin generates the product, regenerating the Zn hydride catalyst. In contrast, the Zn thiolate complex adds HBpin to the ligand imine unit, followed by aldehyde deoxygenation to give a benzothiazoline heterocycle and [Zn](OBpin). Reaction of the latter with HBpin then gives pinBOBpin and Zn-H, leading to the same active catalyst as that derived from the Zn amido precatalyst! For these systems, then, the bifunctional N- and S-donors serve to activate the catalyst rather than participating in a bifunctional catalytic cycle. Dissociation of the borylamido SNS ligand in Chapter 2 led us to reinvestigate a previously reported Cu(I) amido complex Cu[(κ²-SNS)(IPr) that was proposed to hydroborate carbonyls via an outer sphere process [IPr = bis(2,6-diisopropylphenyl)imidazol-2-ylidene]. Indeed, we showed that this complex also undergoes ligand borylation-dissociation to form the active catalyst [CuH(IPr)]₂ which had been reported previously as a carbonyl hydrosilylation catalyst. To compare these complexes with their heavier Group 10 analogue, we prepared and structurally characterized the silver amido SNS complex. Interestingly, this complex was not able to serve as a carbonyl hydroboration catalyst. Then we sought to use the MLC catalyst activation strategy to prepare an especially active Zn hydride hydroboration catalyst. Using a bidentate amine-pyrollide ligand with an aryl ether side-group, the 5-coordinate Zn complex, Zn(κ²-ONN)₂(DDI) (2.11Zn) was prepared and structurally characterized (DDI = 4,5-dichloro-1,3-dimethylimidazol-2-ylidene). On treatment with excess HBpin, formation of ONN(Bpin)₂ [(Bpin)₂-L3] gave rise to the reactive NHC-stabilized ZnH₂ catalyst that effected the rapid hydroboration of nitriles and quinoline derivatives under ambient conditions with only 0.01 and 0.05 mol% catalyst loading, respectively. In Chapter 3, in an attempt to prepare a cobalt complex containing both amido and thiolate SNS ligands, we obtained instead the Co(II) dithiolate complex, Co(κ³-SNS)(DDI) (3.2Co). This complex showed a unique selectivity for aldehyde hydroboration, over other functional groups such as ketones, cyanides, nitriles and olefins. A DFT study, in collaboration with Prof. Erin Johnson from Dalhousie University, showed that 3.2Co bifunctionally assembles the HBpin and aldehyde substrates, with Co binding the aldehyde oxygen and sulfur binding the boron of HBpin. With aromatic aldehyde substrates, interesting aromatic-aromatic dispersion effects led to catalyst inhibition which could be reversed by simply rinsing off the product with hexane. These effects were not observed for catalytic hydroboration of aliphatic aldehydes. In Chapter 4 we focused on expanding our MLC investigation to include additional donors beyond N and S. First, a dimeric Zn(II)-(κ⁴-NSNO) complex (4.1Zn) was synthesized and evaluated as a catalyst for nitrile dihydroboration to compare aryloxide and amido donors for B-H bond activation. In fact, 4.1Zn successfully catalyzed dihydroboration of a range of different aromatic and aliphatic nitriles under neat condition. Mechanistic studies determined that the aryloxide donor activates the B-H bond in the first step and the mechanism then likely proceeds through an inner-sphere insertion. As detected by our kinetic study, at high turnovers the catalyst decomposes when Bpin also binds to the amido donor. To compare the potential of other donors for B-H bond activation, a series of divalent NiᴵᴵX(κ³-NNN) complexes were synthesized, with X = bromide (4.3Ni), phenoxide (4.4Ni), thiophenoxide (4.5Ni), 2,5-dimethylpyrrolide (4.6Ni), diphenylphosphide (4.7Ni), and phenyl (4.8Ni), and employed as precatalysts for nitrile dihydroboration. Superior activity of the phenoxy derivative (vs. thiophenoxy or phenyl) suggests that B-H bond activation occurs at the Ni-X (vs. ligand Ni-N_pyrrolide) bond. Furthermore, stoichiometric treatment of 4.3Ni-4.8Ni with a nitrile showed no reaction, whereas stoichiometric reactions of 4.3Ni-4.8Ni with pinacolborane (HBpin) afforded the same Ni-H complex for 4.3Ni, 4.4Ni and 4.6Ni. Considering that only 4.3Ni, 4.4Ni and 4.6Ni successfully catalyzed nitrile dihydroboration reaction, we suggest that the catalytic cycle involves a conventional inner sphere pathway initiated by substrate insertion into Ni-H. In summary, our investigations confirm the importance of mechanistic studies and catalyst speciation for studies involving potential bifunctional catalysis. In Chapter 5 we summarize the findings of this thesis, placing them in the context of the current state of the art and speculating on future investigations they may enable.

