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The development of new strategies and associated reagents that enable previously inaccessible synthetic disconnections is largely attributing to the remarkable progress in exploring new chemical space for drug discovery and innovative complex molecule syntheses. In the Wengryniuk laboratory, we are devoted to discovering new synthetic methodologies that are based on umpolung or reverse polarity, strategies, enabled by Nitrogen-ligated (bis)cationic hypervalent iodine reagents (N-HVIs). I(III) N-HVIs represent an attractive new class of oxidant as they are environmentally benign, highly tunable, and have shown ability in enabling distinguished modes of reactivity. This dissertation focuses on demonstrating the synthetic utility of these N-HVI reagents towards C–O bond formation via a reverse polarity approach.In Chapter 1, a summary of the reactivity and characteristics of hypervalent iodine reagents is provided. Chapter 2 describes a mild and metal-free strategy for alcohol oxidation mediated by I(III) N-HVI reagents. This method demonstrates the first method for chemoselective oxidation of equatorial over axial alcohols and was the first in situ synthesis and application of N-HVIs for a simple one-pot procedure. Chapter 3 discusses a novel strategy for a dual C–H functionalization to access functionalized chroman scaffolds via an umpolung oxygen activation cyclization cascade. Computational studies in collaboration with Prof. Dean Tantillo (UC-Davis) along with experimental probes in our laboratory, support the formation of an umpoled oxygen intermediate as well as competitive direct and spirocyclization pathways for the key C–O bond forming event. The utility of the developed method is demonstrated through a downstream derivatization of the iodonium salt moiety to access C–H, C–X, and C–C substitution via established Pd-catalyzed cross couplings. Total synthesis of (±)-conicol natural product was performed in 8 steps and 23% overall yield, further demonstrating the synthetic utility of the developed method. Key synthetic steps include a smooth construction of the chroman core via N-HVI mediated C–H etherification of a pendant alcohol followed by a late-stage double bond installation. Overall, this dissertation summarizes the current state of research enabled by N-HVI reagents, with a focus on their utility in reverse polarity heteroatom activation strategies, and it serves as a practical guide for future development in the field. / Chemistry

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Nonalternant aromatic π-electron systems show promises for surface functionalization due to their unusual electronic structure. Based on our previous experiences for metal surfaces, we investigate the adsorption structures, adsorption dynamics and bonding characteristics of azulene and its alternant aromatic isomer naphthalene on the Si(001) surface. Using a combination of density functional theory, ab initio molecular dynamics, reaction path sampling and bonding analysis with the energy decomposition analysis for extended systems, we show that azulene shows direct adsorption paths into several, strongly bonded chemisorbed final structures with up to four covalent carbon–silicon bonds which can be described in a donor–acceptor and a shared-electron bonding picture nearly equivalently. Naphthalene also shows these tetra-σ-type bonding structures in accordance with an earlier study. But the adsorption path is pseudo-direct here with a precursor intermediate bonded via one aromatic ring and strong indications for a narrow adsorption funnel. The four surface-adsorbate bonds formed lead for both adsorbates to a strong corrugation and a loss of aromaticity.

Dropp-genereringstekniker är viktiga för industrier som läkemedelsindustrin, livsmedelsindustrin, kosmetikindustrin etc. Traditionella droppgenereringstekniker är dock begränsade i mängden av material som kan processas till droppform. Ett exempel inkjet som är en väletablerad teknik för att generera droppar med hög hastighet (1-10 kHz) och precision (10-20 μm), men kan bara stöta ut vätskor med låga viskositet, ungefär 10-100 gånger viskositeten av vattnet. Akustophoretisk utskrift motiv är att övervinna denna materialbegränsning och har framgångsrikt avkopplat dropputstötning från bläckviskositet. Metoden utnyttjar ickelinjära akustiska krafter för att skriva ut en stor mängd av material med hög kontroll, med viskositet som sträcker sig över fyra storleksordningar (0,5 mPa · s till 25 000 mPa · s). Emellertid är utstötningen baserad på bildandet av en hängande droppe, och i den aktuella prototypen begränsas materialpaletten av akustophoretisk utskrift genom sprider sig över munstycket, vilket begränsar den minsta tillåtnas ytspänningen till ungefär 60 mN / m. I detta arbete införs en munstycksbeläggningsteknik för att expandera mängden av utskrivbara material, med tillåtna ytspänningar så låga som 25 mN / m. Genom att utnyttja generera nanostrukturer med låg ytenergi på munstyckspetsen, tillverkas superavstötande beläggning. Grunden för nanostrukturerna genererades med hjälp av sot från ett paraffin-vaxljus. Ett robust tillverkningsprotokoll har etablerats, och beläggningen fysikaliska egenskaper och prestanda har karaktäriserats. Tre nya tillämpningsområden undersöktes, vilket demonstrerade noviteten hos denna nya metod. Detta arbete banar vägen för en ny uppsättning material som ska behandlas i en droppe-per droppe metodik. / Droplet generation techniques are essential for industries such as the pharmaceutical, food industry, cosmetic industry, etc. However, traditional droplet generation techniques are limited in the palette of materials that can processed in a droplet form. For example, inkjet which is a well-established technology to generate droplets of high speed (1-10 kHz) and precision (10-20 μm), but can only eject fluids with low viscosities, roughly 10-100 folds the one of water. Acoustophoretic printing aims to overcome this material limitation and have successfully decoupled droplet ejection from ink viscosity. The method harnesses nonlinear acoustic forces to print a wide range of materials on demand, spanning over four orders of magnitudes (0.5 mPa·sto 25,000 mPa·s). However, the ejection is based on the formation of a pendant drop, and in the current prototype, the material palette of acoustophoretic printing is limited by nozzle wetting, limiting the allowable minimum surface tension to about 60 mN/m. In this work, a nozzle coating technique is introduced in order to expand the material window by processing fluid with a surface tension as low as 25 mN/m. By leveraging self-assembling of nanostructures on the nozzle tip, superamphiphobic coating is successfully manufactured by using a candle soot template.A robust manufacturing protocol has been established, and the coating characterized in its physics and performance.

