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Brittain-DR-1965-Phd-Thesis.Pdf
POLYMETHYLENE PYRIDINES , A thesis submitted by David Robert Brittain in partial fulfilment of the requirements for the degree of DOCTOR OP PHILOSOPHY in the University of London Organic Chemistry Department, dune, 1965. Imperial College, LONDON, S.W.7. ABSTRACT This thesis describes a series of attempts to syn- thesise 2,5- and 1,4-polymethylene bridged pyridines. Nuclear magnetic resonance theory predicts that protons, which are held directly over an aromatic ring, will be abnormally shielded compared with protons in aliphatic straight-chain hydrocarbons. This prediction has been verified for the central methylene protons of paracyclo- phanes. The degree of shielding, expressed in terms of the distance from the aromatic ring, is a measure of the induced ring current and hence the aromaticity of the benzene ring. Similar measurements upon 2,5- or 1,4— polymethylene bridged pyridines would make it possible to determine the degree of aromaticity of the pyridine ring relative to benzene. A review of the subject of aromaticity is presented in which special reference has been made to its inter- pretation by nuclear magnetic resonance. The synthetic work has not been brougL.t to a truly satisfactory conclusion. However, the synthetic routes to 2,5-dialkylpyridines have been thoroughly investigated and a wide variety of such compounds prepared. The functional groups at the ends of the alkyl chains have been varied in an effort to produce a derivative which would cyclise to give a 2,5-bridged pyridine. The attempted intramolecular oxidative coupling of 2,5-dihex- 51 -ynylpyridine received much attention. In the attempts to obtain a 1,4-bridged pyridine, two tricyclic compounds, each containing two quaternised pyridine rings linked by polymethylene chains, were obtained. -
The Development and Application of Metal-Catalyzed Processes for Organic Synthesis
The Development and Application of Metal-Catalyzed Processes for Organic Synthesis by Edward J. Hennessy B.A. Chemistry Northwestern University, 2000 Submitted to the Department of Chemistry in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY at the Massachusetts Institute of Technology June 2005 © 2005 Massachusetts Institute of Technology All Rights Reserved Signature of Author: " - - 1_"' .Da-uirnt of Chemistry May 19, 2005 Certified by: Stephen L. Buchwald Camille Dreyfus Professor of Chemistry Thesis Supervisor Accepted by: Robert W. