A catalytic (in Brønsted superacid) and a stoichiometric process were developed to synthesise aryl boronic esters with boron cations via electrophilic arene borylation. The treatment of CatBX (Cat = catecholate; X = Cl, Br) with the triethyl salt [Et3Si][closo-CB11H6Br6] in arene solvent gave a transient boron electrophile that reacted as a synthetic equivalent of [CatB]+ in intermolecular electrophilic aromatic borylation at 25 °C. The by-product of the reaction was a strong Brønsted acid that was able to catalyse arene borylation using CatBH at high temperature. This catalytic process furnished aryl boronic esters in high yield with H2 as the only by-product. The use of the robust and weakly coordinating anion [closo-CB11H6Br6]- and the electrophile-resistant catecholborane were crucial for the catalytic process. The reaction mixture of R2BCl (R2 = Cat, Cl4Cat, Cl2), aprotic amine and AlCl3 mainly gave a borenium salt [R2B(amine)][AlCl4] which was in equilibrium with neutral species as revealed by NMR spectroscopy and reactivity studies. This reaction mixture was effective for the regioselective borylation, by electrophilic aromatic substitution, of a range of N-heterocycles, thiophenes and anilines at room temperature. The transterification in situ provided the synthetically useful and more stable pinacol boronate esters in excellent isolated yield. This process displayed remarkable functional-group tolerance for a boron based strong Lewis acid with weak bases (for example -NMe2), ether, and halogen groups all compatible. This process represents a new and inexpensive one-pot direct arene borylation methodology for producing pinacol boronate esters.

Thesis advisor: Shih-Yuan . Liu / Chapter 1. Use of boron as a pharmacophore is as growing but still underdeveloped strategy for expanding chemical space in biomedical research. In addition to more established methods of incorporating boron in drug development, an attractive and emerging method of introducing boron into biologically active compounds is through boron-nitrogen containing heterocycles. In particular, the Liu group has focused on exploring the interactions of monocyclic 1,2-azaborines in biological space. In order to install complicated chemical functionality needed for further studies, methods for late stage functionalization of 1,2-azaborines must be developed. Described herein is a method for functionalizing 1,2-azaborine at the C3- and C5-positions, with bromine and iodine handles, respectively. Chapter 2. Described is the application of the turbo Grignard reaction to 1,2-azaborines bearing a B–Cl bond. The reaction utilizes iPrMgCl·LiCl to form aryl carbon nucleophiles and is tolerant of sensitive functional groups such as nitriles and esters. Development of the reaction obviates the need to use toxic organotin reagents to install aryl groups at the B-position that bear sensitive, electrophilic functionalities. / Thesis (MS) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This work is concentrated on the thermodynamic and kinetic aspects of water, alcohols, alkyl halides, ethers, and lactones bound and activated by the electrophilic [Cp'Ru(N0)] +2 and [Cp’Ru (NO)(CH3)] + centers (Cp' = cyclopentadienyl group). Counterions in these systems include OSO2CF3- (OTf-) and [(3, 5-(CF3)2C6H3)4B]- ([BAr4']-). The displacement of OTf- in Cp'Ru(N0) (0Tf)2 by H20 in dichloromethane is exothermic but entropically unfavorable due to the required reorganization of the solvent cage around released triflate ions. Thermodynamic parameters are also determined for OTf displacement by chloride and tetrahydrofuran (THF) using the 19F nuclear magnetic resonance (NMR) spectroscopy. The conversion of the [Cp’Ru (NO)(OH2)2] +2 to [Cp’Ru (NO)(μ-OH)} 2 +2 in aqueous solutions is characterized thermodynamically and kinetically by potentiometric and NMR methods. The results of the study of rhodium triflato complex trans- [Rh (CO)(PPh3)2(OTf)] show that OTf coordinates to the metal center in wet dichloromethane solutions, but the compound crystallizes as a water-coordinated triflate salt trans- [Rh (CO)(PPh3)2(OH2)] [OTf]. Thermodynamic parameters for alcohol (methanol, ethanol, isopropanol) binding to the Cp*Ru(N0) (0Tf)2 are determined from the 19F NMR spectroscopic data. The kinetics of the oxidation of alcohols to aldehydes or ketones via Ru (II) >>> Ru (0) redox process is studied by NMR methods. The results of the study support {3-hydrogen elimination mechanism, comprising one of the very few mechanistic investigations on reactions of this kind. Alkyl iodides are found to bind to the [Cp*Ru (NO)(CH3)] + fragment via displacement of a THF ligand in the presence of a BAr4 •-counterion, forming alkyl halide complexes that convert to [Cp’Ru (NO)(μ-I)]2+2. The mixed ruthenium-chromium complex [CpCr (NO)2(μ-I) (Ru (Cp’) (NOW is characterized as primarily a [Ru-I >> Cr] system as opposed to a [Ru << I-Cr] model. The complex [Cp*Ru (NO)(CH3) (THF)] is found to catalyze aerobic oxidation of THF to -y-butyrolactone. The new -y-butyrolactone ruthenium complex is isolated and characterized by X-ray methods in the solid state. The mechanism of catalytic oxidation is studied by 18O-labeled infrared spectroscopic methods. Radical decomposition of the intermediate hydroperoxy-tetrahydrofuran gives 1, 6-diol-diformate [CH(O)-(CH2)6-CH(O)]. The radical mechanism for the catalytic oxidation of THF is proposed.

