Recent Submissions

  • Reactivity of a Low Valent Gallium Compound

    Kassymbek, Aishabibi; Department of Chemistry
    The work described in this thesis is conducted to expand the reactivity of the β-diketiminate gallium(I) compound, NacNacGa (NacNac=[ArNC(Me)HC(Me)NAr]−, Ar=2,6-iPr2C6H3). The reactivity of NacNacGa towards various unsaturated compounds is studied. In particular, reaction between NacNacGa and phenyl isothiocyanate resulted in the oxidative addition of the C=S bond under ambient conditions, leading to the isolation cyclization product NacNacGa(κ2-S2CNPh) and sulfide isocyanide-bridged dimer (NacNacGa)2(μ-S)(μ-CNPh). Additionally, a [1+4] cycloaddition with a conjugated aldehyde (methacrolein) and a [1+2+3] cycloaddition with isocyanate and carbodiimide are presented. The oxidative cleavage of P=S bond of triphenylphosphine sulfide at increased temperatures gave the previously reported sulfide bridged gallium dimer. In situ oxidation of NacNacGa in the presence of substrates featuring donor sites led to the C-H activation reactions. As such, C-activation of pyridine N-oxide, pyridine, cyclohexanone, DMSO, and Et3P=O by a transient NacNacGa=O resulting in the corresponding gallium hydroxides is demonstrated. DFT calculations suggested initial formation of adducts between substrates and NacNacGa=O followed by a C-H bond abstraction from the substrate. Similarly, a transient gallium imide NacNacGa=NSiMe3, generated from the reaction of NacNacGa with trimethylsilyl azide, is shown to cleave C-H bonds of pyridine, cyclohexanone, ethyl acetate, DMSO, and Et3P=O with the formation of gallium amides. In an attempt to isolate a gallium alkylidene, NacNacGa was treated with trimethylsilyl(diazomethane). Instead, a monomeric gallium nitrilimine and a metalated diazomethane were obtained. The gallium nitrilimine undergoes 1,3-addition reaction with phenylsilane and catecholborane forming gallium hydrazonides. Its reaction with diborane resulted in the formal nitrene insertion into the B-B bond to produce a gallium diborylamide. DFT calculations revealed intermediate gallium alkylidene formation from the reaction of NacNacGa with diazomethane that upon reaction with the second equivalent of diazomethane leads to a gallium nitrilimine.
  • Design of Redox-active Ligands: In Pursuit of Stable Radicals, their Complexes, and Assembly of Paramagnetic Coordination Clusters.

    Bonanno, Nico Matteo; Department of Chemistry
    This thesis describes the design, synthesis, properties, and coordination chemistry of redoxactive ligands. This thesis also explores new ways of expanding our ligand systems, in order to improve their binding capacities. We accomplished this by utilizing familiar redox-active moieties and structures to those published previously in our group, but with enhanced topological capacities and predictable structural outcomes. Chapter 1 begins with a general outline of the fundamental principles that govern organic radicals including; their reactivity, their properties and applications, and how these can be applied to the design of ligands for polynuclear assembly. Chapter 2 starts with a brief overview of arylazo ligands and the synthesis of a new hydrazone substituted phenalenol ligand (2.1). In the following section (2.2) we use this ligand to produce homoleptic ligand mixed-valence complexes featuring trivalent cobalt and iron metals. The chapter is concluded (2.3) with the synthesis of a new ditopic aryl-azo ligand and its cobalt coordination chemistry involving a neutral tetra-radical/tetra-nuclear molecular grid featuring valence tautomerism. Chapter 3 begins with the design and synthesis of a new ditopic diamino phenol ligand, which was found to oxidize to a neutral stable phenoxyl radical (3.1-3.2). The solution properties, which include reversible pi-dimerization of this stable radical are also described (3.3), and later the substitution chemistry of this new ligand is explored (3.4). In chapter 4, we describe the coordination chemistry of this new ditopic aminophenol ligand, which includes assembly into several coordination clusters involving copper (4.2), iron (4.3), nickel (4.4), and zinc (4.5). These coordination clusters feature the ligand in a variety of oxidation states; including rare examples of dianion “aminyl” radical clusters. In chapter 5, we begin with a description of a new synthetic derivative which can be used for the construction of larger tetratopic or asymmetric diamino phenol ligands. In 5.2 we describe the synthesis of a tetratopic aminophenol ligand along with its reactivity and aerial oxidation to a tri-phenoxyl radical. In 5.3, we conclude the thesis with the use of an asymmetric diamino phenol ligand and it’s Cu(II/III) coordination chemistry, which displayed unique reactivity with molecular oxygen.
  • Reactivity of Aluminum Carbenoid with Unsaturated Substrates

