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>

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.

Electrophilic aromatic substitution (EAS) and directed ortho-metalation (DoM) involve the direct substitution of an arene hydrogen. A major drawback involving EAS is the necessity for harsh forcing conditions for the reaction to proceed. Catalysts such as Lewis acids FeBr3 and AICI3 for the introduction of halogens and acyl groups, respectively, are each highly toxic and corrosive. Textbook preparations of aryl iodides classicaly involved the use of iodine and nitric acid. This approach affords only modest yields and does not provide regiospecific substitution of most substituted aromatics because most contain ortho/para directors which afford mixtures of isomers. The novelty of our procedure for the synthesis of the iodinated aromatics is twofold in that regiospecific para-iodination is observed and hydrocarbon media are utilized. Hydrocarbon media are less hazardous and greener than media used for halogenations reported in literature. This procedure always yields derivatives regiospecifically substituted para to an electron donating substituent. Moreover, this method eliminates the need to use hazardous oxidative catalysts. DoM is a reaction regiospecifically substitute an arene hydrogen at the ortho position. The media used in DoM reactions are less hazardous than those required for a variety of EAS reactions. The only problem for this reaction is use of extremely strong bases, alkyllithium reagents, which are known to be air and water sensitive. However, the DoM reaction does eliminate the need to separate ortho/para isomer mixtures so that only a single product is generated. The metalation yields predominantly products regiospecifically substituted ortho-to the direcing metalating group (DMG). With our deficiency catalysis concept and subsequent purificaion methods, relatively pure ortho-lithiated intermediates have been prepared. The study of catalysts/promoters on the derivatization of these intermediates is anticipated to be extremely insightful. For this study, we have shown that highly selective, efficient ortho-lithiation can be achieved by deficiency catalysis utilizing n-BuLi as the only strong metalating base.

Chapter 1 presents a mini-review of the prominent theoretical models which are employed in the prediction of the outcome of organic chemical reactions. The chapter covers the most widely used empirical and semi-empirical models, as well as some more recently developed models. Most have a common theme in that they were developed using electrophilic aromatic substitution as a model reaction. Chapter 2 describes the development of a predictive model based on the average local ionisation energy. The model is shown to be of use in predicting both the regioselectivity and relative reactivity of a wide range of molecules in electrophilic aromatic substitution reactions. An attempt is made to expand the model beyond electrophilic aromatic substitution to various other electrophilic reactions. Chapter 3 details the investigation into the predicted enhancement of reactivity of aromatic rings. Calculations of electrostatic surface potential surfaces show that the proximity of an electron rich atom to an aromatic ring increases the electron density of the ring. Analysis of the local ionisation energy surfaces of these molecules suggests that the reactivity of these rings towards electrophiles is also increased. Preliminary studies on model systems using NMR spectroscopy aim to determine whether this effect can be observed experimentally. Chapter 4 introduces a method for applying the average local ionisation energy to nucleophilic reactions. The ability of the model to predict the regiochemical outcome and relative reaction rates of various molecules is examined in a variety of reaction types, including nucleophilic aromatic substitution. Chapter 5 reports studies into the polarisation-induced cooperative effects that exist between hydrogen bonding groups. The cooperative effect has been measured quantitatively in some simple hydroxybenzene derivatives. An improved understanding of this effect, developed using small molecule models, should lead to an improved ability to predict the extent of this effect in larger systems.