<p> Fluorine-18 labelled F2, produced by the nuclear reaction, 18O(p,n)18F, and recovered from an oxygen-18 gas target, has been used to elucidate the mechanism for the formation of XeF+AsF6- from Xe, F2, and AsF5 under low temperature and dark conditions. Formation of XeF+AsF6- was confirmed by Raman spectroscopy. A method was designed to allow for the dilution of the 18F activity onto a pool of carrier 19F2 such that suitable quantities of low specific activity [18F]F2 could be produced for the mechanistic study of this reaction. Based on the 18F distributions within the products and unreacted [18F]F2 and AsF5, it was shown that an F2-AsF5 activated complex containing an electrophilic fluorine reacts with the weak electron donor, xenon gas, in a Lewis acid-base type reaction. The absence of random fluorine exchange within the activated complex indicated that a transient Fδ+ was responsible for the enhanced oxidizing ability of the F2-AsF5 complex, rather than the production of a formal "F+" or F· intermediate. Fluorine-18 investigations into the reaction of the F2-AsF5 activated complex with other possible electron donors have shown some 18F transfer with krypton gas. Attempts to establish the formation of KrF+ using 19F NMR spectroscopy have shown no evidence for the presence of the cation in the Kr/F2/AsF5 system. The systems Kr/F2/HF/SbF5 and OF2/F2/AsF5 were not seen to undergo a reaction.</p> <p> The results of such sensitive radiotracer experiments required a complete analysis of the composition of the target gas delivered from the 18O(p,n)18F oxygen gas target; the presence of reactive agents other than [18F]F2 could affect the distribution of activities in reaction mixtures. Oxygen difluoride, which was suspected as a possible side product of the double bombardment method, was identified as a constituent of the target gas by 19F NMR characterization. An analysis of the effect of the variation of irradiation parameters has concluded that the quantity of [18F]OF2 activity is independent of the production irradiation parameters and is most likely a consequence of the presence of small amounts of O2 within the target during the recovery irradiation.</p> <p> The application of CsSO4F as an electrophilic fluorinating agent has provided preliminary evidence for the flourination of biologically active aromatic amino acids. Cesium fluoroxysulphate was found to react with 3,4-dihydroxyphenylalanine (L-Dopa) in an CH3CN solution containing BF3 to produce a mixture 2-, 5-, and 6-fluoro-L-dopa. Fluorine-19 NMR spectroscopy was used to confirm the presence of the 2-, 5-, and 6-fluoro-isomers of fluorodopa in the reaction mixture.</p> / Thesis / Master of Science (MSc)

Esta tese consiste do estudo de reações de ciclofuncionalização de compostos &#946;-enamino carbonílicos e &#946;-dicarbonílicos, contendo uma cadeia alquenílica nas posições &#945; ou &#947;. Os eletrófilos empregados para este fim foram: iodo, brometo de fenilselenenila e tricloreto de p-metóxifeniltelurio. Os iodo-&#946;-enamino ésteres e cetonas cíclicas, após desidroiodação mediada por base, levaram à formação dos correspondentes pirróis, indóis e aminobenzofuranos. A ciclização dos &#946;-ceto ésteres e &#946;-dicetonas levou a enol éteres e benzofuranos funcionalizados. Estes resultados, juntamente com outros obtidos em nosso grupo de pesquisa, foram utilizados em um estudo comparativo entre reagentes de iodo, selênio e telúrio frente a reações de ciclização eletrofílica de substratos &#946;-dicarbonílicos. / This thesis presents a study of the cyclofunctionalization of &#946;-enamino carbonyl and &#946;-dicarbonyl compounds, substituted by an alkenyl group at the &#945; or &#947; positions. Iodine, phenyl-selenenyl bromide and p-methoxyphenyltellurium trichloride were employed as the electrophilic reagent. The cyclic iodo-&#946;-enamino esters and ketones, after base-promoted dehydroiodination, led to the corresponding pyrroles, indoles and aminobenzofurans. The cyclization of the &#946;-keto esters and &#946;-diketones afforded five- and six-membered enol ethers and benzofuranones. These results, together with others previously obtained in our research group, allowed us to compare the behavior of the three above mentioned electrophiles toward the cyclofunctionalization of &#946;-dicarbonyl substrates.