    Dmitrienko, Anton; Department of Chemistry
    Reactivity patterns of the β-diketiminate aluminum(I) complex NacNacAl towards a variety of unsaturated molecules were determined. Reaction of NacNacAl with one equivalent of benzophenone affords η2(C,O) adduct III-2 that undergoes cyclization reactions with benzophenone (III-3), aldimine (III-4), quinoline (III-5), pyridine (III-6), phenyl nitrile (III-7), trimethylsilyl azide (III-8), and a saturated cyclic thiourea (III-9). The latter reacted via unusual C−N cleavage. Analogous η2-coordination products were prepared with p-tolyl benzoate (IV-6), N,N-dimethylbenzamide (IV-9) and (1‐phenylethylidene)aniline (IV-13). Addition of pyridine to such species results in [2+2] cycloaddition products analogous to III-6, except for the case of p‐tolyl benzoate when a migration of the alkoxy group from the ester moiety accompanied by hydrogen transfer from pyridine preserves the aromaticity within the latter. Chemoselective couplings between aliphatic ketones and pyridine were exemplified by reactions with non-enolizable (1R)-(‒) fenchone and enolizable yet sterically encumbered isophorone. The reaction with the CH‐acidic ketone (1R) (+) camphor afforded a hydrido alkoxide (IV-11) as the result of enolization. Whereas the reaction of NacNacAl with (1R)‐(−)‐fenchone in the absence of pyridine led to CH activation in the isopropyl group of the NacNac ligand. NacNacAl demonstrated diverse reactivity in reactions with N‐heterocycles. 4 Dimethylaminopyridine induces rearrangement of NacNacAl by deprotonation of backbone methyl group of the ligand. C−H activation of the methyl group of 4‐picoline produced a species with a reactive terminal methylene. Reaction of NacNacAl with 3,5 lutidine led to the cleavage of the sp2 C−H bond (4‐position). Another reactivity mode was observed for quinoline, which undergoes 2,2′‐coupling. Finally, a reaction of NacNacAl with phthalazine produced a product of the N−N bond cleavage. NacNacAl reacted with a series of polycyclic aromatic hydrocarbons via [4+1] cycloaddition. While a reaction with anthracene was irreversible, with the formation of products of activation of the lateral and central rings, reactions with phenanthrene, triphenylene, and fluoranthene were reversible. Heating reaction mixtures at 90 °C yielded dialuminum hydride VI-6. Mechanistic studies showed that the reaction proceeds via dissociation of polycycles with the release of NacNacAl that undergoes further intermolecular transformations. All novel complexes were characterized by spectroscopic methods and X-ray diffraction analysis for most of them.
  • Dynamic DNA Nanotechnology for Probing Single Nucleotide Variants and DNA Modifications

    Wang, Guan; Department of Chemistry
    In the last decades, various DNA hybridization probes have been developed that attempt to conquer the challenge of single-nucleotide-variants (SNVs) detection. Even though a powerful toolbox including the toehold-exchange reaction, the dynamic ‘sink’ design, and the polymerase chain reaction (PCR) has been built, it still faces practical problems. For example, the natural DNA is usually in double-stranded form whereas most hybridization probes aim for single-stranded targets; the concentration of extracted DNA samples is totally unknown thus may lay outside the optimal design of probes/primers. To achieve ultra-high sensitivity and specificity, expensive and sophisticated machines such as digital droplet PCR and next-generation-sequencing may be inapplicable in rural areas. Therefore, the quantitative PCR method is still the gold standard for clinical tests. Thus motivated, my PhD career was mainly focused on the fundamental understanding of the challenges in SNVs discrimination and developing robust, versatile, and user-friendly probes/strategies. In this thesis, Chapter 1 provides a general introduction of dynamic DNA nanotechnology and its representative applications in discriminating SNVs. Chapter 2 to 4 describe three completed projects that aim to understand the thermodynamic and kinetic properties of strand displacement reactions and to circumvent the challenges of discriminating SNVs through finely tuned probes/assays.
  • Synthesis of Cyclopropenium-Appended Organocatalysts and Applications

    Smajlagic, Ivor; Department of Chemistry
    Enclosed within this dissertation is the development and application of multiple cyclopropenium-containing compounds formally belonging to two closely-related classes of organocatalysts, namely thioureas and squaramides. The former catalyst, coined as a thiourea-cyclopropenium, is deployed in pyranylation reactions of alcohols and phenols, as well as Friedel–Crafts alkylation, while the latter—a squaramide-cyclopropenium catalyst—targets oxime ether bond formation. Accompanying these innovative synthetic methodologies are comprehensive experimental and computational mechanistic studies that work in synergy to delineate numerous key features, all of which provide valuable information with respect to understanding the multifaceted nature of catalysis. Experimental and spectral data are provided for all new compounds.
  • Approaches towards C-10-hydroxylated analogues of narciclasine

    Ticli, Vincenzo; Department of Chemistry
    Discussed in this thesis is the synthesis of a C10-benzyloxy unnatural derivative of narciclasine. The described approach involves the use of homochiral cyclohexadiene diols, products of the biocatalytic transformation of aromatic compounds, as precursors to ring C, and of highly oxygenated aromatic molecules to construct ring A. The document also reports a detailed account of the protocols studied for the intramolecular formation of ring B. Experimental data and spectral data are provided for the novel compounds.
  • Stereoselective Synthesis of N-Propargyl Alkynes and Axial Chiral N-Allenes with Epimeric Imidazolone Auxiliaries

    Sechi, Maria Laura; Department of Chemistry
    This thesis describes the synthesis of an N-propargyl pyrroloimidazolone chiral auxiliary/directing group with syn or anti stereochemistry derived from L-proline hydantoin and its diastereoselective lithiation for the synthesis of central chiral alkynes and axial chiral allenamides. Lithiation followed by quench with alkylating electrophiles or aldehydes/ketones gives access to chiral propargyl or allene derivatives respectively, both in high diastereomeric ratio (>95:5 dr). Use of the anti epimer of the aforementioned imidazolone chiral auxiliary results in the reversal of stereochemistry at the propargyl position of the products, again with high diastereoselectivity. This conclusion was confirmed by the synthesis and comparison of the solely central chiral alkynes from both the syn and anti series, obtained via acid-induced elimination of the labile silyloxy protecting group. Therefore, this method allows for the preparation of both enantiomeric propargyl products without the need to prepare additional starting materials from more expensive unnatural D-proline. X-Ray analysis of an allene derivative confirmed that lithiation of the syn pyrroloimidazolone followed by direct quench with prochiral benzaldehydes led to axial chiral allenamides in high selectivity (>95:5 dr) with atypical stereochemistry of the resulting benzylic alcohol. Lithiation followed by transmetalation to a titanium triisopropoxide intermediate before benzaldehyde quench gave epimeric allenamides with opposite stereochemistry at the benzylic alcohol. Density Functional Theory (DFT) computational modelling explained this reversal of stereochemistry at the benzylic position as arising from stereofacial attack in 6,5-bicyclic or 6-membered transition states in the lithium or titanium series, respectively.
  • Investigating the Cluster Chemistry of α-Methyl-2-pyridine methanol (mpmH) with Select 3d Ions

