Nitrogen-containing heterocyclic compounds are very important to the pharmaceutical and agrochemical industries, among others. Over the past few years, the Beauchemin group has been exploring reactivity of N-substituted isocyanates and as part of this has developed a metal-free alkene aminocarbonylation process relying on imino-isocyanates to form azomethine imines. The azomethine imines formed are interesting since they contain a cyclic β-aminocarbonyl motif. Catalysis of this reaction using basic additives allowed milder reaction conditions with electron-rich C=C bonds such as enol ethers. Efforts have also been made towards the derivatization of these azomethine imines into useful products. It was discovered that upon reduction and aromatization of azomethine imines, pyrazolones could be obtained. This is providing a novel modular approach to these compounds, which have relevance in pharmaceuticals and agrochemicals. This reactivity was extended to include imino-isothiocyanates.

In modern synthetic organic chemistry, chemists are driven to develop efficient methods for important C-C and C-N bond formation reactions. The challenge lies with establishing new uses for readily available substrates. In this regard, the synthesis of β-aminocarbonyl compounds from alkenes remains a long-standing challenge. Innovation in reaction discovery often requires finding new reagents, or rare reagents with underappreciated value in synthesis. In Chapter 1, N-isocyanates and other heterocumulenes are introduced as versatile amphoteric reagents. Their amphoteric properties are valuable in the discovery of new synthetic approaches, especially in cycloaddition reactions. While C-isocyanates are bulk industrial chemicals, the formation and reactivity of N-isocyanates remains underexplored. Chapter 2 describes the development of reactivity with rare imino-isocyanates. This includes methods to access the reagent in situ with a blocking group approach, and the establishment of intermolecular cycloaddition reactivity with a variety of alkenes. This stereospecific reaction provides complex N,N’-cyclic azomethine imines, and enables access to β-aminocarbonyl compounds from alkenes. β-Amino amides and esters, pyrazolidinones, and pyrazolones were accessed by reductive derivatization of the aminocarbonylation products. Exploration into the limits of this reactivity gave insight into fundamental properties of imino-isocyanates. This includes the first detection of imino-isocyanates by IR spectroscopy. A kinetic resolution of the azomethine imines obtained from this alkene aminocarbonylation reaction was then developed, which gave access to enantioenriched β-amino carbonyl compounds (Chapter 3). This was accomplished by Brønsted acid catalysed reduction, with a selectivity factor of 13-43. This was the first example of the enantioselective reduction of azomethine imines, and represents a new activation mode for reactions of N,N’-cyclic azomethine imines. Using this reductive method, both enantiomers of the β-amino amide could be obtained from a racemic azomethine imine in ≥ 97% ee. The discovery of new reactivity of imino-isocyanates with imines in described in Chapter 4, which allowed the synthesis of eight new azomethine imines with the triazolone core. Our initial scope studies revealed different trends with imines than with alkenes, including increased reactivity, which led to investigation of the mechanism of this reaction. In addition, this was shown to be a valuable new approach for the synthesis of triazolones from imines.

