[No abstract submitted] / Science, Faculty of / Chemistry, Department of / Graduate

Thesis (Ph. D.)--University of Wisconsin--Madison, 1958. / Typescript. Abstracted in Dissertation abstracts, v. 19 (1959) no. 8, p. 1924. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaf 85).

A cyclic ketene acetal is an olefin that is substituted at one end by two electrondonating hetero atoms, like O, N, S, where these heteroatoms are connected together by a chain. Delocalization of the lone pair electrons of the two hetero atoms to the double bond makes the β-carbon (the exocyclic methylene carbon) electron rich and nucleophilic. A major goal of cyclic ketene acetal chemistry is to provide functionalized cyclic ketene acetal monomers as precursors to polymers of desired properties. The cyclic ketene-N,O-acetal 3-methyl-2-methylene-oxazolidine, generated in situ from 2-methyl-2-oxazolinium iodide and triethylamine, reacted with aryl isocyanates in refluxing THF to give α,α-bis(N-arylamido) lactams via the iodide-catalyzed rearrangement of β,β–bis(N-arylamido) cyclic ketene-N,O-acetal intermediates. However, similar β,β–bis(N-arylamido) cyclic ketene-N,O-acetals having two methyl substituents at C-4, did not rearrange due to hindrance of the iodide attack on C-5. 3,4,4-Trimethyl-2-methylene-oxazolidine reacted with aryl chloroformates to form both mono- and di-aryloxycarbonylation adducts. The two methyl groups at C-4 Template Created By: Damen Peterson 2009 hindered the alternative polymerization route. 3-Methyl-2-methylene-oxazolidine, which does not have two methyl groups at C-4, underwent cationic polymerization under identical conditions. Benzoylation of 2-methyl-2-oxazoline with benzoyl chloride gave a ring-opened N,C,O-trisbenzoylation product via O-benzoylation of the N,C-bisbenzoylated intermediate, followed by chloride attack on C-5. The N,C,O-trisbenzoylated product underwent N,O-double debenzoylation by KOH to give the cyclic ketene-N,O-acetal, 2- oxazolidin-2-ylidene-1-phenylethanone. This compound (an ambident nucleophile), upon deprotonation, reacted with benzoyl chloride to give the β,β-bisbenzoylated cyclic ketene-N,O-acetal, and reacted with phenyl chloroformate to give a novel heterocycle, [1,3]oxazine-2,4-dione. The benzoylation of 2-methyl-2-oxazine gave a similar ringopened N,C,O-trisbenzoylation product. Reactions of 2-methyl-2-oxazoline, 2,4,4-trimethyl-2-oxazoline and 2-methyl-2- thiazoline with trifluoroacetyl anhydride gave C-trifluoroacetylated cyclic ketene-N,O(S)- acetals. However, trifluoroacetylation of 2-methyl-2-oxazine gave the β,β- bistrifluoroacetylated cyclic ketene-N,O-acetal. In summary, a novel iodide-catalyzed rearrangement of β,β–bis(N- arylamido)- cyclic ketene-N,O-acetals was found. The [1,3]oxazine-2,4-dione heterocycle synthesized during this research also demonstrates the synthetic potential of cyclic ketene acetal chemistry in pharmaceutical industry. Functionalization of cyclic ketene acetals based on the chemistry developed in this work will find applications in polymer industry.

No description available.

This dissertation focuses on the synthesis and characterization of an exciting new family of thermoresponsive polyacetal polymers with remarkable properties that are well suited for a myriad of applications. The new polyacetals are the first, intrinsically biodegradable polymers to exhibit a lower critical solution temperature (LCST). Their LCSTs are linearly dependent on the number of carbon and oxygen atoms in the repeat units, which can be easily adjusted over a wide range of temperatures. The LCSTs can be precisely and predictably tuned to any temperature ranging from 7-80°C by simply using mixtures of monomers during synthesis. The LCST transition of polyacetals is sharp and shows no hysteresis. These new materials have the potential to be used in a broad range of technologies that are important not only economically, but also affect the quality of life. In particular, they have the potential to be used as a drug delivery carrier for treatment of pancreatic cancer; an illness that has a dismal prognosis, for which other treatments have proven ineffective. Polyacetals are known to be chemically inert; the primary thesis objectives presented here are to develop frameworks for polyacetal functionalization for use in a variety of applications. Chapter 3 explores strategies to prepare water-soluble polyacetal-drug conjugates from three HIF-1 inhibitors; a highly hydrophobic class of cancer therapeutics. HIF-1 inhibitors explored in this chapter have simple structures containing di-hydroxy functionalities, which can be used for polyacetal main-chain attachment. Step-growth polymerization is used to prepare, for the first time, main-chain drug conjugates that are temperature responsive and pH degradable. Furthermore, the temperature response of main-chain polyacetal-drug conjugates is precisely tuned with the amount of the HIF-1 in the polymer backbone. The pH dependent backbone degradation of the drug conjugates show that pristine HIF-1 inhibitors evolve from the polymer at long degradation times, showing promise for use of this material as a drug delivery vehicle. Strategies outlined in Chapter 3 require specific di-hydroxy functionalities in the molecules of interest, without which, functionalization is not possible. Therefore, Chapter 4 considers polyacetal functionalization of molecules with mono- or poly- hydroxy functional groups, further expanding the scope of these new materials. Two strategies of functionalization are presented, namely, end group functionalization and pendent-chain polyacetal-conjugation using click chemistry. End group functionalization of polyacetal is achieved during step-growth polymerization, in situ, using mono-hydroxy functional molecules. Pendent-chain polyacetal-conjugates are prepared using backbone alkyne functional polyacetal with specialized heterobifunctional linkers that enable the use of orthogonal chemistries such as click-chemistry. Importantly, end group and pendent-chain functional polyacetals retain their temperature response and degradation properties. Both polyacetals evolve pristine mono- functional payloads at the onset of the degradation cycle in contrast to main-chain polyacetal-drug conjugates, which evolve the payload towards the end of the degradation cycle. Knowledge of both degradation mechanisms allows for precise control over the degradation profile of the resulting polyacetals. Chapter 5 further expands on the thesis objectives by the synthesis of ABA type polyacetal block co-polymers and micelles. Polyacetal block co-polymers encapsulate virtually any type of hydrophobic molecule of interest, significantly expanding the number of molecules that can be incorporated into polyacetals. For this purpose, click-functional polyacetal macromonomers are prepared and end-linked with the polymer. The resulting polyacetal micelles show remarkable temperature response, by a second-order θ collapse exhibited by base-polyacetals, and by coacervation of the individual micelles. The temperature response for polyacetal block co-polymers is sharp and reversible, with minimal hysteresis. Pyrene encapsulation studies conducted with polyacetal micelles show that, upon degradation, 99% the encapsulated pyrene is released, showing great promise for use of polyacetal block co-polymers as a delivery vehicle for a variety of applications. Using the methods outlined in Chapter 3-5, virtually any molecule of interest can be incorporated into the polyacetal chain. Lastly, the fundamental origins of the LCST behavior of PAs are explored using molecular dynamic simulations in Chapter 6. For this purpose, PA chains of 10,000 g/mol are accurately modeled using coarse-graining techniques. The experimental LCST transition is reproduced with an accuracy of ±20°C using the coarse grained model, which allows for precise prediction of the temperature response using simulations. The model is further expanded to obtain sequence transferability; that is, the LCST behavior of any sequence or architecture that consists of poly(ethylene oxide) and methylene units can be modeled with precision using this model. We also present sample conformations of the polyacetal during its coil-globule transition, which provides a degree of insight into the mechanism of the LCST.

Tese de doutoramento. Engenharia Química. Faculdade de Engenharia. Universidade do Porto. 2006

Thesis (Ph. D.)--University of Pennsylvania, 1934. / "Reprint from the Journal of physical chemistry, vol. 39, no. 4, and no. 6, 1935." "References: " p. 13, 23.

Thesis (Ph. D.)--University of Pennsylvania, 1934. / "Reprint from the Journal of physical chemistry, vol. 39, no. 4, and no. 6, 1935." "References: " p. 13, 23.

No description available.

This dissertation research is based on two reactions, including those of cyclic ketene acetals with acid chlorides and acid catalyzed olefination reactions in bio-oil. In first four chapters, reactions of in situ generated cyclic ketene acetals were explored. Highly functionalized heterocycles such as pyrrollo-[1,2-c]imidazolediones, were synthesized in one-pot reactions of 2-alkylimidazoles or 2-methylbenzimidazoles with 1,3-diacid chlorides. Some reactions proceed through in situ generated cyclic-N,N′-ketene acetal intermediates. 2-Alkylimidazoles and 2-methylbenzimidazole can be considered as tridentate nucleophiles in these reactions that can give four consecutive attacks on electrophiles which ultimately generate new heterocycles. Reactions of substituted oxazoles and thiazoles with different acid chlorides in the presence of different bases were explored. Arylvinyl esters of substituted benzoic acids containing substituted oxazoles or thiazoles were formed when aroyl chlorides were used. Most reactions occurred through in situ generated cyclic ketene acetals. Reactions of 2-methylbenzoxazole and 5-phenyl-2-methylbenzoxazole with acid chlorides and base in THF generated a series of ortho-amidoesters. All of these reactions showed that aromatic heterocycles based in situ generated cyclic ketene acetals could be used to make highly functionalized heterocycles under mild conditions. These one-pot reactions generated various heterocycles, which might have useful bioactivities. For example, arylvinyl esters of substituted benzoic acids have been reported to show insecticidal activities. The last two chapters describe the olefinations of bio-oil and model bio-oil compounds using acid catalysts. Two different branched olefins were used, representative of those available at petroleum refineries. Amberlyst-15 and Nafion NR-50 were used as heterogeneous acid catalysts. The acid catalyzed olefination of bio-oil was explored using an excess of 1- octene. Some olefinations were performed in the presence of ethanol. Ethanol was used to make the olefin and bio-oil phases partially miscible. Acid catalyzed olefination of raw bio-oil induced some changes in the resulting bio-oil by generating variety of alcohols, ethers and oligomeric mixtures of the starting olefin. Olefination with excess 1-octene showed the decrease of the water content and the acid value and increase of the heating value of the bio-oil. Thus, the acid catalyzed olefination of bio-oil can be considered as a potential bio-oil upgrading technique.