    Abbasi, Parisa; Department of Chemistry
    This thesis describes an investigation of the coordination chemistry of the potentially chiral bridging, chelating ligand, α-methyl-2-pyridinemethanol (mpmH) with select 3d ions for the discovery of polynuclear clusters with single molecule magnet (SMM) properties. Chapter 1 introduces the theory of molecular magnetism, SMMs and the concepts of chiral SMMs, magnetochiral dichroism and multiferroics. In Chapter 2, two NiII clusters, {Ni8} and {Ni18} prepared from rac-mpmH are reported. The {Ni8} cluster crystallizes in a trapezoidal prismatic topology and contains tetrazolate ligands that are formed via a metal-assisted click reaction. The molecular structure of the second {Ni18} cluster is highly disordered comprising of eight edge-sharing cubane subunits. Dc magnetic susceptibility measurements reveal dominant ferromagnetic interactions down to ~18 K, stabilizing spin states with large values, whereas at T < 18 K the antiferromagnetic contribution results in the population of smaller, but appreciable non-zero spin states. Ac magnetic susceptibility measurements confirm the presence of two relaxation processes at two temperature regimes that is extremely rare for a 3d-metal based SMM. The first at low temperature (5 K) is attributed to conventional SMM behavior with τ0 = 3.26 × 10-10 s and Ueff = 11 K. The origin of high temperature (15 K) relaxation process with a large Ueff = 381 K and τ0 = 2.7 × 10-15 s is less clear, but tentatively assigned to spin-glass properties. In Chapter 3, the synthesis and structure of a large mixed-valence [MnII2MnIII28MnIV] polynuclear cluster with a closed cage-like conformation is presented. Ac magnetic susceptibility measurements show the compound is an SMM with Ueff of 58 K, that is large for a 3d cluster, and a τ0 = 3 × 10−8 s. Chapter 4 describes the coordination chemistry of racemic and chiral-mpmH with CuII and FeIII, where the synthesis and magnetostructural properties of a chiral {Cu4} tetramer, a non-chiral 1-D chain, as well as a chiral {Fe6} and a non-chiral{Fe8} cluster are reported. Dc magnetic susceptibility measurements on all four complexes reveal the presence of dominant antiferromagnetic exchange interactions affording S = 0 spin ground states at low temperature that precludes the observation of any SMM behavior.
  • Chemoenzymatic Formal Total Syntheses of Tetrodotoxin and an Approach to Daphenylline

    Baidilov, Daler; Department of Chemistry
    This thesis describes chemoenzymatic formal total syntheses of tetrodotoxin and a concise synthetic approach to daphenylline. Advanced intermediates for the syntheses of tetrodotoxin reported by the groups of Fukuyama, Alonso, and Sato were prepared. Key steps included toluene dioxygenase-mediated dihydroxylation of either iodobenzene or benzyl acetate and a [4+2] hetero-Diels-Alder cycloaddition/Kornblum–DeLaMare rearrangement sequence to construct a common enone intermediate. The resulting key enone was transformed into Fukuyama's intermediate in four steps, into Alonso's intermediate in six steps, and into Sato's intermediate in seven steps. Fukuyama’s route employed a highly stereoselective allyl cyanate-to-isocyanate rearrangement to install the nitrogen atom at C8a. This protocol was also successfully applied in designing a synthetic avenue to daphenylline. The ABC tricyclic skeleton of daphenylline was successfully constructed in just eight steps starting from readily available (S)-carvone.
  • Magnetically Interesting Coordination Complexes Based on Macrocyclic Ligands

