In this thesis, C-F bond activation and C-F bond construction under platinum and iridium catalysis is described. Chapter 1 provides a general introduction on the use of transition metal catalysis for the formation and activation of Csp³-F bonds in organofluorine compounds. In Chapter 2, an investigation on the reactivity of allylic fluorides, under platinum and palladium catalysed alkylation conditions, is presented. The relative reactivity of fluoride versus other commonly used leaving groups was compared via internal competition experiments. Fluoride showed a different reactivity profile, when subjected to Pt and Pd catalytic systems. Based on the observed reactivity trend, a Pd-catalysed fluorination reaction of allylic alcohol derivatives was successfully developed, within the group. In Chapter 3, a new iridium catalysed fluorination using branched, E- or Z-linear allylic carbonates is described. The catalyst [Ir(COD)Cl]₂ leads to an unexpected regio- and stereoretentive selectivity, affording fluorinated products not accessible via palladium catalysis. The effect of a fluoride additive on the selectivity of the Ir-catalysed alkylation reaction is also presented. A highly efficient ¹⁸F-fluorination variant for this new catalytic transformation is reported. Chapter 4 gives full experimental procedures and characterisation data for all compounds.

No description available.

No description available.

The detection of γ-rays from explosive astrophysical scenarios such as novae provides an excellent opportunity for the study of on-going nucleosynthesis in the Universe. Within this context, this work has addressed an uncertainty in the destruction rate of the 18F nucleus, thought to be the primary source of 511 keV γ-rays from novae. A direct measurement of the 18F(p,α )15O cross section has provided the opportunity to extract resonance parameters through the R-Matrix formalism. The inferred parameters of populated states in 19Ne include the observation of a broad 1/2+ state, consistent with a recent theoretical prediction, which will have a significant impact on the rate of destruction of this γ-ray producing radioisotope. The 18O(p,α )15N reaction follows similar nuclear and kinematic processes and is expected to occur in the hydrogen burning layers of AGB stars. Resonance widths have been extracted from a direct measurement in the region around a poorly constrained broad state close to the Gamow window. This has produced a new parameter set for future reference and provides new information on the reaction rate. The complex R-Matrix formalism used in these analyses is a crucial tool in the study of nuclear astrophysics reactions, and many codes have been written to implement the complex mathematics. This thesis presents a comparison of two publicly available codes from the JINA collaboration and a code used extensively by the University of Edinburgh. For this, the recent results of the 18F destruction reaction, presented here, have been used. A minor error was found within one of the codes, and corrected. The final parameters extracted, and the resulting cross sections calculations, are shown to be consistent between the three codes. A further γ-ray line of interest at 1.809 MeV, characteristic of 26Al decay, has been observed throughout the interstellar medium. If, however, this isotope is formed in a known isomeric state, its decay bypasses the emission of this γ-ray, thus complicating the interpretation of observed γ-ray fluxes. To this end, an experiment has been carried out, providing proof of principle of a direct measurement of the 26mAl(p,γ)27Si reaction. The calculation of the isomeric intensity is presented here.

