This thesis is missing pages 9, 39, 108-110. The pages are not in the other copies of the thesis. -Digitization Centre / This work describes efforts towards creating chemical models for a variety of zinc based metalloenzymes. A background on the current progress of modeling zinc enzymes is presented, as is a brief review of zinc biochemistry. The structure of triaquo(tris-2-pyridylphosphine)nickel(ll) dinitrate is presented and compared with its zinc analogue. Both structures have octahedral geometry with no unusual bond lengths. The synthesis and characterization of bis(2,4,5-tribromoimidazole)(diaquo)zinc(II). (II) is also presented in this work. A similar compound, Zn(Im)2 (III) was also prepared in this work. Both compounds were characterized by X-ray crystallography, IR spectroscopy, and elemental analysis. Neutron crystallography was used to characterize (II) as a peraquo species. Both (II) and (III) possess tetrahedral geometry about the zinc atom. (III) is multiply catenated and cannot be considered as a discrete molecular species. The pKa2 of 2,4,5-tribromoimidazole, the organic ligand in (II), was measured and found to be 10.7(2). Bond valence theory was used to analyze (II). Extended Huckel molecular orbital calculations were carried out on (II). (II) was compared with a variety of other zincimidazole compounds. It was discovered that (II) has unusually small carbon-nitrogen-carbon angles within its tribromoimidazole rings. It is uncertain whether this feature is because of the coordination of the tribromoimidazole rings to the zinc atom, or whether it is an inherent feature of the tribromoimidazole rings. A copper analogue of (II) has also been synthesized and has been tentatively assigned the formula Cu(lmBr3)2(OH2)2 . X-ray characterization of this compound has not yet been accomplished. / Thesis / Master of Science (MS)

In chapter 1, I discuss how ligand architecture in tripodal nitrogen-rich ligands can drastically affect the structure of zinc complexes featuring these ligands. The synthesis and characterization of zinc tris(1-methylimidazol-2-ylthio)methyl ([Titm^Me]) and tris(1-Pribenzimidazol-2-ylthio)methyl ([Titm^iPr,benzo]) complexes is presented. The ligand in [Titm^Me]Zn complexes binds the metal to form carbatrane structures that exhibit unusually long and flexible Zn–C bonds. The bonding between the zinc and the carbon in these complexes can therefore be more accurately described as a zwitterionic interaction between a carbanion and a zinc cation. Density functional theory calculations demonstrate that the energy profile for the Zn–C bond is shallow, such that large variations of the Zn–C distance result in very little change in the energy of the complex. The benzannulated ligand [Titm^iPr,benzo] allows access to a rare monomeric zinc hydride species [κ³-Titm^iPr,benzo]ZnH that can react with either CO₂ to produce a zinc formate, or B(C₆F₅)₃ to form the ion pair [κ⁴-Titm^iPr,benzo]ZnHB(C₆F₅)₃. The coordination chemistry of the [Titm^iPr,benzo] ligand also extends to the other metals of group 12. In chapter 2, I report the use of the [Titm^Me] and [Titm^iPr,benzo] zinc complexes presented in chapter 1 as biomimetic models for zinc enzymes. First, [Titm^Me] zinc complexes present structural similarities with the active site of carbonic anhydrase, and can be used to study the binding of carbonic anhydrase inhibitors to the enzyme active site. Then, [κ⁴-Titm^iPr,benzo]ZnX (X = MeB(C₆F₅)₃, BPh₄) complexes and their interactions with ligands of relevance towards antibiotic resistance is reported. The non coordinating nature of the anions in [κ⁴-Titm^iPr,benzo]ZnX (X = MeB(C₆F₅)₃, BPh₄) lead to the formation of a Lewis acidic zinc cationic center, which can be coordinated by an additional ligand of biological interest. The binding of simple β-lactams to the [κ⁴-Titm^iPr,benzo]ZnX complexes can be probed using X-ray diffraction and Nuclear Magnetic Resonance (NMR) spectroscopy, thereby providing a way to model the binding of antibiotics to the active site of the metallo-β-lactamases enzymes responsible for broad antibiotic resistance. The binding of β-lactams can be compared to larger ring size lactams and linear amides. [κ⁴-Titm^iPr,benzo]ZnX (X = MeB(C₆F₅)₃, BPh₄) also allows for the study of the binding of potential metallo-β-lactamases inhibitors, such as, for example, glycinamide, picolinamide, and piperazine-2,3-dione. Binding studies between [κ⁴-Titm^iPr,benzo]ZnX and substrates bearing structural similarities to antibiotics reveal secondary interactions involving peripheral functional groups the cationic zinc center in [κ⁴-Titm^iPr,benzo]ZnX. These studies provide guidelines to modify existing antibiotics, in order to decrease their sensitivity to metallo-β-lactamases. In chapter 3, I explore the reactivity of previously characterized tris(2-pyridylthio)methyl [Tptm] zinc complexes. First, an improved synthesis of [κ⁴-Tptm]ZnF using Me₃SnF as the fluorinating agent is reported. The fluorine atom in [κ⁴-Tptm]ZnF acts as a Lewis base, as illustrated by its reaction with B(C₆F₅)₃ to form [κ⁴-Tptm]ZnFB(C₆F₅)₃, in which the fluorine is transferred to the borane group. The fluoride ligand in [κ⁴-Tptm]ZnF also acts as a hydrogen bond and halogen bond acceptor and is capable of forming adducts with H₂O, indole, and iodopentafluorobenzene. [κ⁴-Tptm]ZnF undergoes metathesis with Ph₃CCl to form