    Ras Ali, Zineb; Department of Chemistry
    The synthesis and study of select 3d and/or 4f coordination complexes prepared from crown ether and Schiff-base dual compartmental macrocycles are described herein, working towards the discovery and study of new families of macrocyclic-based single molecule magnets (SMMs). Chapter 1 introduces the general theory of magnetism, molecular magnetism and SMMs and provides the reader with a brief overview of the relevant coordination chemistry of the two families of macrocycles. In Chapter 2, two 15-crown-5 complexes [Ln(NO3)3(OH2)2(MeOH)], (where Ln(III) = Tb (I) and Dy (II)) have been prepared and characterized. X-ray diffraction studies reveal the two complexes crystallize as 1-D chains. Variable temperature ac magnetic susceptibility studies reveal that (II) is an SMM with two effective energy barriers, Ueff = 26 K (18 cm−1); τ0 = 4.10 × 10−7 s and Ueff = 41 K (29 cm−1); τ0 = 1.35 × 10−8 s, whereas ab initio studies suggest that the observation of slow relaxation of magnetization in the Tb complex (I) is hindered by the presence of rapid quantum tunneling mechanisms (QTM). Solid state photoluminescence measurements reveal the two complexes have well-resolved f–f transitions, where a Gaussian fit of the fine structure of the highest-energy emission band for the Dy(III) complex allows the Stark splitting of the ground state to be determined. In Chapter 3, select Ln(III) complexes with benzo and dibenzo 15-crown-5 macrocycles were synthesized and characterized. Reaction of Dy(III) together with benzo 15-crown-5 afforded a unique [Dy(OH2)8]3+ complex (III), where the hydrated Dy(III) cation is fully encapsulated within a supramolecular cage formed by three benzo 15-crown-5 macrocycles. Interestingly, the close to perfect square antiprismatic geometry of the 4f ion enhances its axial anisotropy, which suppresses quantum tunnelling mechanisms (QTM) in the ground and first excited states, resulting in the observation of SMM behavior in zero dc field. For this system the magnetic data were further supported by solid-state photoluminescence and ab initio studies, The introduction of a second benzene ring into the organic framework of the macrocycle increases its rigidity, where on coordination to Dy(III), affords the partially encapsulated complex (IV), which displays slow relaxation of magnetisation, consistent with SMM properties. In Chapter 4, the coordination chemistry of a dual compartmental Schiff-base macrocycle H2L3 containing O3O2 and N3O2 cavities was explored together with select 3d and 4f ions. In the first part of this chapter, the coordination chemistry of H2L3 with 3d metal ions is presented, where in the presence of NaOH, the Na(I) ions reside in the O3O2 cavity and the 3d ions occupy the second N3O2 cavity. Three coordination complexes containing Cu(II), Zn(II), and Mn(II) ions were prepared and characterized. The Cu(II), and Zn(II) complexes are monomeric with molecular formulae [CuNa(L3b)ClCH3OH]‧6H2O (V) and [ZnNa(L3b)(CH3COO)(CH3OH)]‧H2O (VI) respectively, while the Mn(II) complex crystallizes as a trimer with stoichiometry [Mn3Na2(L3)2(CH3COO)4]·5.75CH3OH·0.5H2O (VII). For complexes (V) and (VI), nucleophilic addition of the NH of the N3O2 cavity to the carbon atom of the adjacent imine results in a contraction of the N3O2 cavity and the formation of a five-membered imidazoline ring to afford the modified ligand L3b.The magnetic properties of (V) and (VII) are also reported. In the second part of this chapter, coordination of the macrocycle to select 4f ions in the absence of any base afforded the mononuclear complexes [Dy(H2L3)(H2O)2(CH3OH)2]Cl3·CH3OH, (VIII), and [Ln(H2L3)(H2O)3(CH3OH)] Cl3, where Ln(III) = Tb (IX), Er (X), and Gd (XI), in which the Ln(III) ion is coordinated in the O3O2 cavity. Magneto-structural studies on these complexes reveal that the Dy complex has a slightly different structure than the other three complexes, however all four 4f ions crystallize with square antiprismatic geometries, where only the Dy(III) complex (VIII) displays SMM properties.
  • Synthesis and Derivatization of Amaryllidaceae Constituents – Narciclasine and Pancratistatin

    Lapinskaite, Ringaile; Department of Chemistry
    This thesis describes the synthesis and derivatization of narciclasine and pancratistatin. A detailed description is given to the total formal synthesis of pancratistatin through a reductive transposition approach and the total and semi-syntheses of 2-epi-narciclasine and its discovery as a new natural product. The last part of this work focuses on the search for a divergent approach to access C-1 narciclasine and C-1-pancratistatin derivatives from natural narciclasine. Experimental and spectral data are provided for the new compounds.
  • Synthesis and Reactivity of Main Group Complexes for Applications in Small Molecule Activation

    Nguyen, Minh Tho; Department of Chemistry
    The work described in this thesis is focused on the preparation of a series of novel main group complexes, featuring unusual structural and bonding situations, and the study of their reactivity toward small molecules. The new zinc complexes dimphZnBu (V-2) and dimphZnCl2Li(THF)3 (V-3), supported by a diiminophenyl (dimph) ligand were prepared. The reaction of complex V-3 with LiHBEt3 resulted in hydride transfer to the C=N imine group to give an unusual zinc dimer (V-7). The latter transformation occurs via formation of compound (ɳ1(C),ĸ1(N)- 2,6-(2,6-iPr2C6H3N=CH)2C6H3)2Zn (V-5) which can be also accessed by reduction of V-7 with KC8. Diiminophenyl (dimph) proved to be an excellent ligand platform to stabilise a low-valent phosphorus centre. The resultant compound dimphP (VI-2), which can be rationalised as an imino-stabilised phosphinidene or benzoazaphopshole, shows remarkable chemical stability toward water and oxygen. VI-2 reacts with excess strong acid HCl to generate the P(III) chloride (dimHph)PCl (VI-6). Surprisingly, substitution of the chloride under some nucleophilic (KOBut) and electrophilic conditions (Me3SiOTf) regenerates the parent compound VI-2 by proton removal from the weakly acidic CH2N position. A related species (dimH2ph)P (VI-10) is produced upon thermal rearrangement of the hydride (dimHph)PH (VI-9). The molecular structure and reactivity of compounds VI-2 and other related compounds are also discussed. The reduction of the O,C,O-chelated phosphorus (III) chloride (VI-16) ( O,C,O = 2,6-bis[(2,6-diisopropyl)phenoxyl]phenyl) with KC8 or PMe3 resulted in the formation of a cyclic three-membered phosphorus compound (VI-18). The intermediacy of phosphinidene VI-17 was confirmed by trapping experiments and a VT 31P{1H} NMR study. The reaction of in-situ generated phosphinidene with either PhSiH3 or HBpin resulted in the formation of an unprecedented phosphine (VI-23). The treatment of VI-16 with two equivalents of DippNHC carbene led to ArP(Cl)NHC product (VI-24). The germylone dimNHCGe (dimNHC = diimino N-Heterocyclic Carbene, VII-8) was successfully prepared by the reduction of germanium cation (VII-7) with KC8. The molecular structure of VII-8 was unambiguously established, using NMR spectroscopy and single-crystal X-ray diffraction analysis. The reactivity of VII-8 was investigated. VII-8 is inactive towards butadiene but undergoes an oxidative cyclization with tetrachloro-o-benzoquinone to give a tetragermanium derivative. VII-8 undergoes oxidation addition of CH3I and PhI, followed by an unusual migration of the Me and Ph groups from germanium to the carbene ligand. Related chemistry takes place upon protonation with dry HCl, which results in the migration of the hydride to the carbene ligand.
  • New Pyrazole-Based Ligands and Their Complexes for Application in Transfer Hydrogenation and Hydrosilylation

    Alshakova, Iryna; Department of Chemistry
    A series of bidentate and tridentate ligands bearing pyrazolyl moiety in combination with phosphine, oxazoline, amine, and sulfide were synthesized. These ligands were applied for the synthesis of ruthenium complexes, that would be efficient in catalyzing transfer hydrogenation reaction in alcohol. From a number of obtained complexes, a mixture of two isomeric ruthenium complexes was found to be the most efficient in reduction of acetophenone and N-benzylideneaniline, as model substrates, with 2-propanol. These ruthenium complexes were successfully applied in transfer hydrogenation of nitriles, heterocyclic compounds, olefins, and alkynes. Activated esters were reduced under similar catalytic conditions when ethanol was used as a hydrogen source. These isomeric ruthenium complexes were also applied in the synthesis of secondary amines via hydrogen borrowing methodology. A number of primary amines and anilines were combined with primary alcohols under the conditions, optimized for transfer hydrogenation of nitriles, resulting in corresponding secondary amines. Furthermore, ammonium formate was used as a nitrogen source for alcohol amination. Thus, secondary and tertiary amines were obtained from primary alcohols. Another project was focused on transfer hydrogenation of carbonyl compounds with lithium isopropoxide. Addition of various ligands and small molecules was found to improve the reaction efficiency for aromatic substrates. Further studies revealed that lithium cation forms stable adduct with aromatic alcohols, while different additives help to break this interaction, thus resulting in significant improvement of the conversion to alcohols. Another strategy that was applied to improve the reaction yields was the addition of a cheap source of lithium cations, such as LiCl. Finally, a new zinc complex was synthesized and applied in the catalytic hydrosilylation of carbonyl compounds. The optimization of reaction conditions reviled that the presence of substoichiometric amounts of methanol in the system significantly accelerates the process. The reaction can proceed at very low catalyst load (down to 0.1mol%) under relatively mild reaction conditions. The substrate scope analysis showed the tolerance to carbon-carbon double bond. Thus, this procedure is efficient for the synthesis of allylic alcohols from α,β-unsaturated aldehydes and ketones.
  • Chemoenzymatic Total Synthesis of ent-Oxycodone

    Makarova, Mariia; Department of Chemistry
    This thesis describes the approach towards chemoenzymatic total synthesis of ent-dihydroisocodeine and chemoenzymatic total synthesis of ent-oxycodone as well as the development of a new method for the preparation of rearranged allylic isocyanates. The synthesis of ent-dihydroisocodeine started from phenethyl acetate and included a microbial oxidation of phenethyl acetate by E. coli JM109 (pDTG601A), a Mitsunobu reaction to the couple A- and C-rings, Heck cyclization to construct the E-ring and Henry reaction to introduce the nitrogen functionality as key steps. The construction of the B-ring proved to be challenging and neither radical cyclization nor attempts to perform photochemistry or nucleophilic opening of an epoxide gave any positive results. The chemoenzymatic total synthesis of ent-oxycodone was accomplished starting from phenethyl acetate in 23 steps. The tricyclic intermediate was furnished in the same manner as described above. The olefin to ketone conversion and a double Henry reaction allowed the construction of the B-ring. Unfortunately, it was established that the resulting hydroxyl group at C14 and amino group at C9 were of the undesired trans stereochemistry. To complete the morphine skeleton the transformation of the side chain at C13 to an N-methyl-p-toluenesufonamide via Mitsunobu reaction as well as the elimination of the amino group at C9 via formation of an N-oxide were performed. Subsequent radical cyclization of the side chain at the C9 position formed the last D-ring. The silyl ether deprotection followed by oxidation provided ent-oxycodone. The other approach to construct the D-ring was based on the formation of a lactone and the elimination of the amino group via an N-oxide. The nitrogen functionality was reinstalled using sodium azide and was accompanied by the introduction of the C10 hydroxyl group. Reduction of the azide and subsequent formation of the amide allowed access to the core skeleton of the target compound. The removal of the C10 hydroxyl group accomplished the synthesis. The last project involved the development of a new method for the preparation of rearranged allylic isocyanates from allylic alcohols using 1-cyano-4-dimethylaminopyridinium as the source of electrophilic cyanide. Experimental and spectral data are provided for all the compounds.
  • New Synthetic Approaches and Structural Models of the Oxygen-Evolving Complex in Photosystem II from the Use of Oximato-Based Ligands