Na primeira parte desta tese são apresentados os resultados referentes ao desenvolvimento de uma metodologia de &#945;-alquinilação eletrofílica de aldeídos com o reagente de iodo hipervalente TMS-EBX, empregando NaHMDS como base e TBAF. Aldeídos acíclicos foram submetidos a esta transformação e 9 exemplos de álcoois homopropargílicos foram obtidos em rendimentos de 50-81%, após uma etapa de redução com NaBH4. A transformação desenvolvida revelou-se aplicável também com o reagente de iodo hipervalente Ph-EBX e 2 exemplos foram obtidos em 24 e 40% de rendimento. O álcool homopropargílico precursor de um inibidor da bactéria que produz a toxina botulínica foi preparado em uma escala de 5 mmol sem a necessidade de alterar as condições reacionais já otimizadas. Na segunda parte desta tese são apresentados os resultados referentes ao desenvolvimento de uma metodologia para a síntese de cetonas cíclicas e 2-cromanonas &#945;-alquinil-&#946;-substituídas por meio de uma sequência de adição 1,4/alquinilação eletrofílica empregando cumarinas e enonas como material de partida, utilizando o reagente de iodo hipervalente TMS-EBX. Os enolatos foram gerados com sucesso a partir de uma reação de adição 1,4 catalisada por cobre utilizando complexos de alumínio e reagentes de Grignard como fontes nucleofílicas. No total foram obtidos 17 exemplos em 34-89% de rendimento e em alta diastereosseletividade. Realizamos três modificações estruturais visando aumentar a complexidade estrutural dos produtos sintetizados. A reação Click, rea- ção de Sonogashira e redução mediada por NaBH4 foram aplicadas com sucesso. Por fim, na terceira parte desta tese são apresentados os resultados preliminares referentes ao desenvolvimento de uma metodologia de síntese de furanos a partir da acetofenona e do reagente de iodo hipervalente Ph-EBX, empregando NaHMDS comoviii base. A acetofenona foi submetida a esta transformação e uma mistura de furanos di- e trissubstituídos foram obtidos em 49% de rendimento. Um experimento controle demonstrou que a alquinilação do ânion terc-butóxido, em uma reação extremamente rápida, é a principal via de consumo do Ph-EBX e o composto (terc-butoxietinil)benzeno foi obtido em 92% de rendimento. Esta reação lateral é a principal responsável pelo baixo rendimento da reação de síntese dos furanos. / In the first part of this work are presented the results relative to the development of a methodology of &#945;-electrophilic alkynylation of aldehydes with the hypervalent iodine reagent TMS-EBX, employing NaHMDS as base and TBAF. Acyclic aldehydes were submitted to this transformation and 9 examples of homopropargylic alcohols were obtained in 50-81% yield, after a reduction step with NaBH4. The developed transformation proved to be works also with the hypervalent iodine reagent Ph-EBX and 2 examples were obtained in 24 and 40% yield. The homopropargylic alcohol precursor of an inhibitor of bacteria that produces a botulinic toxin was prepared at a 5 mmol scale without change the reaction condition already optimized. In the second part of the thesis are presented the results relative to the development of a methodology for the synthesis of cyclic ketones and 2-chromanones &#945;-alkynyl-&#946;-substituted by the1,4-addition/electrophilic alkynylation sequence using coumarins and enones as a starting material and the hypervalent iodine reagent TMS-EBX. The enolates were generated with success from a Cu-catalyzed 1,4 addition using aluminum complexes and Grignard reagents as nucleophilic source. In total 17 examples were obtained in 34-89% yield and high diastereoselectivity. We carried out three structural modification aiming to increase the complexity of the products synthesized. Click reaction, Sonogashira reaction and reduction promoted by NaBH4 were applied with success. Finally, in the third part of the thesis are presented the preliminary results relative to the development of a methodology for synthesis of furans from acetophenone and the hypervalent iodine reagent Ph-EBX, using NaHMDS as a base. Acetophenone was submitted to this transformation and only one example was obtained in 49% yield in a mixture of di- and trisubstituted furans. A control experimentx showed that the alkynylation of tert-butoxide anion, in an extremely fast reaction, is the main path of consumption of the Ph-EBX reagent and the compound (tert-butoxyethynyl)benzene was obtained in 92% yield. This side reaction is the main responsible for the low yield of the reaction of synthesis of furans.