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A primeira parte desta tese aborda estudos sobre a reatividade de compostos de telúrio eletrofílicos, principalmente tetracloreto de telúrio e tricloretos aromáticos de telúrio. Novos aspectos da reatividade de TeCl4 frente a alcinos e algumas acetofenonas foram observados e, a partir da elucidação estrutural dos compostos obtidos, por cristalografia, uma racionalização mecanística foi proposta para cada caso. As proposições apresentadas encontraram respaldo com a detecção de intermediários transientes por estudos de espectrometria de massas com ionização por electron-spray (ESI-MS/MS). Além de novos aspectos da química do Telúrio, os compostos preparados encontraram aplicação como potentes e seletivos inibidores de cisteíno proteases. Com esta aplicação estabelecida, foram sintetizadas ambos os enantiômeros de uma telurana e a atividade inibitória destas frente a Catepsina B mostrou dependência da estereoquímica devido a dependência estereoquímica da interação entre a enzima e o inibidor. A segunda parte deste trabalho trata do desenvolvimento da reação de abertura de anel de aziridinas por reagentes organometálicos de cobre derivados de teluretos vinílicos e arílicos que resultaram em derivados de aminas homoalílicas ou homobenzílicas. Em seguida, a reatividade de aziridinas alílicas foi estudada frente a uma série de reagentes organometálicos de lítio, magnésio, cobre e zinco que mostraram influenciar a regio- e estereosseletividades das reações de abertura. / The first part of this thesis deals with the study of the reactivity of electrophilic tellurium compounds, mainly tellurium tetrachloride and aromatic tellurium trichlorides. New aspects of the reactivity of TeCl4 towards alkynes and some acetophenones were disclosed. A mechanistic rationale for each of the processes studied was possible by the determination of the stereochemistry for each product by monocrystal X-ray diffraction analysis. The proposition of the formation of cationic intermediates in the addition reaction of TeCl4 to alkynes was corroborated by the detection and characterization of transient intermediates by ESI-MS/MS experiments. Besides the new aspects of the Tellurium chemistry found, the prepared compounds showed a high and selective activity as inhibitors of cysteine proteases. A pair of enantiomers of a tellurane showed different activities against Human Catepsin B due to a stereochemical dependence in the enzyme/inhibitor interaction. The second part of the present work deals with the development of the ring opening reaction of aziridines by organometallic reagents of copper prepared from vinylic and arylic tellurides. These reactions led to homoallylic and homobenzylic amine derivatives. Finally, the reactivity of 2-alkenyl aziridines was studied towards a series of organometallic reagents of lithium, magnesium, copper and zinc which biased the regio- and stereoselectivities of the ring opening reactions.

A primeira parte desta tese aborda estudos sobre a reatividade de compostos de telúrio eletrofílicos, principalmente tetracloreto de telúrio e tricloretos aromáticos de telúrio. Novos aspectos da reatividade de TeCl4 frente a alcinos e algumas acetofenonas foram observados e, a partir da elucidação estrutural dos compostos obtidos, por cristalografia, uma racionalização mecanística foi proposta para cada caso. As proposições apresentadas encontraram respaldo com a detecção de intermediários transientes por estudos de espectrometria de massas com ionização por electron-spray (ESI-MS/MS). Além de novos aspectos da química do Telúrio, os compostos preparados encontraram aplicação como potentes e seletivos inibidores de cisteíno proteases. Com esta aplicação estabelecida, foram sintetizadas ambos os enantiômeros de uma telurana e a atividade inibitória destas frente a Catepsina B mostrou dependência da estereoquímica devido a dependência estereoquímica da interação entre a enzima e o inibidor. A segunda parte deste trabalho trata do desenvolvimento da reação de abertura de anel de aziridinas por reagentes organometálicos de cobre derivados de teluretos vinílicos e arílicos que resultaram em derivados de aminas homoalílicas ou homobenzílicas. Em seguida, a reatividade de aziridinas alílicas foi estudada frente a uma série de reagentes organometálicos de lítio, magnésio, cobre e zinco que mostraram influenciar a regio- e estereosseletividades das reações de abertura. / The first part of this thesis deals with the study of the reactivity of electrophilic tellurium compounds, mainly tellurium tetrachloride and aromatic tellurium trichlorides. New aspects of the reactivity of TeCl4 towards alkynes and some acetophenones were disclosed. A mechanistic rationale for each of the processes studied was possible by the determination of the stereochemistry for each product by monocrystal X-ray diffraction analysis. The proposition of the formation of cationic intermediates in the addition reaction of TeCl4 to alkynes was corroborated by the detection and characterization of transient intermediates by ESI-MS/MS experiments. Besides the new aspects of the Tellurium chemistry found, the prepared compounds showed a high and selective activity as inhibitors of cysteine proteases. A pair of enantiomers of a tellurane showed different activities against Human Catepsin B due to a stereochemical dependence in the enzyme/inhibitor interaction. The second part of the present work deals with the development of the ring opening reaction of aziridines by organometallic reagents of copper prepared from vinylic and arylic tellurides. These reactions led to homoallylic and homobenzylic amine derivatives. Finally, the reactivity of 2-alkenyl aziridines was studied towards a series of organometallic reagents of lithium, magnesium, copper and zinc which biased the regio- and stereoselectivities of the ring opening reactions.