Nanoparticles promise many interesting applications because of their exceptional chemical and physical properties. Therefore nanoparticles offer a pathway for the fabrication of new functional, smart materials. Since the primary particle strongly tends to strong agglomeration, and since the surface of nanoparticles is often not compatible with polymers, it is not possible to disperse single particles homogeneously in a polymer melt. Formations of agglomerates are responsible for strong differences in concentration of the nanoparticles in the material matrix and therefore impede a homogeneous property profile. Furthermore properties of compounds are not only determined by single components, but considerably by the interface between these single components. Hence, a strong chemical and physical adhesion between the constituents is required. Thus, surface modification of nanoparticles is a crucial issue. This work focuses on the control of the particle/polymer interface in composite materials which has a thickness of some nanometers. This interface regulates the compatibility of the surface of the nanoparticles and their environment. This interface is also the place where the transmission of energy between nanoparticle and polymer occurs. The interlayer of this boundary surface should be occupied with functional “primer”-macromolecules that provide at least two types of functional groups: one species of functional group should assure the bonding of the primer to the surface of the nanoparticle, and the second type enables the compatibilizing to the matrix, and when indicated also the covalent adhesion to the ambient polymer system. The macromolecular scaffold of the primer permits the selective adjustment of important interface properties as elasticity, durability and the surface energy of the particle – matrix interface. Within this thesis hyperbranched polyethylene (PEI) imine was used as starting platform for “Quat-Primer Polymers” bearing a multitude of functional moieties in form of primary, secondary and tertiary amino groups. Chapter 2 gives a literature – review on hyperbranched polymers – with focus on PEI, stabilization of colloids by polymers, as well as polymer – “nanocomposites”. In Chapter 3 the reaction of PEI with glycidyltrimethylammonium chloride will be described to obtain hyperbranched polymers that consist of (i) the hyperbranched PEI scaffold, (ii) primary, secondary and tertiary amino groups that can be used for further modification reactions with amino-reactive compounds, and (iii) ammonium moieties that can adsorb to negatively charged surfaces. It will be shown that these Quat-Primer polymers have the ability to stabilize several nanoparticles in water to form aqueous dispersions and that they are capable to partially deagglomerate nanoparticles leading to smaller diameters of the particles in the dispersion. Additionally the reaction of hyperbranched polyethylene imine with glycidol will be described displaying a possibility to change the reactivity of the functional groups and exhibiting that also the generated hydroxyl groups generated by the ring-opening reaction of epoxides with PEI react with epoxide rings to form ether linkages. In Chapter 4 the synthesis of several amino-reactive ATRP initiators will be described and two methods to graft PMMA arms to “Quat-Primer polymers” presented in the previous chapter including the “grafting from” and the “grafting to” technique. These synthesized Quat-Primer polymers bearing ammonium moieties, as well as PMMA arms can be used to fabricate PMMA nanocomposites with homogeneously distributed nanoparticles. The developed method allow for grafting monomers that can be used in ATRP polymerization, including acrylates, acrylonitriles and styrenes, to hyperbranched polyethylene imine. Chapter 5 will display pathways to graft caprolactam derivatives to hyperbranched polyethylene imine to generate Quat-Primer polymers bearing ammonium moieties, as well as caprolactam rings. These quat-primer polymers can be used for the fabrication of PA-6 nanocomposites by dispersing nanoparticles in presence of these Quat-Primer polymers and subsequent polymerization.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第17773号 / 理博第3896号 / 新制||理||1562(附属図書館) / 30580 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 大須賀 篤弘, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18094号 / 理博第3972号 / 新制||理||1573(附属図書館) / 30952 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 時任 宣博, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

The addition of isocyanates to C=N double bonds of imines gives triazindione heterocycle structures; their thermal properties are reported. Mono-isocyanates were used to form 2:1 adducts with the imine bases 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (tBuTMG). A 2:1 stoichiometry of the adducts was proven by NMR and IR spectroscopy, and single crystal X-Ray diffraction; certain cleavage temperatures (70 and 160 °C) were measured. Thermal analysis (TG-MS) of adducts indicates the release of free isocyanate during adduct cleavage. Furthermore, a new class of step-growth oligomers (MN = 750–7,000 g∙mol–1) composed of multi-functional isocyanates and these imine bases was introduced. Their systematic spectroscopic and thermal analysis is shown revealing the similarity in their chemical properties to the 2:1 adducts. Radical homo- and copolymerization of acrylates is initiated by the meta-stable adducts and oligomers of this work; the generation of novel telomeric block-copolymer architectures composed of polyacrylate and oligourea building blocks is demonstrated. / Dieser Beitrag ist aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Among non-viral vectors, cationic polymers, such as poly(propylene imine) (PPI), play a prominent role in nucleic acid delivery. However, limitations of polycationic polymer-based DNA delivery systems are (i) insufficient target specificity, (ii) unsatisfactory transgene expression, and (iii) undesired transfer of therapeutic DNA into non-target cells. We developed single-chain antibody fragment (scFv)-directed hybrid polyplexes for targeted gene therapy of prostate stem cell antigen (PSCA)-positive tumors. Besides mono-biotinylated PSCA-specific single-chain antibodies (scFv(AM1-P-BAP)) conjugated to neutravidin, the hybrid polyplexes comprise -cyclodextrinmodified PPI as well as biotin/maltose-modified PPI as carriers for minicircle DNAs encoding for Sleeping Beauty transposase and a transposon encoding the gene of interest. The PSCA-specific hybrid polyplexes efficiently delivered a GFP gene in PSCA-positive tumor cells, whereas control hybrid polyplexes showed low gene transfer efficiency. In an experimental gene therapy approach, targeted transposition of a codon-optimized p53 into p53-deficient HCT116p53 /PSCA cells demonstrated decreased clonogenic survival when compared to mock controls. Noteworthily, p53 transposition in PTEN-deficient H4PSCA glioma cells caused nearly complete loss of clonogenic survival. These results demonstrate the feasibility of combining tumor-targeting hybrid polyplexes and Sleeping Beauty gene transposition, which, due to the modular design, can be extended to other target genes and tumor entities.

