This research work includes three parts, with the first section describing the synthesis and applications of neutral 3-coordinate aluminum complexes. As demonstrated in this part, aluminum complexes in a 3-coordinate geometry can be formed only with a ring size greater than or equal to a 6-member ring when supported by diamido ligands. It is found that 1,2-diamido ligands designed for 5-member ring formations can accommodate the formation of only 4-coordinate dinuclear species, which show no activity when used as a single component catalyst in the ring-opening polymerization (ROP) of cyclic esters under specified reaction conditions. Three-coordinate neutral (1,4-diamido)AlMe complexes are successfully synthesized, revealing a higher activity in the ROP of cyclic esters than the existing 6-member analogues under the same reaction conditions. A detailed discussion of the structure-reactivity relationship of Al catalysts in the ROP of cyclic esters is presented. The second part of this thesis project consists of investigations into the applications of 1,4-diamido ligands for the formation of 3-coordinate NHP (N-heterocyclic phosphine) and 2-coordinate NHP+ cations (phosphenium cations). These novel NHP species are the first to be shown in a 7-member ring supported by 1,4-diamido ligands. Various N-substituents in the 1,4-diamido ligands are examined for the formation of a cyclic structure based on their steric hindrance. It is found that a Dipp (2,6-diisopropylphenyl) group is unable to allow for the formation of a 7-member NHP due to its excessive steric bulk. The less bulky mesityl (2,4,6-trimethylphenyl) group at the N-positions in the ligands leads to successful formation of these novel NHPs and NHP+ species. Furthermore, an investigation is carried out to explore their π-accepting property by means of 31P NMR studies. The NHP and NHP+ species synthesized in this project show chemical shifts downfield relative to the existing 5- and 6-member analogues in 31P NMR experiments, suggesting a high potential of 7-member NHPs to be used as π-acceptor ligands. The second section also examined the resulting NHPs and NHP+ species for coordinating to various metals. The last part of this research work is dedicated to presenting the first example of chelating 3–triNHC (tri-N-heterocyclic carbene) ligands that allow for the formation of (triNHC)Pd(II) complexes in a meridional fashion, wherein the triNHC ligand coordinates to the metal center in a pseudo-meridional fashion. Novel [(triNHC)MePdX]X (X = Cl or acetate) complexes are successfully synthesized, and they display extraordinary stability against air and heat. Low activities of the resulting complexes are found in promoting C-C coupling reactions, possibly due to the low solubility of the resulting complexes in organic solvents. Various attempts to change the N-substituents to groups other than methyls are conducted to improve the solubility of the complexes in organic solvents for higher activities in C-C coupling reactions. The results from these attempted modifications to these complexes are discussed in detail. All complexes are characterized by standard spectral methods such as mass spectrometry, X-ray crystallography, elemental analysis, 1H NMR, 13C NMR and 31P NMR spectroscopy.

Les travaux présentés dans cette thèse ont eu pour objectif la valorisation d’une structures bicyclique bifonctionnelle à géométrie contrainte, celle de l’acide 2-aminobicyclo[2.2.2]octane 1-carboxylique (ABOC). La contrainte conformationnelle est une caractéristique particulièrement recherchée dans la conception d’agent chiraux pour la synthèse asymétrique ainsi que dans la synthèse de macromolécules se structurant spontanément (foldamères). Un travail sur la synthèse de petits peptides incorporant le (R) ou (S)-ABOC, a dans un premier temps conduit à l’identification d’un nouvel organocatalyseur bifonctionnel de la réaction d’aldolisation. Ce tripeptide incorporant en plus de l’ABOC un résidu proline en position N-terminale et un résidu Asp-OMe en position C-terminale a permis l’obtention d’excès énantiomérique élevés (jusqu’à 87%). Les analyses structurales ainsi que des calculs théoriques ont montré l’importance du bicycle de l’ABOC induisant la formation d’un coude dans la molécule et permettant la proximité des fonctions