Ph₃CF, thereby providing a rare example of C–F bond formation promoted by a zinc complex. Then, [κ³-Tptm]ZnH is used as a catalyst for the hydrosilylation of aldehydes and ketones using phenylsilane to produce tris alkoxysilane products. The catalyst is very active with aldehydes, and shows slower reactivity towards dialkyl ketones. The reaction proceeds via insertion of the carbonyl group in the Zn–H bond to form a zinc alkoxide, which then undergoes metathesis with the silane to generate the desired product and regenerate the zinc hydride species. The complicated NMR spectroscopic features of the products resulting from the hydrosilylation of prochiral ketones are explained by the presence of different diastereomers. Finally, we report that [κ³-Tptm]ZnH is a catalyst for the hydrosilylation of silylformates to methoxy silanes with (EtO)₃SiH, (MeO)₃SiH and κ⁴-N(CH₂CH₂O)₃SiOMe. We show that CO₂ can be reduced to methoxy silane species in a one pot reaction using (MeO)₃SiH and catalytic amounts of [κ³-Tptm]ZnH. In chapter 4, I report the synthesis and characterization of a silicon based analogue of [Titm^iPr,benzo], namely the tris(1-Pribenzimidazol-2-yldimethylsilyl)methyl [Tism^iPr,benzo] ligand. The ligand possesses unique structural features, due to the proximity between the dimethylsilyl groups and the methyl carbanion. The formation of [κ⁴-Tism^iPr,benzo]Li proceeds via the doubly base stabilized silene intermediate [κ³-C(SiMe₂benzimid^iPr)₂]SiMe₂. [κ⁴-Tism^iPr,benzo]Li can be used as a precursor for copper and nickel [Tism^iPr,benzo] and [C₃-Tism^iPr,benzo] complexes, where [C3-Tism^iPr,benzo] represents the isomerized tris carbene version of [Tism^iPr,benzo]. [κ³-C(SiMe₂benzimid^iPr)₂]SiMe₂ reacts with ZnMe₂ to produce [κ³-C(SiMe₃)(SiMe₂benzimid^iPr)₂]ZnMe, which can be transformed to the phenoxide compound. This compound acts as a catalyst for the hydrosilylation of CO₂ to silyl formates and methoxy silanes. [κ³-C(SiMe₂benzimid^iPr)₂]SiMe₂ itself reacts with CO₂ to produce an unusual β-lactone.

Metallohydrolases with dinuclear-zinc active sites perform many important biological hydrolytic reactions on a variety of substrates. In this regard, metallo-β-lactamases (mβ1, class B) represent a unique subset of zine hydrolases that hydrolyze the β-lactam ring in several antibiotics. The antibiotic resistance that results from this hydrolysis is becoming an increased threat for the clinical community. These metalloenzymes can hydrolyze a wide range of β-lactam substrates, such as cephamycins and imipenem that are generally resistant t the serine-containing β-lactamases. Therefore, the clinical application of the entire range of antibiotics is severely compromised in bacteria that produce mβls. Due to the lack of information on the mechanism of mβls, to-date, no clinically known inhibitors is there for mβls. In this present study, we synthesized several mono and dizinc complexes as models for the mβls and investigated the differences in their hydrolytic properties. This study supports the assumption that the second zinc in the dinuclear enzymes does not directly involve in the catalysis, but may orient the substrates for hydrolysis and the basic amino acid residues such as Asp and His may activate the zinc-bound water molecules, fulfilling the role of the second zinc in the mononuclear enzymes. The effect of various side chains on the hydrolysis of some commonly used cephalosporin antibiotics by mβl from B.cereus is described. It is shown that the cephalosporins having heterocyclic thiol side chains are more resistance to mβl-mediated hydrolysis than the antibiotics that do not have such side chains. This is partly due to the inhibition of enzyme activity by the thiol moieties eliminated during the hydrolysis. It is also observed that the heterocyclic side chains in pure form inhibit the lactamase activity of mβl as well as its synthetic mimics. The mode of binding of these heterocyclic side chains to the zinc has been analyzed from the crystal structure of the tetranuclear zinc complexes. The theoretical studies suggest that the eliminated heterocyclic thiols undergo a rapid tautomerism to produce the corresponding thiones. These thiones are found to irreversibly inhibit the LPO-catalyzed iodination reaction. The reaction of various thiones with I2 leads to the formation of thione-iodine complexes similar to that of the most commonly used antithyroid drug methimazole(MMI). These observations suggest that some of the latest generation of antibiotics may show negative effects on thyroid gland upon hydrolysis. Synthetic organophosphorus compounds have been used extensively as pesticides and petroleum additives. These compounds are very toxic to mammals and their widespread use in agriculture leads to serious environmental problems. Therfore, degradation of organophosphorus trimesters and remediation of associated contaminated sites are of worldwide concern. In this regards, the bacterial phsophotriesterase (PTE) enzyme plays an important role in degrading a wide range of organophosphorus esters and the active side of PTE has been shown to be very similar to that of mβl. This identification prompted us to check the hydrolysis of phosphotriesters by the mβl and its mimics. It has been observed that the dinuclear zine(II) complexes that do not allow a strong binding of phosphodiestes would be a better PTE mimics.