There are numerous advantages of replacing traditional non-biodegradable synthetic plastics with bio-based plastics. Starch is globally available, cheap, renewable, and biodegradable. However, starch has a poor product performance and is relatively difficult to process, as conventional melt processing techniques cannot be used. By introducing thermoplastic properties to starch, the mechanical properties and processability can be enhanced. The aim of the project was to modify starch and give it thermoplastic properties. The implementation of this included various experiments, where aromatic, cyclic and aliphatic side groups were added to the biopolymer. The effect of the different side groups provided valuable insight into how the material properties changed. Subsequently, the thermoplastic properties of the modified starch were analyzed by different analytical methods, including Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC). In conclusion, the TGA showed lower thermal stability in the functionalized starch compared to native starch. Some indications of thermoplastic behavior were observed from the DSC. Trade-off between functionality and thermostability needs to be overlooked when aiming to increase thermoplastic behavior and future work should explore TEMPO oxidation, to obtain better results from the TGA. / Det finns många fördelar med att ersätta traditionella, icke-biologiskt nedbrytbara syntetiska plaster med biobaserade plaster. Stärkelse är globalt tillgängligt, billigt, förnybart och nedbrytbart. I nuläget har stärkelse dock en bristande produktprestanda och är relativt svår att bearbeta eftersom konventionella smält bearbetningstekniker inte kan användas. Genom att ge stärkelse termoplastiska egenskaper kan man förbättra de mekaniska egenskaperna och bearbetbarheten. Syftet med projektet var därför att modifiera stärkelse och introducera termoplastiska egenskaper. Genomförandet av detta innefattade flera olika experiment där aromatiska, cykliska och alifatiska sidogrupper tillsattes till stärkelsen. Effekten av de olika sidogrupperna gav värdefull insikt i hur materialegenskaperna förändrades. Därefter analyserades de termoplastiska egenskaperna hos den modifierade stärkelsen med olika analytiska metoder, inklusive Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric analysis (TGA) och Differential Scanning Calorimetry (DSC). Slutsatsen var att TGA visade en lägre termisk stabilitet hos den funktionaliserade stärkelsen jämfört med i den naturliga stärkelsen samt att vissa indikationer på termoplastiskt beteende observerades med hjälp av DSC analysen. En avvägning mellan funktionalitet och termisk stabilitet bör tas i beaktande i strävandet efter att öka termoplastiskt beteende. Framtida arbete inom ämnet rekommenderas att utforska TEMPO-oxidation för att uppnå bättre resultat från TGA.

No description available.

No / Scytonemin-imine, a novel derivative of scytonemin, has been isolated and identified very recently and proposed to serve as a photoprotective biomarker for certain bacteria growing under intense photon flux density. This study predicts theoretically the Raman spectrum of scytonemin-imine by density functional theory calculations and provides comparison of major bands to those of scytonemin, the parent compound for which both the experimentally characterized and theoretically predicted spectra exist in the literature. It is proposed to be an addendum to the collection of our previous work on scytonamin and its derivatives to facilitate recognition of the diagnostic Raman spectral signatures for scytonemin-imine.