Isocyanates are invaluable bulk chemicals that play a central role in the synthesis of various polymers and provide a key platform for the synthesis of nitrogen-containing molecules such as carbamates and ureas. Unfortunately, isocyanates suffer from high toxicity, low functional group tolerance, and a propensity to undergo deleterious side-reactions. Consequently, blocked (masked) isocyanate derivatives have been the subject of increased interest resulting from their reduced toxicity and exceptional control over isocyanate reactivity. This strategy has largely been relegated to the polymerization literature, although its use in the synthesis of complex urea and carbamate derivatives is well established in synthetic organic chemistry. However, prominent gaps in the blocked isocyanate literature were clear at the outset of this research project. First and foremost, the development of heteroatom-substituted isocyanates, such as N- and O-substituted derivatives, remained relatively scarce despite their potential for the synthesis of important nitrogen-containing derivatives. Furthermore, the additions of carbon-centred nucleophiles on blocked N-, O-, and even C-substituted blocked isocyanates were exceedingly rare. Finally, the use of a blocking group strategy in catalytic transformations of isocyanates remained largely absent from the literature. This was particularly striking given the widespread development of catalytic transformations of isocyanates. As such research efforts began focusing on furthering the development of blocked N-isocyanates as a vital platform for heterocyclic synthesis (chapter 2). Initially, the cascade reactivity of blocked N-iso(thio)cyanates was expanded to incorporate electrophiles such as alkynes (section 2.2). This readily provided access to imidazolone and thiazolidine products. Subsequently, the development of a cascade reaction providing access to 1,2,4-triazin-3(2H)-ones was explored (section 2.3). This provided the first examples of an N-isocyanate cascade which hinged on the use of acid catalysis. Moreover, insight into hydrazone isomerization was gained. Finally, these efforts culminated in the development of cascade reactions providing access to a rare class of 1,2,4-triazinones as well as 5-aminopyridazinones (section 2.4). This provided the first example of a cascade reaction involving a C-C bond formation onto a blocked N-isocyanate derivatives. Furthermore, this development was pivotal in re-focusing attention on the development of general strategies to achieve addition of carbon nucleophiles onto blocked isocyanate derivatives. Towards this end, the development of two strategies to achieve carbon-centred nucleophilic additions on both blocked N- And O-isocyanates were developed (chapter 3). Inspiration from the isocyanate literature led to the development of carboxylic acids as formal carbon nucleophiles (section 3.2). This strategy was found to be quite general for the synthesis of hydroxamates from blocked O-isocyanates. Furthermore, encouraging results were generated on the ability of Grignard reagents to form similar products (section 3.3). Particularly important is the paradigm shift this allows from C-N bond formation to C-C bond formation for the synthesis of hydroxamate derivatives. Furthermore, lead results suggest the potential of this reactivity to translate to blocked N-substituted derivatives, a transformation which had failed with carboxylic acids. Finally, the development of a catalytic amide synthesis from blocked isocyanate precursors was targeted (chapter 4). The use of a blocking group strategy was able to address the current major limitation of isocyanates as amide precursors, that is functional group tolerance (section 4.2). Indeed, a commercially available rhodium catalyst was found to allow efficient amidation of various ambiphilic blocked isocyanate derivatives using arylboroxines as nucleophiles. Mechanistic studies including the use of variable time normalization analysis supported the presence of two alternative kinetic regimes contingent on the reaction conditions employed. Furthermore, these data suggested the success of this transformation, in the case of ambiphilic derivatives, hinged on a rate determining isocyanate release (chapter 4). Finally, initial results strongly support the potential for Boc-carbamates to provide a general platform for amidation in the presence of strong nucleophiles such as primary amines. The potential of a blocking group strategy in catalytic reaction development was further displayed with the development of a palladium catalyzed amidation of blocked derivatives with arylboroxine nucleophiles (section 4.3). Indeed, the use of blocked isocyanates was found to be absolutely key in achieving efficient reactivity with the palladium catalyst. This result, coupled with the sparse reports on blocked isocyanates in catalysis, strongly suggest that the use of such a strategy could allow the development of reactivity otherwise unattainable when using free isocyanates.

This Thesis reports the synthesis and reactions of new hydrazide, alkoxyimide and benzimidamide complexes (L)Ti=NX (X = NAr2, NOtBu or C(Ar)NO^tBu; L = dianionic supporting ligand or ligand set). The work is supported by DFT calculations which are used to rationalise the reaction outcomes observed and, in one case, the bonding in alkoxyimide complexes. <b>Chapter One</b> provides a background to hydrazide complexes, starting with their relevance to nitrogen fixation. In addition, Group 4 imide, alkylidene hydrazide and alkoxyimide complexes are also reviewed. The Chapter focuses in particular on the synthesis, structure, and stoichiometric and catalytic reactions of these complexes with unsaturated substrates. <b>Chapter Two</b> describes the development of the virtually unexplored 1,2-diamination reaction. The substrate scope and isolation of the vinylamine products are discussed. The protonation of the vinylimide complex Ti(N2N^Me){NC(Ph)C(Me)NPh2}(py) and the overall diamination reaction itself is then explored through an in-depth experimental and computational study. <b>Chapter Three</b> details the synthesis of cyclopentadienyl-amidinate supported alkoxyimide complexes. The first detailed reactivity study, supported by structural and computational studies, of any alkoxyimide complex is reported. Novel reactivity at Ti=Nα and, in one instance, Nα–Oβ reductive bond cleavage is observed. <b>Chapter Four</b> describes the reactivity of the benzimidamide complex Cp*Ti{PhC(NⁱPr)2}{NC(Ar^F5)NO^tBu} with a range of substrates including heterocumulenes, aldehydes, isonitriles and B(Ar^F5)3. Novel reactivity at Ti=Nα, and 3-component coupling is presented, and the experimental results supported by structural and computational studies. <b>Chapter Five</b> presents full experimental procedures and characterising data for the new complexes reported.

The act of topping tobacco (Nicotiana tabacum L.) involves the removal of the terminal bud or inflorescence of the tobacco plant. This practice ordinarily is accomplished by manually removing the top of each tobacco plant in an entire field which is labor intensive and costly. Chemical topping utilizes sucker control products to inhibit the terminal bud and axillary bud growth without manually removing the top of the tobacco plant. There were several research objectives in order to determine the utility of a chemical topping system: 1) determine if burley tobacco could be chemically topped with currently registered suckercide products while maintaining control of subsequent sucker growth; 2) compare chemical topping to manual topping for yield and leaf quality; 3) identify burley tobacco varieties that are better suited for chemical topping systems; 4) determine the optimum plant growth stage at which chemical topping treatments should be applied; and 5) identify genes that are differentially expressed following suckercide applications. To pursue our objectives, studies were initiated investigating the optimum timing of application, ideal variety maturity, and efficacy of suckercide applications using combinations of maleic hydrazide (MH), butralin, and fatty alcohols (FA). The terminal bud was not well controlled with FA or butralin alone nor was acceptable sucker control or total yield achieved. Our data suggest that chemically topping burley tobacco with a tank mixture of MH and a local systemic may be a suitable alternative to manual topping, as total yield and leaf quality grade index were not significantly different and total TSNA and MH residues were not significantly higher compared to manual topping. The 10% button and 50% button application timings were best suited for chemical topping practices. Treatments that targeted the 10% bloom stage did not completely halt flower development, but all application timings resulted in excellent sucker control. Medium and late maturity burley varieties were found to be suitable for chemical topping methods; however, timing the suckercide application may be less difficult in later maturing varieties. Chemically topping burley tobacco at 10 to 50% button stages with a tank mixture of MH and a local systemic suckercide was found to be a suitable alternative to manual topping, and would potentially result in labor savings for burley tobacco growers. Expression of genes related to phytohormones, meristem development, cell division, DNA repair and recombination were affected following MH treatment, which likely leads to the inhibition of apical and axillary meristem development.

The plant cell wall contains significant quantities of renewable polymers in the form of cellulose, hemicellulose, and lignin. These three renewable polymers have the potential to complement or replace synthetic polymers in a variety of applications. Rapidly determining the quantities of these polysaccharides in lignocellulosic biomass is important yet difficult since plant biomass is recalcitrant and highly variable in composition. Part of this contribution outlines a novel compositional analysis protocol using infrared spectroscopy and multivariate regression techniques that is rapid and inexpensive. Multivariate regression models based on calibration mixtures can be used to discern between populations of lignocellulosic biomass or to predict cellulose, hemicellulose, and lignin quantities. Thus, the compositional analysis step can be expedited so that other processes, like fractionation of the lignocellulose polymers, can be tuned accordingly to maximize the value of the final product. Hybrid materials were also generated using a variety of polymerization techniques and post-polymerization modifications. A novel controlled/living radical polymerization initiator was synthesized (2-bromo-2-methylpropane hydrazide) containing a hydrazide functionality that was covalently linked to the reducing-end of dextran. Despite the rapid coupling of the hydrazide- based initiator to the reducing-end of dextran, the instability of the alkyl bromide bond resulted in several unsuccessful attempts at Cu(0)-mediated controlled/living radical polymerization. Recommendations were given to improve the stability of this compound; however, an alternative approach to synthesizing hybrid copolymers was also investigated in parallel. Hyperbranched polymers were synthesized using commercially available vinyl and divinyl monomers in the presence of a cobalt(II) complex that enabled control over the size, architecture, and mol% of pendant vinyl groups amenable to post-polymerization modification. Modifying the ratio of divinyl monomer to cobalt(II) complex provided a series of hyperbranched polymers with variable morphology and mol% pendant vinyl groups. The pendant vinyl bonds were subsequently converted to amines via thiol additions with cysteamine. These amine functionalized hyperbranched polymers were then used in a subsequent reductive amination reaction with the reducing-end of dextran to produce the amphiphilic core-shell copolymer poly(methyl methacrylate-co-ethylene glycol dimethacrylate)-b-dextran. These amphiphilic copolymers mimicked the colloidal behaviour of conventional block copolymer micelles without requiring difficult syntheses or tedious self-assembly steps. / Thesis (Master, Chemical Engineering) -- Queen's University, 2012-02-28 11:20:01.568

Maleic hydrazide (MH) applications have been standard practice for sucker control in burley tobacco (Nicotiana tabacum L.) production for the last half-century because it is relatively inexpensive, effective and easy to apply. Non-MH suckercides such as fatty alcohols and local systemics can be utilized to reduce or replace MH and lower undesirable residues in the cured leaf. The objective of this study was to evaluate various nozzle types and arrangements for efficiency to determine if sucker control with fatty alcohol could be consistently improved over the currently used TG3-5-3 arrangement, as well as examine sprayer positioning (center vs. off-center) and leaf orientation variables using artificial plants. In the field study, the TG4-6-4 arrangement performed the best (p<0.05) when applying the same volume per hectare providing 80% sucker control with fatty alcohol only, not significantly different (p>0.05) than MH+Butralin treatment. For the artificial plant study, the TG4-6-4 provided more solution collected (p<0.05) at leaf axils as well as the highest percent of solution intercepted. Sprayer position and leaf orientation had less effect on solution intercepted with this arrangement than it did with the TG3-5-3. Results from this study support a recommendation of the TG4-6-4 over the TG3-5-3 for the application of contact chemicals for sucker control in burley tobacco.

Over the past recent years, β-aminocarbonyls have been of great interest to medicinal chemists. As a practical method to obtain these moieties, alkene aminocarbonylation, accounting for the formation of a C-N and a C-C bond, has been the subject of limited research efforts (very specific intramolecular metal-catalyzed variants have been reported). Direct aminocarbonylation of alkenes constitutes a challenging and an important potential innovation in the synthesis of β-aminocarbonyls such as β-amino acids. The research efforts described in the present thesis have been primarily directed towards the development of concerted pathways for the amination of alkenes using hydrazine derivatives as bifunctional reagents. Building on our previous report on the reactivity of hydrazides, progress on the aminocarbonylation of alkenes along with the synthetic scope of this reactivity are herein provided. Therefore, the first part of the present thesis (Chapter 2) focuses primarily on the development of thermolytic conditions for the intramolecular aminocarbonylation of alkenes using amino-isocyanates. Alongside, development of imino-isocyanates have provided complementary synthetic tools for aminocarbonylation. The second part (Chapter 3) describes the work accomplished towards intermolecular aminocarbonylation of alkenes and the synthesis of complex azomethine imine products (Chapter 3). Finally, the last part of the discussion (Chapter 4) will be on the development of new hydrazide reagents for the intramolecular Cope-type hydroamination of alkenes. In doing so, description of the synthetic utility of amino-isocyanates as amphoteric reagents for cascade reactions and heterocyclic synthesis will be provided.

Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for use against the malaria vector Anopheles gambiae. In the process of producing a library of compounds for assay against An. gambiae, it became clear that employing regioselective acylation techniques (in molecules that feature two nucleophilic, acyclic nitrogen atoms α to one another) would be imperative. Synthesis of the library derivatives proceeded rapidly and after topical assay, we found three compounds that were more toxic than the RH-series leads. One of the three displayed an LD50 value of half that of RH-1266, though patch clamp assay concluded that toxicity was not necessarily linked to inhibition of mosquito K+ channel Kv2.1. The acylation of monoarylhydrazines appears simple, but its regioselectivity is poorly understood when assumed as a function of basicity correlating to nucleophilic strength. We determined the ratio of the rate constants for distal to proximal N-acylation using 19F NMR spectroscopic analysis of reactions of 4-fluorophenylhydrazine with limiting (0.2 equiv) acylating agent in the presence of various bases. Acid anhydrides gave consistent preference for distal acylation. The selectivity of acylation by acyl chlorides when using pyridine gives strong distal preference, whereas use of triethylamine or aqueous base in conjunction with aroyl chlorides showed a moderate preference for proximal acylation. This observation yielded a convenient one-step method to synthesize proximal aroylarylhydrazines in yields comparable or superior to that provided by the standard three-step literature approach. Combined with NMR evidence of the distal nitrogen as the unambigiously stronger base of the two nitrogens, we propose a single electron transfer mechanism that predicts the regiochemistry of arylhydrazines toward acylating agents better than the nucleophilicity model based on pKa values. While synthesizing the acylhydrazine library for assay against An. gambiae, NMR spectroscopy revealed rotational isomerisms of two types: chiral helicity (M)/(P) and acyl (E)/(Z)-isomerism due to hindered rotation. Variable temperature NMR allowed the measurement of N-N bond rotational barriers, as well as estimate the barrier of (E)/(Z) interconversion. We obtained the X-ray crystal structures of four diacylhydrazines to test this hypothesis and revealed both the twist conformation around the N-N bond axis and (E)/(Z)-isomerism around the proximal acyl group. Computation (which agreed with the crystal structures) allowed us to estimate which (E)/(Z)-isomers were most likely being observed in solution at room temperature by NMR spectroscopy. In addition, we were able to calculate transition structures corresponding to N-N bond rotational barriers of (E,Z)- and (Z,Z)-isomers of model molecules and rationalize the difference in coalescence temperatures between (E,Z)- and (Z,Z)-isomers. / Ph. D.

No description available.