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Over the past two decades, transitions metals have been extensively employed towards the construction (using coordination driven assembly) and operation (using reversible metal-ligand switching motifs) of supramolecular architectures. This Thesis details the investigation of an array of dynamic platinum(II)-based metallosupramolecular architectures and includes a series of model studies on switchable platinum(II) coordination modes. Chapter Two describes the synthesis and study of a series of prototype noninterlocked molecular machines. The inherent dynamics of intramolecular metalligand substitution reactions (metallotrophic shifts) are exploited to drive a d8 platinum(II-)-phenanthroline component along different ligating architectures to achieve translational (and in one case rotary) motion of the sub-molecular components. Variable temperature NMR studies of these complexes have established the kinetic parameters for the observed shuttling processes. In Chapter Three, the switchable behaviour of a metal-ligand coordination motif is reported in which a proton input is employed to modify the overall thermodynamic bias and light is orthogonally utilized to selectively lower the energetic barrier for the binding event to re-equilibration. A discussion of the light-promoted ligand exchange reaction is presented, supported by a combination of TD-DFT calculations and kinetic studies. Chapter Four describes the exploitation of this discovered pH-switchable metalligand motif for the stimuli-responsive reversible assembly of two dimensional and three dimensional metallosupramolecular architectures. Whilst Chapter Five details how this reversible motif can be exploited to induce controlled exchange between “3+1” and “2+2” square planar platinum donor sets in response to the application of acid-base stimuli.

abstract: Due to analytical limitations, thermodynamic modeling is a lucrative alternative for obtaining metal speciation in chemically complex systems like life. However, such modeling is limited by the lack of equilibrium constant data for metal-complexation reactions, particularly for metal-organic species. These problems were ameliorated estimating these properties from 0-125°C for ~18,000 metal complexes of small molecules, proteins and peptides. The estimates of metal-ligand equilibrium constants at 25°C and 1 bar were made using multiple linear free energy relationships in accordance with the metal-coordinating properties of ligands such as denticity, identity of electron donor group, inductive effects and steric hindrance. Analogous relationships were made to estimated metal-ligand complexation entropy that facilitated calculation of equilibrium constants up to 125°C using the van’t Hoff equation. These estimates were made for over 250 ligands that include carboxylic acids, phenols, inorganic acids, amino acids, peptides and proteins. The stability constants mentioned above were used to obtain metal speciation in several microbial growth media including past bioavailability studies and compositions listed on the DSMZ website. Speciation calculations were also carried out for several metals in blood plasma and cerebrospinal fluid that include metals present at over micromolar abundance (sodium, potassium, calcium, magnesium, iron, copper and zinc) and metals of therapeutic or toxic potential (like gallium, rhodium and bismuth). Metal speciation was found to be considerably dependent on pH and chelator concentration that can help in the selection of appropriate ligands for gallium & rhodium based anticancer drugs and zinc-based antidiabetics. It was found that methanobactin can considerably alter copper speciation and is therefore a suitable agent for the treatment of Wilson Disease. Additionally, bismuth neurotoxicity was attributed to the low transferrin concentration in cerebrospinal fluid and the predominance of aqueous bismuth trihydroxide. These results demonstrate that metal speciation calculations using thermodynamic modeling can be extremely useful for understanding metal bioavailability in microbes and human bodily fluids. / Dissertation/Thesis / Doctoral Dissertation Biochemistry 2019

Faculty of Science School of Chemistry 0204045a tspmkwi@hotmail.com / New possibilities in collection of polarographic and potentiometric experimental data in studies of metal–ligand systems by automated instrumental methods, and subsequent treatment of the polarographic data, whereby the degree of reversibility of the electrode processes varies, have been investigated in this work. An automated instrumental set–up was developed for applications in studies of metal–ligand solution equilibria by potentiometry and sampled Direct Current Polarography (DCP). The new set–up was designed based on virtual instrumentation principles whereby several commercially– available hardware units as well as custom–built electronic components, were interfaced to a personal computer that was equipped with appropriate hardware and control programs. The instrumental set–up was tested and validated by studying the protonation equilibria of the ligand glycine by Glass Electrode Potentiometry (GEP) as well as the complexation of the ligand glycine with Cd2+ by GEP and DCP. The new set–up provides increased versatility, accuracy and convenience in obtaining large numbers of experimental points in solution equilibria studies by DCP and GEP as opposed to the use of tedious and time–consuming manual methods. Nonlinear curve–fitting procedures, based on closed–form models that were derived here from suitable theoretical equations identified from literature, have been investigated in this work for applications in analysis of DC curves recorded on metal–ligand systems with variation in electrochemical reversibility. The applicability and limitations of the curve–fitting procedures developed have been tested in analysis of the DCP data collected on several metal–ligand systems involving Cd2+, Pb2+, Zn2+ and the ligands glycine and sarcosine, whereby the DCP studies of these systems exhibited reversible, quasi–reversible or irreversible electrochemical processes. Information on applicability and limitations of the proposed methods investigated in this work was derived by comparison of the results obtained from DCP, using the proposed methods, with either reported literature data and/or results obtained in this work by the independent analytical technique of GEP, which was deployed wherever it was found to be applicable to study the metal–ligand systems considered.

This thesis explores fundamental design strategies in the field of synthetic ion channel research from two different perspectives. In the first part the synthesis of complex, shape persistent and thermodynamically stable structures based on metal-ligand self-assembly is explored. The second part examines transport systems with dynamic transport behavior in response to chemical inputs which more closely mimic the dissipative assembly of Natural ion channels. In part one, two model systems, the ethylenediamine palladium(II) - 4,4’-bipyridine squares of Fujita and the trimeric bis(terpyridine) - iron(II) hexagonal macrocycles of Newkome, were targeted for structural modification towards becoming transport competent systems via improving the membrane partitioning characteristics of the final coordination compounds by increasing their lipophilicity. Modifications of the Fujita system involved the generation of two lipophilic 4,4’-bipyridines with addition of lipophilic groups of 13 and 17 carbon long alkyl chains respectively at the 3 and 3’ positions. After pursuing multiple unsuccessful synthetic routes the successful syntheses afforded the final lipophilic 4,4’-bipyridines in overall yields of 19 to 21% over two synthetic steps. Mixtures of the newly generated lipophilic 4,4’-bipyridines with a known lipophilic ethylenediamine palladium(II) “corner” exhibited evidence of self-assembly from NMR spectroscopy experiments however attempts at further characterization by ESI-MS and X-ray crystallography were unproductive. The putative self-assembled structures were inactive in HPTS vesicle assays but showed erratic conductance activity in bilayer clamp experiments. However, the magnitude of the conductance observed was not indicative of the passage of ions through the internal pore of the square complex. Modifications to the Newkome hexagons were aimed at generating overall neutral assemblies with external lipophilic groups. These modifications involved imparting a net -2 charge to the ligand via modifications to the terminal tridentate ligands so that upon coordination to octahedral metal centers in the +2 oxidation state the overall hexagonal complex would be neutrally charged. Two bis-polydentate ligands were generated; a dissymmetric molecule comprising one terpyridine and one dipicolinate tridentate ligand (TERPY-DPA) and a symmetrical molecule comprising two 2,2’-bipyridine-6-carboxylate tridentate ligands (BIPYA-BIPYA). The successful syntheses provided the desired trimethylsilylethyl ester protected compounds in yields of 9.2 and 7.5 % over 6 and 8 total synthetic steps for TERPY-DPA and BIPYA-BIPYA respectively. A new approach to metal-ligand complex formation by concomitant fluoride deprotection and assembly was demonstrated with a monomeric complex. Polymetallic complexes formed with a variety of transition metals based on colorimetric changes but the products were very intractable and resisted full structural or transport characterization. Part two develops a system potentially capable of exhibiting dissipative assembly of active transporters. A library of six thioester containing compounds structurally related to known active oligoester compounds was synthesized. The successful syntheses provided the desired compounds in overall yields of 1.0 to 17.7% over 11 to 13 total synthetic steps. The intramolecular cyclization - truncation and thioester exchange reactions central to the dissipative assembly strategy were explored using a model compound. The full length compounds showed transport activity via the HPTS vesicle assay that was significantly below that of the lead compound. Bilayer clamp experiments however, revealed significant transport activity for both the full length as well as the truncated thiol molecules. In the case of the latter the transport events had exceedingly high conductivity for such a small molecule. This unexpected activity for both the full length and truncated compounds, although different, prevented a full implementation of dissipative assembly of transport. / Graduate / 0490 / 0485 / 0494