    Alaimo, Alysha; Department of Chemistry
    The employment of the chelating/bridging ligands salicylhydroxime (shiH3), quinoline-2-aldoxime (qaoH) and 2,6-diacetylpyridine dioxime (dapdoH2) in heterometallic Mn‒Ca chemistry has afforded various compounds with diverse topologies, metal stoichiometries and Mn oxidation state descriptions. Chapter 1 provides a general introduction to the oxygen-evolving complex (OEC) of Photosystem II (PSII) including discussions of fundamental aspects such as composition, structural proposals, mechanism of O‒O bond formation and synthetic approaches. My research results are reported in Chapter 2, 3 and 4. In the first project (Chapter 2), one-pot reactions between Mn(ClO4)2∙6H2O, Ca(ClO4)2∙4H2O and the potentially tetradentate chelating/bridging ligand salicylhydroxime (shiH3), resulting from the in situ metal ion-assisted amide-iminol tautomerism of salicylhydroxamic acid (shaH2), in the presence of various fluorescence carboxylate groups (2-naphthoic acid = L1-H; 9-anthracenecarboxylic acid = L2-H; 1-pyrenecarboxylic acid = L3-H) and base NEt3 has led to a family of structurally similar {MnIII4Ca} clusters (1‒4¬) with distorted square pyramidal topologies. The combined results demonstrate the ability of shiH3 and fluorescence carboxylates to yield new heterometallic Mn‒Ca clusters with (i) the same Mn‒Ca ratio as the OEC of PSII, (ii) structural stability in solution, (iii) a pronounced redox and optical activity and (iv) predominant antiferromagnetic exchange interactions with S = 0 spin ground states. These complexes may be relevant to lower oxidation level species of the catalytic cycle of the OEC. The second project of this thesis, discussed in Chapter 3, involved one-pot reactions between the [Mn3O(O2CPh)6(py)x]+/0 triangular precursors and either CaBr2∙xH2O or CaCl2∙6H2O in the presence of shaH2. This afforded the heterometallic complexes [MnIII4Ca2(O2CPh)4(shi)4(H2O)3(Me2CO)] (5) and (pyH)[MnII2MnIII4Ca2Cl2(O2CPh)7(shi)4(py)4] (6), respectively, in good yields. Further reactions but using a more flexible synthetic scheme comprising the Mn(NO3)2∙4H2O/Ca(NO3)2∙4H2O and Mn(O2CPh)2∙2H2O/Ca(ClO4)2∙4H2O “metal blends” and shaH2 in the presence of external base NEt3, led to the new complexes (NHEt3)[MnIII4MnIV4Ca2(OEt)2(shi)10(EtOH)2] (7) and (NHEt3)4[MnIII8Ca2(CO3)4(shi)8] (8), respectively. Solid-state dc magnetic susceptibility studies of 5‒8 revealed the presence of predominant antiferromagnetic exchange interactions between the Mn centers, leading to S = 0 spin ground state values. From a bioinorganic chemistry perspective, these compounds may demonstrate some relevance to both the high-valent scheme (7) and lower oxidation level species (5, 6 and 8) of the catalytic cycle of the OEC. In the last chapter of this thesis (Chapter 4), the ligands quinoline-2-aldoxime (qaoH) and 2,6-diacetylpyridine dioxime (dapdoH2) were introduced for a first time in heterometallic Mn‒Ca chemistry. This afforded a mixed-valence {MnII/III22Ca2} (9) cluster containing several {Mn4CaOx} subunits and a butterfly-like {MnIV2Ca2} (10) complex, respectively. These compounds demonstrate structural and magnetic relevance to both the low- and high-valent states of the OEC. All research-based Chapters (Chapter 2‒4) are divided into subsections in order to facilitate the understanding of the research concepts by the familiar and non-familiar readers and contextualize the messages, goals and conclusions of each individual project. I felt it was appropriate to begin each Chapter with a short preface of the work that summarizes the most important aspects of the specific project, followed by the complete experimental work and discussion of the results, and end with conclusions and some future perspectives.
  • Probes of tocopherol biochemistry: fluorophores, imaging agents, and fake antioxidants

    Ghelfi, Mikel; Department of Chemistry
    The body has many defence systems against reactive radical species, but none are as crucial in the protection of lipid membranes as vitamin E. As a result of a selection process mediated by the α-tocopherol transfer protein (α-TTP), α-tocopherol is the only form of vitamin E retained in the body. This chaperon protein has been well studied because of its role in vitamin E transport. Furthermore, malfunctions of α-TTP cause vitamin E deficiency leading to ataxia and other neurodegenerative disease. Protection of neuronal tissue is critical and is reflected in the high retention of α-tocopherol in the central nervous system. Neuronal tissues receive α tocopherol from astrocytes, cells that are linked to hepatic tissue and able to express α-TTP, however the exact path of delivery between these cells is still unclear. A technique called fluorescent microscopy allows the tracking of fluorescent molecules in cells to find their location and interactions with other parts of the cell. The focus of this study is the synthesis of a fluorescent tocopherol analogue with a long absorption wavelength, high photostability, and that binds selectively to  α-TTP with high affinity. Most health benefits associated with vitamin E consumption are based on its capability to inhibit lipid peroxidation in cell membranes by scavenging reactive oxygen species (ROS). Oxidative damage in membranes puts cells in a “stressful” state, activating signalling events that trigger apoptosis. Vitamin E down-regulates apoptotic functions like inflammation, macrophage activation and cell arrest in a stressed state, returning the cell back to normal functioning. At the same time, vitamin E has a preventive effect for atherosclerosis, Alzheimer’s and cancer. With the deeper understanding of cell signalling processes associated with vitamin E the question arose whether protein interactions or the ROS scavenging is responsible for cell survival. To test this hypothesis, a non-antioxidant but α-TTP binding tocopherol analogue was synthesized and administered into oxidatively stressed, α-TTP deficient cells. If the cells were unable to restore homeostasis and stop apoptosis with the new molecule, this would suggest that the antioxidant function of α-tocopherol is the reason for survival. Cancer is regarded as one of the most detrimental diseases with a high mortality rate. One key aspect in medical research is the increased drug specificity towards targeting cancer. Chemotherapy applies cytotoxic compounds, which weaken the immune system because both malignant and healthy cells are destroyed. The specificity of the anti-cancer drugs are enhanced when encapsulated into liposomes that bear target-directing molecules such as antibodies which recognize cancer cell specific antigens on the cell membrane. The question remains if the encapsulated drug reaches the cancer or not. Magnetic resonance imaging (MRI) and computed tomography (CT) are used to find malignant tissue in the body. CT imaging uses highly charged X-ray particles to scan the patient, possibly having damaging cytotoxic effects. Obtaining MRI results require the use of contrast agents to enhance the quality of images. These agents are based on transition metals, which potentially have chronic toxicity when retained in the body. Alternatively short-lived radiotracers that emit a γ-photon upon positron decay are used through a process called positron emission tomography (PET). Rapid decay times make the use of PET a less toxic alternative, however the decay products might be toxic to the cell. For this reason a vitamin E based PET agent was created, which produces naturally safe decay products based on known metabolites of vitamin E, useful to track liposomal delivery of chemotherapeutic agents. This work describes the non-radioactive synthetic procedures towards a variety of vitamin E PET analogues. The cytotoxicity of the most promising vitamin E PET tracer was evaluated along with its synthetic byproducts.
  • Half-sandwich Complexes of Ruthenium Supported by N-Heterocyclic Carbene Ligands: Synthesis and Application to Catalysis