Students studying organic chemistry often have difficulty applying prior knowledge from general chemistry in their thinking about organic reaction mechanisms. In the United States, electrophilic aromatic substitution (EAS) mechanisms can be taught towards the end in a second-semester course of organic chemistry, providing students with almost two-semesters' worth of experience with organic chemistry reactions before solving problems on synthesis of substituted aromatic compounds.<div>Little research has been done on how, or if, instructors consider their students' prior knowledge or understanding of these concepts in EAS in their teaching activities. The purpose of this study was to describe how students reason through EAS synthesis problems and to identify concepts or gaps in understanding that inhibit students from successfully solving these types of problems. Participants were interviewed using a think-aloud protocol in which they were asked to describe the reactants and mechanisms necessary to synthesize di- and tri-substituted benzenes using EAS. The interviews were transcribed and analyzed using a qualitative inquiry approach and the data interpreted in terms of the ACS Examinations Institute's Anchoring Concepts Content Maps for general and organic chemistry.</div><div>The findings from this study indicated that while students correctly applied their knowledge of substituent effects to solve these types of problems, they relied on rote-memorization of these effects, resulting in inflexibility when applying them to novel situations. Additionally, students exhibited gaps in understanding of fundamental concepts in resonance theory and Lewis structures, differentiating and utilizing Friedel-Crafts reactions, and recognizing when to use oxidation/reduction reactions in their syntheses.</div><div>Another component of this study focused on instructors of organic chemistry from a range of institutions in the United States. The purpose of this study was to describe how organic chemistry instructors perceived their students' reasoning about these types of problems, and to describe the characteristics of each instructors' topic-specific pedagogical content knowledge (TS-PCK) and the three general knowledge domains (GKDs) instructors draw upon to inform their TS-PCK. These knowledge domains are knowledge of students, subject matter knowledge, and pedagogical knowledge. These participants were remotely-interviewed using a think-aloud protocol in which they were asked to describe their classroom practices and teaching strategies when teaching EAS, and to describe how they would synthesize the same aromatic compounds as their students (a selection of which were interviewed in the previous study). Participants were asked to consider how their students would approach the syntheses and to specify what parts of the syntheses their students would find challenging, and why. The interviews were transcribed and analyzed using a qualitative inquiry approach. </div><div>The findings from this study indicated that the instructors were aware of their students' tendencies to use rote-memorization without understanding in the course, but there was still a mis-alignment between how instructors' perceived their students' reasoning through EAS synthesis problems and the reasoning the students actually used. The instructors believed that their students would only rely on the directing effects of substituents in their reasoning, but the students demonstrated they were aware of the activating and deactivating effects too. Additionally, instructors believed their students would not be hindered by an understanding of resonance or Lewis structures in their syntheses.</div><div>Finally, there are some recommendations for addressing the students' propensity for rote-memorization by providing a visual way to represent directing and activating/deactivating effects of substituents using electrostatic potential maps. There are also suggestions for further building on this work. <br><div><br></div></div>

After a general introduction about the properties and preparation of organofluorine compounds (Chapter 1), this thesis is divided into two parts focussing on the development of new methods for C-F bond formation (Part A) as well as studies towards the development of novel fluorinating reagents (Part B). Part A: New Methods for Carbon-Fluorine Bond Formation Part A consists of two chapters outlining the development of a Pd-catalysed hydrofluorination of alkenylarenes (Chapter 2) as well as a halofluorination of alkynes (Chapter 3). Chapter 2 This chapter describes the development of a novel, regioselective, syn-specific hydrofluorination of alkenylarenes under Pd-catalysis leading to the formation of benzylic fluorides. An extensive substrate scope is presented together with a model of the catalytic cycle, based on observations during the development of this reaction, deuterium labelling experiments as well as mechanistic control experiments starting from isolated palladacycles. Chapter 3 In this chapter the development of a novel iodo- as well as bromofluorination of internal and terminal alkynes, leading to the formation of (E)-halofluoroalkenes, is presented. For the former substrate class, the effects of steric as well as electronic bias on regioselectivity are discussed. For the latter substrate class, this methodology could be extended to the corresponding double iodofluorination, and for both