Nitrogen is a vital element for the existence of life, as shown by its frequent presence in essential biomolecules, and inclusion into valuable drugs. Sulfonamides and their heterocycle counterpart, sultams, are N-containing functional groups and metabolically stable amide isosteres. Sulfa drugs, which contain these moieties, have a broad spectrum of medical applications. The industrial value of sultams has prompted the development of novel methods for their synthesis, and metal-catalyzed C-H amination reactions with nitrene precursors have recently shown promise. The current thesis presents a survey of conditions for benzo[d]sultam synthesis via intramolecular C-H amination of N-acyloxysulfonamides. Initially, using Ru(Bpy)3(PF6)2 as a photocatalyst and Et3N as a base enabled benzo[d]sultam formation by tertiary C-H amidation. The photoredox conditions were optimized to accommodate other 2,6-disubstituted-N-acyloxysulfonamides upon omission of the base, which consistently gave sulfonamide byproducts. Control reactions indicated that a thermal base-induced reaction was simultaneously occurring, both enabling productive C-H amidation and byproduct formation. Systematic optimization of base-induced conditions enabled sultam synthesis from 2,6-dialkyl- and tertiary ortho-monoalkyl-precursors in moderate yield, but sulfonamide formation still impeded the reaction.   An additional control reaction indicated that a thermal Ruthenium-catalyzed C-H amidation reaction was possible. Indeed, heating N-acyloxysulfonamides in the presence of Ru(Bpy)3(PF6)2 and in the absence of light and base enabled efficient C-H amidation, particularly with DCE as a solvent. A representative scope of 12 benzo[d]sultams was then synthesized including entries derived from ortho-monoalkyl-N-acyloxyarylsulfonamides. Aside from optimizing an efficient reaction for the synthesis of benzo[d]sultams through the cyclization of N-acyloxyarylsulfonamides, including the challenging primary C-H amidation of orthomonomethyl-substrates, the unique reaction conditions developed in this thesis set precedent for future investigation of hydroxylamine derived nitrene precursors. The optimization and design of superior ruthenium catalysts could allow for more challenging C-H amination reactions with hydroxysulfonamide derivatives and similar N-oxy nitrene precursors.

Functionalized poly(para-xylylene) (PPX) coatings can be useful for biomaterials applications due to their biocompatibility and useful chemistry for the immobilization of biomolecules. However, their application is not widespread due to the difficulty in synthesizing the corresponding precursors. Here, a two-step method for amine functionalization of [2.2]paracyclophane (PCP) via direct nitration and reduction is developed. Nitration at super acidic conditions and temperatures as low as -78 °C, improved the stability of PCP toward strong acids and successfully minimized side reactions such as oxidation and polymerization. This procedure resulted in quantitative yields of 4-nitro-PCP, which was successively reduced by Raney nickel catalysis with sodium borohydride. Compared to the many other reduction systems, this method is simple, inexpensive and applicable in large scales. Additionally, carboxylation of PCP using the Freidel-Crafts acylation was attempted and so far, we have been able to show the synthesis of intermediate acylated products. Then, through the chemical vapour deposition polymerization of amino-PCP amine-functionalized poly(para-xylylene) (PPX-A) thin films were coated on Si wafer substrates. The substrates coated with PPX-A showed a higher surface energy compared with those of coated with un-substituted or chlorine substituted PPX films. Furthermore, results of the surface characterization demonstrated that the CVD process was able to transfer the functionalities of the precursors to deposited polymer films without alteration. However, the stability of primary amine groups in air and aqueous solutions is a matter of concern. Aging of amino-PCP and corresponding PPX-A films showed a decrease in the amount of primary amines which was accompanied by the appearance and increase of oxygen, indicating that the decrease of available amine groups is associated with oxidation. Nevertheless, both aminated precursor and polymer films remained intact under argon. The method presented here has great potential for widespread application of PPX-A as a convenient biomaterial for microarrays and cell culture. / Thesis / Master of Science (MSc)