    Mai, Van Hung; Department of Chemistry
    This thesis presents the preparation and catalytic reactivity of novel half-sandwich ruthenium complexes supported by N-Heterocyclic Carbene (NHC) ligands. The cationic half-sandwich ruthenium complexes [Cp(IPr)Ru(CH3CN)2]+ show interesting reactivities toward the transfer hydrogenation of different unsaturated substrates, such as ketones, olefins, N-heterocycles, and nitriles. Kinetic studies disclose that a neutral trishydride ruthenium complex is actually involved in the catalytic cycle, playing the role as a resting state. Further investigations on the sub-class of trishydride ruthenium complexes bearing NHC ligands (Cp'(NHC)RuH3) reveal that these complexes have an unusual and great catalytic performance toward the hydrodefluorination (HDF) of fluorinated aromatic and aliphatic compounds. The combined kinetic studies, cross-over experiments and rate law analysis suggest an unusual mechanistic pathway for the Cp*(IPr)RuH3 catalyzed HDF. This study is one of the rare examples where isopropanol is employed as a reducing agent for the metal-mediated HDF reaction. A class of silyl dihydride ruthenium complexes, derived from Cp(IPr)RuH3 are prepared. These silyl hydrido derivatives are great compounds for the study of the inter ligand hypervalent interaction (IHI), an interesting phenomenon for many non-classical silane complexes. This study also suggests that the replacement of phosphines by their isolobally analogous NHC ligands result in stronger IHI interactions in the corresponding compounds. Another type of non-classical interaction was systematically scrutinized in a ii series of new cationic and neutral silane sigma complexes of ruthenium bearing different silyl moieties. These new NHC-supported ruthenium complexes allow for direct comparation with the known phosphine analogues, which reveals interplay of steric and electronic factors on the extent of Si-H complexation to metal and the extent of additional interligand interactions between Ru-Cl and chlorosilane ligand. Finally, new trishydride ruthenium complexes bearing NHC ligands (Cp'(NHC)RuH3) catalyze the H/D exchange reaction of various N-heterocycle substrates; their catalytic performance can be considered as one of the mildest, and most efficient approaches.
  • High-Nuclearity Lanthanide(III) Complexes as Single-Molecule Magnets and Luminescent Materials

    Mazarakioti, Eleni; Department of Chemistry
    The employment of the bridging/chelating Schiff base ligands, N-salicylidene-o-aminophenol (saphH2), N-salicylidene-o-aminocyclohexanol (sachH2) and N-salicylidene-2-amino-5-chlorobenzoic acid (sacbH2), in lanthanide (LnIII) cluster chemistry has afforded four families of polynuclear and dinuclear complexes with new structural motifs, and interesting magnetic and optical properties. Chapter 1 deals with most of the fundamental aspects within the areas of polynuclear metal complexes, molecular magnetism and optics as these are applied to 4f-metal based systems, while the research results are reported in Chapters 2, 3 and 4. In the first project (Chapter 2), the coordination chemistry of the organic chelating/bridging ligand, N-salicylidene-o-aminophenol (saphH2) in lanthanide cluster chemistry was investigated. The general LnIII/X-/saphH2/base reaction system has led to a family of (NHEt3)[Ln7(OH)2(saph)10(Me2CO)2] (Ln = Gd (1); Tb (2); Dy (3)) clusters with a new core topology that comprises two {Ln4} butterflies sharing a common metal vertex. The {DyIII7} analogue exhibits slow magnetization relaxation, whereas all heptanuclear compounds show ligand-centered blue-green emissions. The second project of this thesis, which is discussed in Chapter 3, comprises the first use of the Schiff base ligand N-salicylidene-2-aminocyclohexanol (sachH2; mixture of cis- and trans-analogue) in metal cluster chemistry which has afforded a new family of [Ln7(OH)6(CO3)3(sach)3(sachH)3(MeOH)6] (Ln = Gd (4); Tb (5); Dy (6)) clusters with ideal D3h point group symmetry and metal-centered trigonal prismatic topology. Solid-state and solution studies revealed single-molecule magnetism (SMM) and photoluminescence behaviors. Moreover, in order to investigate the steric and stereoisomerism effects of the ligand on the chemical and structural identity of the {Ln7} clusters, the pure trans-analogue of the sachH2 ligand was utilized. As a result, a new family of octanuclear [Ln8(OH)4(CO3)2(trans-sach)8(EtOH)4] (Ln = Gd (7); Tb (8); Dy (9); Eu (10)) clusters were obtained, while the solid-state studies revealed SMM behavior and lanthanide-centered emissions. In the last chapter of this thesis (Chapter 4), the Schiff base ligand N-salicylidene-2-amino-5-chlorobenzoic acid (sacbH2) was introduced for a first time in lanthanide cluster chemistry. This has afforded a family of dinuclear [Ln2(NO3)4(sacbH)2(H2O)2(MeCN)2] compounds (Ln = Gd (11); Tb (12); Dy (13)) with the Dy-analogue exhibiting SMM behaviour with a high-energy barrier for the magnetization reversal and interesting magnetization dynamics. All research-based Chapters (Chapters 2-4) are divided into subsections in order to facilitate the understanding of the research concepts by the familiar and non-familiar readers and contextualize the messages, goals and conclusions of each individual project. I felt it prudent to always begin with a short preface of the work that summarizes the most important aspects of the specific project, followed by the complete experimental part and discussion of the results, and finishing up with conclusions and some future perspectives.
  • High-Nuclearity Metal Complexes and Single-Molecule Magnets from the Employment of Oximato- and Alkoxido-based Ligands