acide carboxylique (Asp) et amine secondaire (Pro) intervenant dans la catalyse. Dans un second temps, l’optimisation de la synthèse du (R) ou (S)-1,2-diaminobicyclo[2,2,2]octane (DABO) a permis de mettre en évidence l’impact important d’une double liaison endo-cyclique dans la réactivité de l’amine en tête de pont lors du réarrangement de l’acide carboxylique de l’ABOC en amine primaire. En effet, seules les conditions d’Hofmann appliqué au substrat présentant une insaturation dans le squelette bicyclique ont permis d’obtenir la diamine chirale avec de bon rendement. Cette nouvelle diamine vicinale chirale contrainte par un bicycle carboné a d’abord permis la synthèse de composés thiourée-amine autour du bicycle pour l’organocatalyse de la réaction d’addition de Nitro-Michael asymétrique. Cependant, et malgré les nombreux efforts d’optimisation, l’utilisation de ces molécules n’a jamais permis l’obtention d’excès énantiomériques supérieurs à 39%. En revanche, la synthèse de nouveaux ligands chiraux salen, salan et diamines secondaires basés sur le DABO et l’application des complexes de cuivre correspondants dans la catalyse de la réaction de nitroaldolisation asymétrique a abouti à l’obtention de bons rendements et d’une stéréosélectivité allant jusqu’à 86% d’excès énantiomériques. Le complexe donnant les meilleurs résultats a fait l’objet d’une étude DFT approfondie permettant de proposer la structure de l’état de transition le plus stable et de rationaliser la stéréosélectivité observée. Enfin la synthèse du DABO a permis d’entreprendre la synthèse de nouvelles oligourées mixtes homochirales se structurant en hélice-12/14 stables, alors qu’aucune structuration n’avait été observée lors de l’étude d’oligourées mixtes homochirales synthétisées à partir de l’ABOC. / The work presented in this thesis was aimed at the valorisation of a bicyclic bifunctional structure with constrained geometry, the 2-aminobicyclo[2.2.2]octane 1-carboxylic acid (ABOC). Conformational restriction is a particularly sought characteristic in chiral agent designed for asymmetric synthesis as well as in the synthesis of spontaneously structuring macromolecules (foldamers). A work on the synthesis of small peptides incorporating (R) or (S)-ABOC, initially led to the identification of a novel bifunctional organocatalyst for the aldolization. This tripeptide incorporating in addition to ABOC a proline residue in the N-terminal position and an Asp-OMe residue in the C-terminal position allowed to obtain high enantiomeric excess (up to 87%). Structural analysis as well as theoretical calculations showed the importance of the ABOC bicycle, inducing the formation of a turn in the molecule and allowing the proximity of the carboxylic acid (Asp) and secondary amine (Pro) functions involved in catalysis. The optimization of the synthesis of (R) or (S)-1,2-diaminobicyclo[2,2,2]octane (DABO) allowed to demonstrate the important impact of an endo-cyclic double bond in the reactivity of the bridgehead amine during the rearrangement of the carboxylic acid of the ABOC to the primary amine. Indeed, only the Hofmann conditions applied to the substrate exhibiting unsaturation in the bicyclic skeleton allowed to obtain the chiral diamine in good yield. This novel chiral vicinal diamine conformationally restricted by a carbon bicycle first allowed the synthesis of thiourea-amine compounds around the bicycle for the organocatalysis of the asymmetric nitro-Michael addition. However, despite many optimization efforts, the use of these molecules has never led to enantiomeric excesses greater than 39%. On the other hand, the synthesis of new chiral salen, salan and secondary diamines ligands based on DABO and the application of the corresponding copper complexes for the catalysis of the asymmetric nitroaldolization reaction resulted in good yields and a stereoselectivity up to 87% enantiomeric excess. The best-performing complex was subjected to a DFT study to propose the structure of the most stable transition state and to rationalize the high stereoselectivity. Finally, the synthesis of DABO allowed to undertake the synthesis of new homochiral mixed oligoureas structuring as stable 12/14-helices, while no structure had been observed during the study of homochiral mixed oligoureas synthesized from the ABOC.

