Dissertations / Theses on the topic 'Selective electrophilic aromatic substitution'

This thesis investigates the potential of the alkaloid isocryptolepine 16 as a lead compound in antimalarial drug development. Fifteen derivatives of the parent alkaloid were prepared and fully characterised, twelve of which were novel compounds. A select group of compounds were subsequently evaluated for both antimalarial activity and cytotoxicity.Three previously reported synthetic methodologies to the parent alkaloid were initially investigated; wherein two approaches were able to be reproduced or improved. These two synthetic methodologies were subsequently applied to the preparation of derivatives. The first of these methodologies, the Jonckers Method, involved two consecutive palladium catalysed coupling reactions. During the course of these investigations it was found that these two reactions could be combined into a single ‘domino’ reaction resulting in a reduction in the number of steps required to prepare the parent alkaloid. This methodology was then applied to the preparation of both ring-substituted and structural isomers. The second methodology, The Molina Method, involved a benzotriazole-mediated strategy and was applicable to preparing isocryptolepine derivatives with ring substituents on the quinoline ring. Finally a method for selective electrophilic aromatic substitution was developed and applied to the preparation of a further range of halogenated derivatives.Eight of the prepared derivatives were selected for biological evaluation. Antimalarial activity was assessed against a chloroquine sensitive and resistant strain of P. falciparum, whilst cytotoxicity was evaluated against mouse embryonic fibroblasts (3T3 cells). All compounds were found to be more active compared to the parent alkaloid against the chloroquine resistant strain of P. falciparum; specifically 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 85 nM) and 8-bromo-3-chloroisocryptolepine 105 (IC[subscript]50 = 100 nM) were the most potent. Cytotoxicity evaluations revealed that ring substitution did not enhance cytotoxicity and the most potent antimalarial derivative, 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 9.01 μM), displayed a 4-fold reduction in cytotoxicity.In conclusion, isocryptolepine 16 and its derivatives have significant potential as antimalarial lead compounds, with many derivatives possessing enhanced bioactivity versus the parent. This study has also identified 8-bromo-2-chloroisocryptolepine 107 to be a very promising lead compound which warrants further biological or pharmaceutical investigation.

Chapter 1 highlights the many advantages of heterogeneous inorganic solids as catalysts, and summarises the various microporous and mesoporous solids that have been employed as catalysts. The synthesis and characterisation of the mesoporous materials that were used in the study are described. Chapter 2 focuses on the nitration of naphthalene. An introduction to nitration is given, and the results of nitration over a range of solids are presented. Unusual dinitronaphthalene product ratios were achieved over Al-MCM-41. Reactions catalysed by heteropoly acid immobilised within the pores of mesoporous materials are also described. Chapters 3 to 6 focus upon the alkylation of naphthalene. Emphasis is placed upon the importance of 2,6-dialkylnaphthalenes (2,6-DAN) as intermediates for the production of high performance engineering plastics, and why there is still significant room for improvement in both 2,6-DAN yield and selectivity. A molecular modelling study of 2,6- and 2,7- di-<I>tert</I>-butylnaphthalene (DTBN) highlighted the potential for achieving selectivity for the 2,6-over the 2,7-isomer. Zeolite H-Mordenite (HM) was the most selective catalyst for 2,6-DTBN, but showed poor activity. Efforts to increase both the 2,6-DTBN yield and selectivity over HM focused upon varying the reaction time; temperature; pressure; solvent; amount of alkylating agent, solvent, and catalyst; Si/Al ratio of the catalyst; and mode of addition. Optimisation resulted in a 60% yield of 2,6-DTBN with a 2,6/2,7 ratio of over 50. <I>tert</I>-Butylation reactions were achieved using mainly <I>tert</I>-butanol as the alkylating agent. The identification of by-products in the <I>tert-</I>butylation reaction has been attempted. Alkylation with other alkylating agents has been attempted, but selectivity for 2,6-DAN was inferior to that achieved in the <I>tert</I>-butylation reaction using <I>tert</I>-butanol.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2006.<br>Title from first page of PDF file (viewed June 7, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 280-290).

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.