Despite the prevalence of supramolecular architectures derived from metal-ligand or hydrogen-bonding interactions, few studies have focused on the simultaneous use of these two strategies to form discrete metal-ligand hydrogen-bonded (MLHB) assemblies. The design, synthesis, and characterization of 2-quinolone based hybrid subunits, 7-DPQ and 5-PYQ, that contain phosphine and pyridyl metal binding sites, respectively, is reported. Both subunits give two-fold symmetric hydrogen-bonded tectons that assemble with metal precursors to give hybrid MLHB structures. Treatment of [Cp*RhCl2]2 with the 7-DPQ subunit yields hybrid MLHB assemblies with closed topology. 1H diffusion ordered spectroscopy experiments established the stability of the structures in solution, and the measured hydrodynamic radii match those determined crystallographically, suggesting that the closed topology is maintained in solution and the solid state. In order to further explore possible MLHB architectures and test the selectivity boundaries of our quinolone-based subunits we report the selective assembly of 5-PYQ with mono- and bis-platinated anthracene precursors. Addition of 5-PYQ to [1-trans-Pt(PEt3)2NO3]-8-chloroanthracene yielded a hybrid MLHB structure with preorganization for a hybrid MLHB polymer. Despite the systems preorganization for the hybrid polymeric structure the assembly of 5-PYQ with 1,8-bis(trans-Pt(PEt3)2NO3)anthracene selects only for one discrete closed self-assembled macrocycle. The strong π-π stacking interactions of the 5-PYQ subunits erode the hydrogen-bonding fidelity to favor ambidentate coordination modes of 5-PYQ and give the non-hybrid macrocycle. In the course of investigating the intricacies of hybrid MLHB supramolecular structures we observed that, in addition to metal-ligand and hydrogen-bond interactions, the π-π stacking interactions of the 7-DPQ and 5-PYQ subunits played a critical role in determining the final assemblies. In fact, the prominent π-π interactions were typically found to be more favorable than the quinolone interligand hydrogen-bonding interactions. These results contribute to the overall knowledge of the design principles, synthesis, characterization, and fundamental assembly trends when exploiting both hydrogen-bonding and metal-ligand interactions to form stable supramolecular architectures. These studies have provided the foundation for expanding the accessible space of supramolecular chemistry to include rationally designed hybrid MLHB systems to give structures that more closely mimic the complex supramolecular systems observed in Nature. This dissertation includes both previously published/unpublished and co-authored material. / 10000-01-01

Cooperativity between the metal center and the ligand has been shown in nature to be an important feature of systems that catalyze two-electron processes that first-row transition metals usually cannot catalyze on their own. In these cases, the ligand acts as a site of reactivity that in many instances can store electrons or react directly with substrates in solution. The design and study of systems where there is synergy between the metal and the ligand have been leveraged to catalyze polymerization and hydrogenation-type reactions as well as the activation of small molecules such as dihydrogen. Specifically, the pyridine(diimine) ligand scaffold has been reported to store up to three electrons on the ligand backbone that can later be used in catalysis. Wanting to expand on this work, we have designed and synthesized a new pincer that has redox-noninnocent properties similar to pyridine(diimine) ligands but incorporates a pyrazine ring instead of a pyridine ring to give rise to new electronic properties. Pyrazine(diimines) also have an uncoordinated 4-position nitrogen that can be further functionalized to fine-tune the electronic properties of the ligand. In Chapter II we will discuss bisligated iron(II) pyrazine(diimine) (PZDI) complexes in three different oxidation states where we used spectroscopic and computational techniques as well as comparison to known pyridine(diimine) iron(II) complexes to support our assignments of ligand-based reduction. Chapter III will focus on monoligated pyrazine(diimine) iron(II) complexes as compared to analogous pyrazine(diimine) systems where the central metal is manganese, cobalt, or nickel, as well as compare our pyrazine(diimine) iron(II) complexes to reported pyridine(diimine) iron(II) analogs. We have also synthesized a new inverted pyridine(diimine) ligand scaffold that has an NCN binding pocket, which will be discussed in Chapter IV. In the design of the inverted pyridine(diimine) ligand we have left in place the 4-position nitrogen from our previously described pyrazine(diimine) ligand, maintaining a Lewis basic site for functionalization. Overall, we hope to describe the results we observed with both monoligated and bisligated iron(II) pyrazine(diimine) complexes as well as discuss our approach to the design of and progress towards a new inverted pyridine(diimine) ligand scaffold.