Résumé confidentiel / Résumé confidentiel

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Les 1,2-diamines sont présentes dans de nombreux produits biologiquement actifs, ce qui a poussé les chimistes organiciens à développer de nouvelles voies d’accès à ces motifs. Dans ce contexte, la maitrise de leur stéréochimie est essentielle puisque leur activité biologique en découle. Afin de répondre à cette problématique, nous nous sommes intéressés au développement d’une réaction d’amination électrophile de dérivés d’énamides catalysée par des acides phosphoriques chiraux. Ces catalyseurs interagissent avec les substrats via des liaisons hydrogènes permettant d’activer simultanément un nucléophile et un électrophile. Notre stratégie s’est révélée très efficace et a permis de synthétiser une gamme de 1,2-diamines extrêmement variée. De nombreux motifs d’intérêt biologique, incorporant notamment des hétérocycles, très employés en chimie pharmaceutique et cosmétique, ont été compatibles avec ce procédé. Dans un second projet, nous nous sommes intéressés au design de composés d’iode hypervalent chiraux. Ces composés ont connu un essor considérable ces dernières années en raison de leur stabilité à l’air et à l’humidité, leur faible toxicité et leur réactivité intéressante. Cependant, malgré ces développements, l’exploitation des dérivés d’iode hypervalent dans des versions catalytiques asymétriques mériterait d’être plus amplement étudiée. Dans ce contexte, de nouveaux précatalyseurs ont été élaborés au laboratoire puis employés dans des réactions d’oxygénations énantiosélectives. La structure particulière de ces composés a permis d’obtenir les meilleurs excès énantiomériques de la littérature à ce jour. / The 1,2- diamines can be found in many biologically active compounds, which pushed organic chemists to develop new methodologies to synthesize those molecules. In this context, the stereochemistry is essential because the biological activity ensues. Thus, we were interested in developing an enantioselective amination of enamide derivatives catalyzed by chiral phosphoric acids. These catalysts interact with substrates via hydrogen bonds to activate a nucleophile and an electrophile simultaneously. Our strategy proved to be very effective and allowed us to synthesize a wide range of 1,2- diamine. Many compounds of biological interest, including heterocycles used in pharmaceutical and cosmetic industry, were tolerated with this process. In another project, we looked at the design of chiral hypervalent iodine compounds. These compounds have recently gained considerable attention because of their stability to air and moisture, their low toxicity and their interesting reactivity. However, despite considerable development, the use of hypervalent iodine derivatives in catalytic asymmetric reactions deserves to be further studied. In this context, new pre-catalysts were developed in our laboratory and used in enantioselective oxygenation reactions. The special structure of these compounds yielded the best enantiomeric excesses of the literature to date.

Indiana University-Purdue University Indianapolis (IUPUI) / Purpose: The primary objective of this laboratory study was to investigate whether the ability of SDF to remineralize caries lesion is modulated by their baseline mineral distribution. The exploratory objective was to determine whether the staining caused by SDF is modulated by lesion mineral distribution. Materials and methods: This in vitro study utilized bovine permanent enamel specimens. SDF was compared to the clinical reference standard, 5% sodium fluoride varnish (FV), and deionized water (DIW) was the negative control. By utilizing three lesion creation protocols (methylcellulose [MeC], hydroxyethylcellulose [HEC], Carbopol [C907]), artificial caries lesions with different mineral distributions (n=20 per subgroup) were created in the enamel specimens Interventions were applied and the lesions remineralized using artificial saliva. Changes in mineral loss, lesion depth, mineral density of the surface zone, and lesion mineral distribution were determined using transverse microradiography. Throughout the study, color of the lesion and changes thereof were measured using a spectrophotometer. Data were analyzed by using two-way ANOVA. Pair-wise comparisons were performed using Fisher’s Protected Least Significant Differences to control the overall significance level at 5%. Results: For changes in mineral loss, DIW in MeC showed significantly greater change (more remineralization) than both SDF (p<0.01) and FV (p=0.01), which were not different from one another (p=0.13). There were no statistically significant differences between SDF and FV in the other lesions (C907 – p=0.18; HEC – p=0.56). For changes in lesion depth, there was no statistically significant interaction between study factors lesion protocol and treatments (p=0.23) as well as the individual factors lesion protocols (p=0.08) and treatments (p=0.82). For changes in surface zone mineral density, SDF showed significant change in mineral density compared to FV (p=0.02); however, SDF was not different from with DIW (p=0.25). For lesion mineral distribution, MeC exhibited the greater mineral loss in the lesion body and lowest mineral density at the surface zone. HEC lesions were the deepest but exhibited modest differences in mineral loss between the lesion body and the surface zone. C907 lesions were somewhat between MeC and HEC. SDF in MeC had the highest mineral gain in the surface zone, while DIW resulted in the highest mineral gain in the lesion body. SDF in HEC showed the highest mineral gain in the surface area compared to FV and DIW, with all treatments resulting in the largest mineral gain to a similar extent in the lesion body. In C907, SDF showed the most mineral gain in the lesion body compared to DIW and FV, while differences in the surface zone between treatments were less pronounced. For color changes post intervention, SDF showed more darkening in C907 and HEC lesions compared to MeC (p<0.01) and compared to FV and DIW. For post remineralization, SDF treated C907 lesions became significantly whiter (p<0.01) compared to SDF in MeC and HEC which continued to get darker. Conclusion: SDF did exhibit different remineralization abilities and behaviors and the modulation was based on lesion baseline mineral distribution. Staining resulting from SDF treatment varied significantly based on lesion mineral distribution.