Functionalized reactive polymer coatings can be used in various biomaterials applications such as immunoassays and biomolecule immobilization. Poly(para-xylelene) is a relatively new biomaterial that has attracted attention over the past few decades in these areas due to its unique properties and biocompatibility. The introduction of functionalized, particularly aminated, poly(para-xylylene) will extend the application of these polymer coatings to a wide variety of biological studies. However, their application is not widespread due to the difficulty in synthesizing the corresponding precursors. Here, a two-step method for amine functionalization of [2.2]paracyclophane via direct nitration and reduction is developed. Nitration at super acidic conditions and temperatures as low as -78 °C, improved the stability of [2.2]paracyclophane toward strong acids and successfully minimized side reactions such as oxidation and polymerization. This procedure resulted in quantitative yields of 4-nitro[2.2]para-cyclophane, which was successively reduced by Raney nickel catalysis with sodium borohydride. Compared to the many other reduction systems, this method is simple, inexpensive and applicable in large scales. It does not require harsh reaction conditions and within short reaction times, delivers quantitative amounts of the reduced product. At the end, 4-amino[2.2]paracyclophane was collected in 77% overall yield. Additionally, carboxylation of [2.2]paracyclophane using the Freidel-Crafts acylation was attempted and so far, we have been able to show the synthesis of intermediate acylated products. The successful syntheses of products were verified by FT-IR, NMR and MS, and comparison of their solubility and physical properties showed significant changes upon substitution of the pristine [2.2]paracyclophane. Then, through the chemical vapour deposition polymerization of 4-amino[2.2]paracyclophane amine-functionalized thin films were coated on Si wafer substrates and their properties were compared with Parylene N and C, two well-known poly(para-xylylene) films. The substrates coated with amino-poly(para-xylylene) showed a higher surface energy compared with those of coated with un-substituted or chlorine substituted poly(para-xylylene) films. Furthermore, results of the surface characterization conducted by grazing angle reflectance IR spectroscopy and XPS, demonstrated that the CVD process was able to transfer the functionalities of the precursors to deposited polymer films without alteration. However, with the applied process parameters we obtained a higher functional density of amine groups on the surface. These polymer films can be deposited on a variety of substrates and be used as functional surfaces for a variety of applications. However, the stability of primary amine groups in air and aqueous solutions is a matter of concern. Aging of 4-amino-[2.2]paracyclophane and corresponding poly(para-xylylene) films in air and mili-Q water was studied via XPS and NMR spectroscopies. The results showed a decrease in the amount of primary amines with storage time in air or water for both aminated precursor and polymer. The kinetics for these changes, however, were not equal for the precursors and polymer films. The decay of amine groups was accompanied by the appearance and increase of oxygen, indicating that the decrease of available amine groups is associated with oxidation which can transform them to more stable amide and nitro compounds. In total, practical challenges involved in manufacture, durability and applications of amine-functionalized Parylene coatings are discussed and a reliable scheme for fabricating such films with high tunabiliy of the surface functional density is demonstrated. The highly practical method presented here provides great potential for widespread application of amine-functionalized poly(para-xylylene) as an outstanding biomaterial for microarrays, tissue engineering and cell culture studies. / Thesis / Master of Science (MSc)

<p>  </p> <p>Alkyl radicals are powerful intermediates for the generation of carbon-carbon bonds, which play an indispensable role in the synthesis of natural products, pharmaceuticals, and pesticides. Traditionally, there are two main methods for the generation of alkyl radicals. The first is C-H bond functionalization via hydrogen-atom-transfer (HAT). HAT processes have been used as an effective approach for selectively activating C-H bonds via radical pathways. The other strategy to explore the generation of alkyl radicals is C-X bond functionalization via halogen-atom-transfer (XAT). Alkyl halides are one of the largest classes of building blocks in synthesis and they can be obtained from the corresponding alcohols. The most straightforward and effective way to form such alkyl radicals is the direct homolytic cleavage of C-X bonds. In past decades, photoredox catalysis has emerged as a powerful and greener tool for the synthesis of radicals under mild reaction conditions, which has brought tremendous attention. Although remarkable success has been made in this field, some methods still require costly transition metal catalysts or toxic reagents. Herein, we display a series of visible light-induced approaches under transition-metal free conditions or using earth-abundant metals. These novel photo-induced transformations and corresponding mechanistic work will be discussed in the following order:</p> <p>We will first present our work on metal-free visible-light-promoted C(sp3)-H functionalization of aliphatic cyclic ethers using trace O2.  This reaction uses a trace amount of aerobic oxygen as the sole green oxidant under blue light at room temperature to achieve the synthesis of sulfone and phosphate derivatives in good to excellent yields using cyclic ethers and vinyl sulfones. Then, we report on a photo-induced C(sp3)-H chalcogenation of amide derivatives and ethers via a ligand-to-metal charge-transfer. This reaction converts secondary and tertiary amides, sulfonamides, and carbamates into the corresponding amido-<em>N,S</em>-acetal derivatives in good yields, using an earth abundant metal catalyst under mild conditions.</p> <p>Finally, we present a photoredox polyfluoroarylation of alkyl halides via halogen atom transfer. This method converts primary, secondary, and tertiary unactivated abundant alkyl halides into the corresponding polyfluoroaryl compounds in good yields and has good functional group compatibility.</p>