    Giannopoulos, Dimosthenis; Department of Chemistry
    The employment of 2-pyrrolyloximes, pyridine-2,6-diketones and 3-hydroxy-2-naphthohydroxamic acid in homometallic 3d- and heterometallic 3d/4f-metal cluster chemistry has yielded new families of Fe, Mn and Mn/Dy clusters. These complexes were shown to possess interesting structural motifs and single-molecule magnetism (SMM) behaviour. The introductory chapter discusses the fundamentals of molecular magnetism, polynuclear metal complexes, as well as the approaches used for the synthesis of new polynuclear metal complexes and the selection criteria for the chelating/bridging ligands. Chapters 2, 3 and 4 report the results of the current thesis. In Chapter 2, the synthesis and characterization of a family of complexes resulting from the employment of 2-pyrrolyloximes in high-nuclearity transition metal cluster chemistry is reported. Complexes {Fe10} (1) and {Fe12} (2) are two of the highest nuclearity iron clusters containing an oximate ligand, while complex 3 is a barrel-like {Mn25Na} complex that exhibits SMM behaviour. Although there are previously reported examples of discrete {Mn25} barrel-like SMMs, complex 3 is the highest nuclearity Mn cluster organized into a 1D polymer through chelation with diamagnetic metal centers. Chapter 3 includes the synthesis and characterization of new Mn complexes featuring ligands that result from the metal-assisted reactivity of pyridyl- and pyrazine-based diketones. Complexes {Mn6} (4) and {Mn10} (5) are the highest nuclearity Mn clusters containing any form of the ligand 2,6-di-(2-pyridylcarbonyl)pyridine [(py)CO(py)CO(py)]. Despite the large number of {Mn6} and {Mn10} complexes reported in the literature, both complexes 4 and 5 possess unique topologies in their respective oxidation state levels. Complex {Mn3Na2} (6) possesses a iii unique metal stoichiometry and is the only compound containing any form of the ligand pyridine-2,6-diylbis(pyrazine-2-ylmethanone) [(pz)CO(py)CO(pz)]. More interestingly, complex 6 contains the first {MnIII3(μ3-O2−)}7+ triangular core where the Mn centers are solely bridged by an oxido group, essentially being a unique ‘edge-naked’ equilateral triangle. In Chapter 4, the synthesis and characterization of complexes bearing the ligand 3-hydroxy-2-naphthohydroxamic acid are presented. The {Mn10} complexes 7 and 8 are the highest nuclearity 3d-metal and the first homometallic Mn clusters containing the hydroxime form of the ligand. Both compounds possess unique metal topologies, which are affected by the nature of the carboxylate ligand present in the reaction mixture, and they behave as SMMs. The use of 3-hydroxy-2-naphthohydroxamic acid in Mn/Dy cluster chemistry has afforded the {Mn4Dy} complexes 9 and 10, as well as a family of {Mn8Dy2} complexes (11 and 12). These compounds are the first Mn/Dy complexes containing this particular hydroxime ligand and they also possess unique metal stoichiometries and topologies. The reported heterometallic products resulted from our efforts to deliberately replace the divalent Mn atoms located in 7 and 8 with DyIII as a means of enhancing the magnetic properties of the former. Complexes 11 and 12 were found to be single-molecule magnets.
  • Synthesis and Reactivity of Low Valent Main Group Element Complexes

    Chu, Terry; Department of Chemistry
    The β-diketiminate aluminum(I) complex NacNacAl (III-1) was shown to activate a range of substrates containing robust single and double bonds. Compound III-1 oxidatively adds a variety of H–X bonds (X = H, B, Al, C, Si, N, P, O) to give a series of four-coordinate aluminum hydride derivatives including the first example of an aluminum boryl hydride. In the case of Al–H addition, the reaction was shown to be in equilibrium and reversible. Furthermore, cleavage of aryl and alkyl C–F bonds, the latter a rare reaction with only a handful of examples in the literature, was observed with III-1. Robust C–O and C–S bonds were also activated by III-1 along with RS–SR and R2P–PR2 bonds. All novel aluminum complexes were characterized by spectroscopic methods and X-ray diffraction analysis for the majority of them. Activation of the C=S or P=S bonds in a thiourea or phosphine sulfide, respectively, was accomplished by III-1 to give the first examples of Lewis base-stabilized monomeric terminal aluminum sulfides. The nature of the Al=S bond was examined computationally as well as experimentally. Related reaction with a urea derivative gave an unexpected aluminum hydride while reaction of III-1 with phosphine oxides gave a putative aluminum oxide as a result of P=O bond cleavage. However, the aluminum oxo promptly deprotonates a neighbouring molecule to furnish an aluminum hydroxide as the isolated product. Reduction of the cationic germanium(II) complex IV-1 affords the formally zero valent germanium complex IV-4 stabilized by the bis(imino)pyridine platform. Compound IV-4 was fully characterized by spectroscopic methods and X-ray diffraction analysis. The molecule has a singlet ground state and DFT studies revealed partial delocalization of one of the germanium lone pairs into the ligand framework. Complex IV-4 was unreactive towards H–X bond activation, the lack of reactivity ascribed to the large singlet-triplet energy gap calculated. The same bis(imino)pyridine ligand was also used to prepare reduced zinc complexes. Monoreduction of the zinc dichloride precursor gave the formally Zn(I) compound IV-6. Further reduction of IV-6 in the presence of DMAP gave the formally zero valent zinc complex IV-9. Both compounds were fully characterized by spectroscopic methods, DFT calculations, and X-ray diffraction analysis which revealed that both zinc atoms are four-coordinate and adopt unusual square planar and see-saw geometry, respectively.

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