De nouveaux polyuréthanes ont été synthétisés sans isocyanate et en intégrant des synthons biosourcés afin de développer des matériaux innovants et performants pour des applications dans le domaine de l’industrie automobile et du bâtiment. À l’issue d’un état de l’art, divers synthons et différentes stratégies ont été retenus afin d’obtenir de nouvelles architectures (macro)moléculaires et conférer aux matériaux finaux les propriétés physico-chimiques recherchées. Dans un premier temps, la réaction entre un biscyclocarbonate issu d’une molécule modèle, l’acide sébacique, et des diamines dimériques ainsi que plusieurs paramètres réactionnels ont été étudiés. Cette première étude a permis de montrer l’intérêt du ratio entre les monomères ainsi que l’influence de la fonctionnalité des diamines sur les propriétés chimiques, thermiques, rhéologiques et mécaniques des matériaux polyuréthanes sans isocyanate. Cette approche a permis dans un second temps de synthétiser des matériaux pouvant être entièrement biosourcés et de comparer leurs propriétés à celles des polyuréthanes conventionnels. Les performances de certains des matériaux thermodurcissables obtenus ont confirmé l’intérêt de cette stratégie pour les applications visées. Enfin, une troisième approche a été consacrée à la synthèse de polyuréthanes sans isocyanate thermoplastiques via la synthèse de prépolymères. Les différentes études ont montré l’importance de la structure des divers synthons sur l’organisation macromoléculaire, et ainsi sur les propriétés des matériaux finaux. / Novative and performant polyurethane materials without isocyanate were synthesized using biobased molecules for applications in automotive and building industries. After a state of the art, different building blocks were selected and various strategies were established to develop new (macro)molecular architectures. First, reactions between a biscyclocarbonate from a model structure and dimer diamines were studied as well as the impact of various reaction parameters. Secondly, this approach was adapted to fully biobased materials. The properties of these nonisocyanate polyurethanes were compared with those of conventional ones. The influence of the monomer structures on the final materials was also demonstrated. The performance of some thermoset materials have confirmed the importance of the chosen strategies for the desired applications. Finally, a third approach was dedicated to the synthesis of thermoplastic nonisocyanate polyurethanes via a prepolymer synthesis. The various studies have revealed the specific impact of the building block structure on the macromolecular organization, and thus on the properties of the final materials.

Indiana University-Purdue University Indianapolis (IUPUI) / Objective: This study aimed to evaluate surface microhardness changes in early, incipient, non-cavitated white-spot, enamel caries lesions treated with silver diamine fluoride (SDF) longitudinally. The utilization of silver nitrate and potassium fluoride test groups served as additional controls to assist in evaluating if the remineralization effects were due to the silver or fluoride component in SDF. Hypotheses: 1. SDF treatment will result in increased surface microhardness of early, incipient, non-cavitated white-spot, enamel caries lesions compared to all other tested interventions. 2. Specimen storage for 2-weeks in artificial saliva will result in greater surface rehardening in lesions treated with SDF compared to other tested interventions. Design: This laboratory study had 5 intervention groups (SDF, silver nitrate (AgNO3), potassium fluoride (KF), 5.0-percent sodium fluoride varnish (FV), deionized water (DI)) × 2-time intervals after intervention (immediate & delayed pH-cycling), resulting in 10 groups (n = 18). Early, incipient, non-cavitated white-spot, enamel caries lesions were created in bovine enamel and extent of demineralization was determined using Vickers surface microhardness (VHNlesion). Intervention treatments were applied. Half the specimens from each group underwent immediate 5-day pH-cycling and half were stored in an incubator with artificial saliva for two weeks before undergoing 5-day pH-cycling. After pH-cycling, lesion hardness was evaluated using VHNpost. Specimens were then exposed to a second demineralization challenge and lesion softening was evaluated using VHNsecdem. Surface rehardening was calculated: ΔVHN =VHNpost - VHNlesion. Surface softening was calculated: ΔVHNsecdem =VHNsecdem – VHNpost. Data was analyzed using two-way ANOVA. Results: Immediately cycled, SDF had significantly (p < .0001) greater remineralization than DI, AgNO3, and FV. All delayed cycling groups had significantly (p < .0001) greater remineralization than FV. Significantly greater remineralization was noted in delayed AgNO3 (p < .0001), DI (p = .0003), and FV (p = .0006) compared to immediately cycled. After the second demineralization challenge, FV had significantly less surface softening than AgNO3 (p = 0.0002), DI (p = 0.0003), KF (p = 0.0225), and SDF (p = 0.0388) intervention groups. No significant difference was found between the pH-cycle timings. Conclusion: Based on our findings, FV maybe better suitable than SDF to treat early, incipient, non-cavitated white-spot, enamel caries lesions. Longitudinally, SDF exhibited greater remineralization than both FV and DI groups, though not statistically significant. However, upon a second demineralization challenge, FV significantly outperformed SDF in preventing surface softening. / 2021-09-30

A COMPARISON OF THE ANTIMICROBIAL EFFICACY OF SILVER DIAMINE FLUORIDE AND SILVER NITRATE: AN IN VITRO STUDY By: Nicholas L Luke, D.D.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Dentistry at Virginia Commonwealth University. Virginia Commonwealth University, May 2018 Thesis Advisor: William O. Dahlke Jr., D.M.D. Pediatric Dentistry, Department Chair Purpose: To determine the antimicrobial efficacy of SDF and SN/NaF. Methods: Three bacterial species were combined to create an in vitro biofilm. Treatment was completed with SN, SN/NaF, SDF, SDF½ or untreated (control). Results: The untreated group demonstrated significantly higher growth than all other treatment groups across the study. On the BHI-plates (1-day), there were significant differences between all treatments except SDF and SDF½. On the BHI-plates (3-days), SN/NaF was not significantly different from SDF or SDF½. On the L-MRS-plates (1-day), both SN treatment groups yielded significantly higher growth than the SDF groups. On the L-MRS-plates (3-days), SN yielded significantly higher growth than SN/NaF, SDF, and SDF½. Conclusion: SDF is more effective than SN/NaF, with the exception of BHI-plates (3-days) only and SN/NaF is more effective than SN on primarily S. mutans and L. acidophilus. There is evidence of a possible antimicrobial tolerance of oral bacteria to silver.

Cyanide-catalyzed aldimine coupling was employed to synthesize compounds with 1,2-ene-diamine and α-imine-amine structural motifs: 1,2,N,N'- tetraphenyletheylene-1,2-diamine (13) and (+/-)-2,3-di-(2-hydroxyphenyl)-1,2- dihydroquinoxaline (17), respectively. Single crystal X-ray diffraction provided solidstate structures and density functional theory calculations were used to probe isomeric preferences within this and the related hydroxy-ketone/ene-diol system. The enediamine and imine-amine core structures were calculated to be essentially identical in energy. However, additional effects-such as π conjugation-in 13 render an enediamine structure that is slightly more stable than the imine-amine tautomer (14). In contrast, the intramolecular hydrogen bonding present in 17 significantly favors the imine-amine isomer over the ene-diamine tautomer (18). Aldimine coupling (AIC) is the nitrogen analogue of the benzoin condensation and has been applied to dialdimines, providing the first examples of cyclizations effected by cyanide-catalyzed AIC. Sodium cyanide promoted the facile, intramolecular cyclization of several dialdimines in N,N-dimethylformamide, methanol, or dichloromethane/water (phase-transfer conditions) yielding a variety of six-membered heterocycles. Under aerobic conditions, an oxidative cyclization occurs to provide the diimine heterocycle. Cyanide-catalyzed aldimine coupling was employed as a new synthetic method for oligomerization. Nine rigidly spaced dialdimines were oxidatively coupled under aerobic conditions to yield conjugated oligoketimines and polyketimines with unprecedented structure and molecular weight (DP = 2 - 23, ~700 -8200 g/mol). The α- diimine linkage was established based on IR spectroscopy, NMR spectroscopy, size exclusion chromatography, and X-ray crystallographic characterization of the model oxidized dimer of N-benzylidene-(p-phenoxy)-aniline. Cyclic voltammetry indicates ptype electrical conductivity, suggesting they are promising candidates for plastic electronic devices. The cyanide-catalyzed benzoin condensation reaction of 4-substituted benzaldehydes followed by oxidation to the diketone, and the Schiff Base condensation of two equivalents of o-aminophenol provides 2,3-(4-X-phenyl)2-1,4-(2- hydroxyphenyl)2-1,4-diazabutadiene. The ligand is given the moniker X-dabphol. These ligands are readily metallated to form M-X-dabphol complexes. The copper complexes catalytically fix CO2 with propylene oxide to yield propylene carbonate. DFT studies along with a comparison with Hammet parameters help validate and elaborate on the catalytic cycle and the catalytic results obtained. The nickel complex is competent for olefin epoxidation. Synthesis, characterization, X-ray structure, DFT analysis, and catalytic activity of the parent nickel dabphol complex are reported.