The terpene and terpenoid family of compounds is considered to be the largest group of natural products. These compounds not only display great diversity in their structural features but are also known to have a multitude of biological activities including but not limited to anti-bacterial, anti-cancer, anti-inflammatory, and anti-HIV properties. Remarkably, all the terpenoids formed in nature come from two molecules viz. isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate both consisting of just five carbons but assembled in many ways. Nature utilizes highly efficient, enzyme-mediated cascade reactions to transform simple linear molecules to more complex cyclic scaffolds. Cascade or domino reactions are organic chemistry’s most powerful tools that, if executed correctly, mimic the extreme complexity of reactions occurring in nature. Our group has successfully utilized cationic cascade cyclization reactions, to prepare a large library of natural products along with their analogues. It was during the synthesis of one such natural product that it was discovered that a methoxymethyl (MOM) “protecting group” had been transferred within the same molecule. The optimization of this process not only allowed the synthesis of the desired tricyclic framework but also resulted in the liberated MOM group doing an EAS reaction which gave a new C-C bond. This transferred MOM group was further elaborated to different functional groups. Use of the tandem reaction sequence in an attempt to prepare radulanin E has been described. Total syntheses of two chalcone-based analogous meroterpenoids have been successfully completed using the aforementioned sequence. An advanced intermediate for an entire new class of acridine-based schweinfurthins has been elaborated. The results will be discussed in detail.

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.

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.

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.<br>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.

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>

碩士<br>國立臺灣師範大學<br>化學系<br>103<br>2-Aminobenzimidazole derivatives are important nitrogen-containing heterocycles which often were embedded in many biologically active molecules. This thesis focuses on the synthesis of 1-aminobenzimidazole derivatives from benzonitriles. In the first part, a direct approach for the synthesis of 2-(N-alkylamino)benzimidazoles from o-bromobenzonitriles was developed. The reaction of o-bromophenylcyanamides, obtained from o-bromobenzonitriles via Tiemann rearrangement, with various primary and secondary alkylamines employing of copper(I) iodide and 1,10-phenanthroline in 1,4-dioxane via Buchwald–Hartwig amination reaction protocol afforded a series of 2-(N-alkylamino)benzimidazoles. In the second part, a metal-free approach for the synthesis of 1-alklyl-2-(tosylamino)benzimidazoles from benzonitriles was developed. A series of N-aryl-N-alkyl-N’-hydroxyguanidins were obtained from N-alkylation followed by hydroxylamine addition of phenylcyanamides, synthesized from benzonitriles via Tiemann rearrangement. p-toluenesulfonyl chloride-promoted intramolecular electrophilic aromatic substitution reaction of N-aryl-N-alkyl-N’-hydroxyguanidins afforded a series of 1-alkyl-2-(tosylamino)benzimidazoles.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014<br>β-fluoro alcohols are an important class of natural and synthetic molecules with biological activity as, for example, antibacterial and antiviral drugs, and caspase inhibitors, and are used as precursors for the preparation of other drugs. Diols and polyols have demonstrated over the years to be useful building blocks, but their use is often subdued by the assistance of protecting groups. Protecting groups are fundamental in organic synthesis, being common their use in synthesis involving polyfunctional molecules such as polyols. Professor Azzena group developed a protecting group category for protection of alcohols based on biphenyl and terphenyl ethers that can be cleaved by reduction with alkali metals. A couple of synthetic plans were designed concerning the selective introduction of this protecting group in a diol, which can be introduced by Mitsunobu, Williamson or aromatic nucleophilic substitution, with retention or inversion of configuration. The selectively protected diol can be a useful intermediate in further synthetic steps that could involve, although not necessarily, secondary hydroxyl activation by formation of a tosylate and subsequent nucleophilic substitution or other modification on the diol since the ether is a very stable protective group. The last step of the design is related with selective deprotection of the protecting group without damage of the modifications operated on the secondary hydroxyl group.<br>Os β-fluoro álcoois são uma importante classe de moléculas naturais e sintéticas com actividade biológica como, por exemplo, actividade antibacteriana e antiviral, actividade inibitória das caspases, e são usados como precursores para a preparação de outros fármacos. Os dióis e polióis têm demonstrado ao longo dos anos serem úteis blocos de construção, mas o seu uso necessita frequentemente da assistência de grupos de protecção. Os grupos de protecção são fundamentais na síntese orgânica, sendo comum o seu uso na síntese envolvendo moléculas polifuncionais como os polióis. O grupo do Professor Azzena desenvolveu uma categoria de grupos protectores para a protecção de alcoóis, bifenil e terfenil éteres que podem ser clivados por redução com alquilometais. Alguns planos sintéticos foram elaborados baseados na introdução selectiva deste grupo de protecção num diol, o qual pode ser introduzido por Mitsunobu, Williamson ou substituição nucleofílica aromática, com retenção ou inversão da configuração. O diol protegido selectivamente pode ser um útil intermediário para passos sintéticos seguintes que podem envolver, embora não necessariamente, a activação do grupo hidroxilo secundário com formação do tosilato e consequente substituição nucleofílica ou outra modificação no diol uma vez que o éter é um grupo de protecção muito estável. O último passo dos métodos propostos está relacionado com a desprotecção selectiva do grupo de protecção sem danificar as modificações operadas (ou realizadas) no grupo hidroxilo secundário.<br>Department of Chemistry and Pharmacy, Università di Sassari