transformations it was found to exclusively lead to the fluorination of the internal carbon. An extensive substrate scope as well as different iodofluorination-cross-coupling sequences including Suzuki, Sonogashira and Ullmann couplings, are illustrated. A representative reaction was successfully carried out on gram-scale and an iodofluorination-Suzuki-coupling sequence was used to prepare a fluorinated tamoxifen derivative. Part B: Hydrogen-Bonded Fluoride Complexes as Novel Reagents for Carbon-Fluorine Bond Formation Part B consists of two chapters describing structural as well as reactivity studies of fluoride-alcohol (Chapter 4) and fluoride-urea complexes (Chapter 5). Chapter 4 In this chapter the synthesis of 19 novel hydrogen-bonded tetraalkylammonium fluoride-alcohol complexes is described. For a subset of 15, the solid-state structures as determined by single-crystal X-ray diffraction experiments are presented. Trends of reactivity and selectivity were determined using these complexes as sources of fluoride anion in a model SN2 reaction. Preliminary results from in silico modelling of the fluoride-alcohol system provide a basis for explaining the results. Chapter 5 This chapter summarises the synthesis and solid-state structures of 20 hydrogen-bonded fluoride complexes using the urea and related squaramide and amide motifs. Also, the size of the tetraalkylammonium counter-cation was varied to study the influence on the solid-state structure. The reactivity and selectivity of a series of complexes was studied using the same model SN2 reaction as in Chapter 4 and results were compared accordingly. Different UV-vis and NMR spectroscopic techniques were used to study the behaviour of the fluoride-urea system in solution. Preliminary results demonstrate the use of 1,3-diarylureas as organocatalysts for nucleophilic fluorination.

As key components of flexible organic electronics, the synthesis of polythiophenes via less toxic and more cost-effective routes is demanded. An efficient synthetic route for the production of thienyl-containing homopolymers and copolymers has been developed. The synthetic approach consists of: i) the synthesis in high yield and high purity of thienyl borane monomers protected with N-methyliminodiacetic acid (MIDA) via C-H electrophilic borylation. This reaction uses a combination of inexpensive reagents BCl3, AlCl3, and 2,6-dichloropyridine (Cl2Py) for the regioselective electrophilic aromatic substitution of thiophenes, followed by addition of a second aprotic amine pre-esterification to reduce the Brønsted acidity of the reaction mixture. In situ esterification provided the desired thienyl MIDA boronateester monomers in one-pot at room temperature. ii) Subsequent Suzuki-Miyaura polymerisation of the synthesised monomers to produce well defined thienyl containing pie-conjugated polymers in high molecular weight and high yields. Key reaction parameters for successful Suzuki-Miyaura polymerisation of thienyl-derived MIDA boronate esters under mild temperatures (i.e., 55 °C in THF) were found: a) an optimal monomer:H2O:base ratio, which enables controlled hydrolysis of the BMIDA moiety into its corresponding boronic acid at appropriate rates for high fidelity polymerisation. b) Nature of the base, where K3PO4 provided the best results for production of homopolymers (e.g., rr-P3HT), or KOH which gave excellent results for the formation of copolymers across a range of electronically different comonomers (e.g., pCPDT-BT). Thus, it is demonstrated that the approach is a general strategy for the highly efficient production of thienyl containing pie-conjugated regioregular, regiosymmetric and Donor-Acceptor polymers.

Bromoarenes are important aromatic building blocks that are commonly used to synthesize various functional compounds in pharmaceutical, agrochemical and related industries.1,2 This great demand for bromoarenes makes their preparation a widely studied area of synthetic organic chemistry. However, further understanding of the reactivity and regiochemistry of aromatic functionalization reactions is still necessary, as much about the secondary substitution and solvent effects remain unknown. Resonance Theory is a widely used theoretical model to predict the regiospecifity and reactivity of the bromination of various aromatic compounds.3 The reactivity and regiospecificity of many substituted aromatic compounds is well explained using resonance theory.4 However, kinetic understanding of the p-bromination of halosubstituted aromatic compounds has not been investigated to the best of our knowledge.5,6In this thesis, the reactivity and regiospecifity of the p-bromination of activated secondary substituted aromatic compounds as well as media effects on the process will be discussed. Synthesizing bromoarenes has been accomplished using many different experimental setups.7-11 N-bromosuccinimide is the most highly utilized electrophilic aromatic brominating agent. Many of the NBS- based aromatic bromination reactions have been reported using strong acids, strong bases, halogenated solvents, nonpolar solvents and polar solvents alike.12 The bromination reactions reported herein were performed using two different solvents, acetonitrile and acetone, to investigate the effects of solvent polarity on p-bromination. Although acetonitrile is one of the most commonly used solvents in the p-bromination of aromatic compounds, acetone has not been investigated.