The arsenal of drugs available for treating Leishmania infections is limited and presents high toxicity. Therefore, new, effective, and less toxic leishmaniasis treatments are still needed. In this work, two series of derivatives, containing a semicarbazone or hydrazide-N- acylhydrazone scaffolds was designed and synthetized as protease inhibitors. From these series, derivatives LASSBio 1483, LASSBio 1705, LASSBio 1707 and LASSBio 1736 highlighted, showing in vitro and in vivo leishmanicidal activities. Thus, these derivatives presented a potent leishmanicidal activity against amastigotes of L. major (IC50 of 1.5 µΜ to LASSBio 1483, 8.5 µΜ to LASSBio 1705 and 1.,9 µΜ to LASSBio 1707) , L. amazonensis (IC50 of 3.5 µΜ to LASSBio 1483 and 84.0 µΜ to LASSBio 1736), L. braziliensis (IC50 of 31.7 µΜ to LASSBio 1483, 8.0 µΜ to LASSBio 1705 and 5.3 µΜ to LASSBio 1736) and L. chagasi (IC50 of 53.3 µΜ to LASSBio 1707 and 57,6 µΜ to LASSBio 1736). Also, the leishmanicidal activity of derivatives LASSBio-1483, LASSBio 1705, LASSBio 1707 and LASSBio 1736 were mediated via induction of apoptosis as evidenced by externalization of phospholipids, despolarization of mitochondrial membrane and elevation of activation of caspases. The ultrastructural morphological effects against the parasite of LASSBio 1483 and LASSBio 1736 against L. chagasi promastigotes were also verified. The treatment of L. amazonensis -infected BALB/c mice with derivatives LASSBio 1483 (effect of 30.5% and 33.3% in infected ear, by p.o and i.p., respectively), LASSBio 1705 1483 (effect of 58.5% in infected ear and 61.1% in lymph node, i.p.), LASSBio 1707 (effect of 56.5% in lymph node, i.p.) and LASSBio 1736 (effect of 53.6% in infected ear, i.p.)or the treatment of L. chagasi - infected hamsters with LASSBio 1707 (effect of 53.6, i.p.)and LASSBio 1736 (effect of 46.0%, i.p.) led to a significant reduction of parasite burden when compared to controls that received PBS. The treatment with these derivatives did not result in hepatic or renal toxicity in these animals models of leishmaniasis. These data make LASSBio 1483, LASSBio 1705, LASSBio 1707 and LASSBio 1736 new lead-candidates against cutaneous and visceral leishmaniasis. / Conselho Nacional de Desenvolvimento Científico e Tecnológico / O arsenal de fármacos disponíveis para o tratamento das infecções por Leishmania spp. é limitada e de elevada toxicidade. Portanto, novos tratamentos, eficazes e menos tóxicos para leishmaniose ainda são necessários. Neste trabalho, duas séries de derivados contendo as subunidades semicarbazona ou hidrazida-N-acilhidrazona foram desenhados e sintetizados como inibidores de proteases. A partir destas séries, os derivados LASSBio 1483, LASSBio 1705, LASSBio 1707 e LASSBio 1736 se destacaram, mostrando atividade leishmanicida in vitro e in vivo . Assim, esses derivados apresentaram atividade leishmanicida potente contra amastigotas de L. major (CI 50 de 1,5 µΜ para LASSBio 1483, 8,5 µΜ para LASSBio 1705 e 15,9 µΜ para LASSBio 1707) , L. amazonensis (CI 50 de 3,5 µΜ para LASSBio 1483 e 84,0 µΜ para LASSBio 1736) , L. braziliensis (CI 50 de 31,7 µΜ para LASSBio 1483, 8,0 µΜ para LASSBio 1705 e 5,3 µΜ para LASSBio 1736) e L. chagasi (CI 50 de 53,3 µΜ para LASSBio 1707 e 57,6 µΜ para LASSBio 1736). Além disso, a atividade leishmanicida dos derivados LASSBio 1483, LASSBio 1705, LASSBio1707 e LASSBio 1736 foi mediada via indução de apoptose como evidenciado pela externalização de fosfolipídeos de membrana, despolarização da membrana mitocondrial e ativação de caspases. Os efeitos morfológicos ultra-estruturais de LASSBio 1483 e LASSBio 1736 em promastigotas de L. chagasi também foram verificados. O tratamento de camundongos BALB/c infectados por L. amazonensis com os derivados LASSBio 1483 (efeito de 30,5% e 33,3% na orelha infectada, por v.o. e i.p., respectivamente), LASSBio 1705 (efeito de 58,1% na orelha infectada e de 61,1% no linfonodo, i.p.) , LASSBio 1707 (efeito de 56,5% no linfonodo, i.p.) e LASSBio 1736 (efeito de 38,8% na orelha infectada , i.p.) ou o tratamento de hamsters infectados por L. chagasi com LASSBio 1707 (efeito de 53,6%, i.p.) e LASSBio 1736 (efeito de 46,0%, i.p.), na dose de 30 µmols/kg/dia, levaram a uma redução significativa da carga parasitária quando comparados aos controles que receberam PBS. O tratamento com estes derivados não resultaram em toxicidade hepática ou renal nestes modelos animais de leishmaniose. Estes dados fazem de LASSBio-1483, LASSBio-1705, LASSBio-1707 e LASSBio-1736 novos candidatos a protótipos a fármacos contra leishmaniose cutânea e visceral