The aim of this thesis was to investigate the synthesis and the conformational analysis of fluorinated pyrrolidines. We focused on two strategies namely, the iodoamination and fluoroamination of fluorinated precursors. Iodoamination Our first approach for the synthesis of fluorinated pyrrolidines relied on the iodocyclisation of allylic fluorides bearing pendant nitrogen nucleophiles. These allylic fluorides were obtained by fluorodesilylation of suitably functionalised allylsilanes. After validation of this methodology, the scope and limitations of the iodoamination were investigated. Furthermore, we were able to probe the influence of the fluorine moiety on the level of diastereocontrol of the cyclisation. Fluoroamination The second route focused on a key reaction: an unprecedented electrophilic fluoroamination of an aminated allylsilane. From a mechanistic point of view, the presence of the silyl group act as a 1,2-dipole and activate the double bond towards electrophilic fluorination. This methodology required the initial screening of a silyl directing group that would promote electrophilic addition, without subsequent desilylation. Finally, we investigated the level of diastereocontrol displayed by these cyclisations as a function of the E/Z geometry of the starting aminated allylsilane. Conformational analysis Moreover the 3-fluoropyrrolidines obtained via iodoamination served to investigate the stereoelectronic influence of the fluorine gauche effect on ring conformations. Solid state single crystal X-ray analysis and solution phase NMR spectroscopy were used for this purpose. Due to complicated conformational analysis of saturated five-membered rings in solution, 1D 19F-1H heteronuclear nOe (HOESY) experiments have been optimised for applications to this type of small molecules. These have been employed to estimate 19F-1H internuclear distances and were combined with vicinal 3JFH and 3JHH scalar coupling constants in order to analyse the ring conformations.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Development of Ru-Based Catechothiolate Complexes for Z-selective Ring-Opening/Cross-Metathesis and Cross-Metathesis. We have developed a broadly applicable Ru-catalyzed protocol for Z-selective ring-opening/cross-metathesis (ROCM). Transformations are promoted by 2.0–5.0 mol % of a Ru-based catechothiolate complex, furnishing products in up to 97 % yield and >98:2 Z:E ratio. The Z-selective ROCM processes are found to be compatible with terminal alkenes of different sizes that include the first examples involving heteroaryl olefins, 1,3-dienes, and O- and S-substituted alkenes as well as allylic and homoallylic alcohols. Reactions with an enantioenriched α-substituted allylic alcohol are shown to afford congested Z-olefins with high diastereoselectivity. The insights gained from these investigations provided the impetus to develop electronically modified Ru catechothiolate catalysts that are readily accessible from a commercially available dichloro-Ru carbene and an easily generated air-stable zinc catechothiolate. The new complex is effective in catalyzing Z-selective cross-metathesis (CM) of terminal alkenes and inexpensive Z-2-butene-1,4-diol to directly generate linear Z-allylic alcohols, including those that bear a hindered neighboring substituent or reactive functionalities such as a phenol, an aldehyde or a carboxylic acid. Transformations typically proceed with 5.0 mol % of the catalyst within 4–8 hours under ambient conditions, and products are obtained in up to 80% yield and 98:2 Z:E selectivity. Utility is highlighted through synthesis of a molecular fragment en route to anti-tumor agent neopeltolide and in a single-step stereoselective gram-scale conversion of renewable feedstock to synthetically valuable Z-allylic alcohols. Chapter 2. Kinetically Controlled Z- and E-Selective Cross-Metathesis to Access 1,2- Disubstituted Alkenyl Halides. We have discovered that previously unknown halo-substituted molybdenum alkylidenes are capable of participating in highly efficient olefin metathesis reactions that afford linear 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by 1.0–10.0 mol % of a Mo-based pentafluorophenylimido monoaryloxide pyrrolide (MAP) complex that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, delivering a myriad of alkenyl chlorides, bromides and fluorides in up to 91% yield and >98:2 Z:E ratio. Through mechanism-based modification of the aryloxide ligand, a newly synthesized Mo-based MAP complex was shown to be effective in promoting kinetically controlled E-selective CM to access the corresponding thermodynamically less favored E-isomers of alkenyl chlorides and fluorides. Reactions typically proceed within 4 hours at ambient temperature with 1.0–5.0 mol % of the catalyst, which may be utilized in the form of air- and moisture-stable paraffin pellets. Utility of the aforementioned protocols is demonstrated through preparation of biologically active compounds and related analogues as well as late-stage site- and stereoselective fluorination of complex organic molecules. Chapter 3. Molybdenum-Based Chloride Catalysts for Z-Selective Olefin Metathesis. A new class of Mo-based monoaryloxide chloride (MAC) complexes for Z-selective olefin metathesis has been developed. The MAC catalysts are capable of promoting CM with commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene to furnish the higher-energy Z-isomers of trifluoromethyl-substituted alkenes in up to 95% yield and >98:2 Z:E selectivity. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloroethene and 1,2-dibromoethene can be accomplished with appreciably improved efficiency and Z-selectivity. The method enables synthesis of biologically active compounds and CF3-analogues of medicinally relevant molecules. Density functional theory (DFT) calculations shed light on the origins of the activity and selectivity levels observed in these transformations. Chapter 4. Stereoselective Synthesis of Z- and E-Trisubstituted Alkenes by Merging Cross-Coupling with Cross-Metathesis. We have discovered that challenging acyclic E- and Z-trisubstituted alkenes, particularly alkenyl chlorides and bromides, can be accessed efficiently and in high stereoisomeric purity (up to >98% E and 95% Z) through a sequence involving catalytic cross-coupling followed by stereoretentive CM promoted by Mo-based catalysts. Initial exploratory studies with 1,1-disubstiuted alkenes revealed crucial mechanistic features of the transformations that led us to utilize readily accessible trisubstituted olefins as substrates, in combination with commercially available 1,2-dihaloethenes as cross-partners for CM. Applications to synthesis of biologically active compounds and synthetic precursors underscore utility. The stereoretentive transformations may be extended to trisubstituted non-halogenated alkenes such as aliphatic olefins. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

As hidroxiapatitas (HA) são amplamente utilizadas como biomateriais osteocondutores, mas não possuem propriedades osteoindutoras e osteogênicas. O fluoreto, por sua vez, quando presente no meio em doses adequadas (da ordem de 10-5 M), é capaz de aumentar a proliferação de osteoblastos e a atividade da fosfatase alcalina. Assim, o objetivo do presente estudo foi modificar um biomaterial existente, constituído por HA bifásica (70% HA + 30% β-TCP) porosa, pela adsorção de fluoreto. A capacidade de liberação de fluoreto deste material para meio de cultura osteogênico foi também avaliada. Foi ainda feita caracterização físicoquímica do material com fluoreto adsorvido, em comparação ao material original (FTIR, DRX e MEV). Para os ensaios de adsorção de fluoreto, soluções com diferentes concentrações deste elemento, na forma de NaF, foram adicionadas à HÁ bifásica na proporção de 10 g de HA por 50 mL de solução contendo fluoreto. Os testes foram feitos em duas etapas. Na primeira etapa, as concentrações de fluoreto empregadas variaram entre 100 e 2000 ppm e foi feita incubação por 3, 6, 18 ou 24 h, em temperatura ambiente, sob agitação constante. Após estes intervalos de tempo, removeu-se o sobrenadante e colocou-se o restante na estufa a 40oC, até a completa secagem dos grânulos. Os mesmos foram armazenados para posterior quantificação de fluoreto adsorvido, que foi feita com o eletrodo, após difusão facilitada por exametildisiloxano. Na segunda etapa, as concentrações de fluoreto empregadas variaram entre 0,625 e 80 ppm, sendo feita incubação por 24 ou 48 h. Para a avaliação da liberação de fluoreto da HA adsorvida, as amostras de HA com fluoreto adsorvido foram incubadas à temperatura ambiente com meio de cultura α-MEM, na proporção de 10 g de HA por 50 mL de meio, sob agitação, por 3, 6, ou 24 h e o sobrenadante foi coletado para quantificação de fluoreto. Foi observada uma relação dose- resposta entre a concentração de fluoreto que se adsorveu à HA e concentração de fluoreto presente nas soluções em que a HA foi incubada. O tempo de incubação nas soluções fluoretadas não alterou a concentração de fluoreto adsorvido (exceto para uma diminuição da adsorção para o tempo de 48 h). A porcentagem de adsorção de fluoreto variou entre 15 e 35%. Houve uma redução na concentração de fluoreto liberada para o meio, em função da redução da concentração de fluoreto na solução de incubação da HA. Liberações da ordem de 10-5 M foram observadas para a HA incubada por 24 h em 80 ppm fluoreto. A avaliação físico-química da HA bifásica porosa com fluoreto adsorvido revelou características semelhantes ao material original, sem fluoreto adsorvido. Em conclusão, a incubação da HA bifásica porosa em solução contendo 80 ppm de fluoreto por 24 horas é capaz de levar a uma adsorção de fluoreto tal que permite a liberação deste elemento na ordem de 10-5 M em meio de cultura osteogênico. Esta adsorção de fluoreto não altera as propriedades físico-químicas do material. / Hydroxyapatites (HA) are broadly employed as osteoconductive biomaterials, but they do not possess osteoinductive or osteogenic properties. Fluoride, when present in the environment in appropriate doses (around 10-5 M) is able to increase the proliferation of osteoblastos and the activity of alcaline phosphatase. Thus, the aim of the present study was to modify an existing biomaterial (biphasic HA, containing 70% HA and 30% β-TCP), through the adsorption of fluoride. The ability of this material to release fluoride for osteogenic culture medium was also evaluated. The biomaterial containing adsorbed fluoride was characterized physic-chemically (FTIR, DRX and SEM), in comparison to its counterpart without adsorbed fluoride. For the fluoride adsorption experiments, solutions with different fluoride concentrations (as NaF) were added to biphasic HA (10 g HA : 50 mL fluoridecontaining solution). Tests were carried out in 2 stages. In the first stage, fluoride concentrations used ranged between 100 and 2000 ppm. Incubation was done for 3, 6, 18 or 24 h, at room temperature, under constant agitation. After incubation, supernatant was removed and the pellets were allowed to dry at 40oC. The resulting material was stored for subsequent fluoride analysis that was done with the electrode, after examethyldisiloxane-facilitated diffusion. In the second stage, the fluoride concentrations ranged between 0.625 and 80 ppm and incubation was carried out for 24 or 48 h. For the evaluation of the release of adsorbed fluoride, samples of HA containing adsorbed fluoride were incubated in α-MEM medium at room temperature (10 g HA : 50 mL medium), under agitation, for 3, 6 or 24 h. Supernatant was collected for fluoride quantification. A dose- response relationship was observed between the concentration of fluoride that adsorbed to HA and the fluoride concentration in the incubation solutions. The time of incubation did not change the concentration of adsorbed fluoride (except for a reduction in adsorption for 48 h). The percentage of fluoride adsorption ranged between 15 and 35%. It was observed a reduction in the concentration of fluoride that was released to the medium, as a function of the reduction of the fluoride concentration in the incubation solution. Fluoride releases around 10-5 M were observed for HA incubated with 80 ppm fluoride for 24 h. Physico-chemical evaluation of the porous biphasic HA containing adsorbed fluoride revealed a pattern similar to the one observed for the original material (without adsorbed fluoride). In conclusion, the incubation of porous biphasic HA in a solution containing 80 ppm fluoride for 24 h allows adsorption of F to HA to an extent that allows the release of 10-5 M fluoride concentrations to the medium. In addition, fluoride adsorption to HA does not change the physico-chemical properties of the material.

Photocopy of typescript. / Digitized by Kansas Correctional Industries

Formation of carbon–fluorine and carbon–fluoroalkyl bonds via transition metal complexes represents an efficient synthetic route towards a wide array of valuable fluorinated organic compounds and fluorinated metallacycles offer a potentially green and atom economical pathway towards these functionalized fluorocarbons. This thesis is focused on cycloaddition reactions of Ni=CF2 complexes with fluoroalkenes (FAs) and acetylenes. Cycloaddition reactions of the FAs vinylidene fluoride (CF2=CH2) and perfluoro(methyl vinyl ether) [CF2=CF(OCF3)] with the electron-rich Ni(0) fluorocarbene, Ni=CF2[P(OMe)3](dppe) affords stable metallacyclobutane complexes, likely through a 1,4-diradical mechanism previously investigated for analogous reactions using computational chemistry. With CF2=CHF (TrFE), however, the observed products are the C3 alkene E-CHF=CF(CF3) and the metallacyclopentane complex, Ni(C4H2F6)(dppe), derived from oxidative coupling of two additional equivalents of TrFE. It is proposed that the instability of the initially formed metallacyclobutane gives rise to a 2,1-F shift, yielding the C3 alkene complex. Reaction of the latter with excess TrFE then liberates the C3 alkene, forming the TrFE alkene complex followed by the observed metallacyclopentane product. In the reaction of 1a with chlorotrifluoroethylene (CF2=CFCl) a single regioisomer of the metallacyclobutane is observed, but reacts further in THF solvent via α-Cl migration to Ni, affording the tetrafluoroallyl complex, NiCl(CF2CF=CFH), in which one F has been replaced by a hydrogen. Finally, reaction of 1a with hexafluoropropene [CF2=CF(CF3), HFP] takes an unprecedented turn, affording the Ni trifluoromethyl perfluoroalkenyl complex from formal transfer of one F from HFP to the Ni=CF2 moiety. The capability of 1a to perform cycloaddition with a broader substrate scope was investigating by reacting it with terminal aryl-acetylenes of varying electronic parameters. Reaction of 1a with 1.5 equivalents of 4-R-phenylacetylene afforded the expected difluorometallacyclobutenes (R = H, Cl, tBu). Further observation revealed a second acetylene insertion to yield a nickelacyclohexadiene in the first example of a 4- to 6-membered ring expansion of perfluorometallacycles. The six-membered metallacycle then undergoes reductive elimination to furnish a difluorocyclopentadiene. The electronic parameters of the aryl-acetylene substrate play a dramatic role in the selectivity of product formation. The more electron-donating substrates 4-tert-butylphenylacetylene and 1-hexyne stabilize the metallacyclobutene, while the electron-withdrawing 4-chlorophenylacetylene affords a more reactive metallacyclobutene making it more prone to the second acetylene insertion. Phenylacetylene represented a middle-ground between the two systems and proved effective for further characterization studies. The electronic effect of the surrounding ancillary ligand system was also studied by substituting dppe in 1a for P(OMe)3 and dipe to give analogous Ni(0) difluorocarbene complexes 1b and 1c (dipe = 1,2-bis(diisobutylphosphino)ethane). The -acidic phosphite ligands in 1b gave exclusively nickelacyclohexadiene and difluorinated cyclopentadiene due to a reactive metallacyclobutene, whereas the more electron rich 1c formed the metallacyclobutene product almost exclusively. The results presented here will allow for future investigations of fluorinated metallacycle reactivity, increasing our ability to prepare value-added fluorocarbon products for pharma, agrochemicals, and polymer applications.

Thesis advisor: Amir H. Hoveyda / Chapter One Development of Simple Organic Molecules as Catalysts for Enantioselective Allyl Additions to N-Phosphinoylaldimines and Isatins A new catalytic protocol for the enantioselective addition of organoborates to imines and carbonyls is described. This novel method, which does not require transition metals utilizes a modular and easily accessed aminophenol to dictate the stereochemistry of the products. Allyl-additions to N-phosphinoylaldimines and isatins, as well as allenyl-additions to isatins are studied and literature relevant to these transformations is discussed. Additionally, two separate methods for obtaining "crotyl-type" addition products to aldimines; one requiring α-chiral allylboronates and the other requiring a zinc-alkoxide, are discussed. Studies to elucidate the mechanism of this catalytic protocol are also contained in this chapter. Chapter Two Enantioselective Additions to Fluorinated Ketones: A Platform for Studying the Interaction Between Organofluorine and a Small Molecule Utilizing the new protocol discussed in Chapter One, allyl- and allenyl-groups are added enantioselectively to ketones containing a fluorinated substituent. Myriad tertiary alcohols are synthesized, demonstrating the value of this method. This study also allows for examining how organofluorine containing compounds bind to other organic molecules, which is a current topic of intense interest in the field of medicinal chemistry. Mechanistic studies support the idea that, in many cases, the fluorine of the substrate is electrostatically attracted to the ammonium-ion in the catalyst. Chapter Three Enantioselective Additions of Organoboronates to Ketones and Alphaketoesters Promoted by an Aminophenol Containing Catalyst Modification of the aminophenol disclosed in Chapter One allows for increased enantioselectivity for the allyl-addition to both simple ketones (such as acetophenone) and alphaketoesters. For simple ketones, a critical component of the optimal catalyst is replacing the tert-butyl group ortho to the phenol with the sterically large triphenylsilyl group. For alphaketoesters, this tert-butyl group was replaced with the sterically smaller metyl group. Rationale for why these contradictory changes in the catalyst structure lead to higher enantioselectivity for reactions with these two classes of ketones is discussed. Chapter Four Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of γ-Substituted Siloxyfurans with Aldimines A previously disclosed Ag-catalyzed enantioselective vinylogous Mannich reaction (EVM) with α-, β-, and unsubstituted siloxyfurans is extended to include γ-substituted siloxyfurans. This method, which generates a tertiary stereogenic center concurrent with an adjacent to a quaternary stereogenic center, requires a rarely used 2-thiomethylaniline N-protecting group for the aldimines. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.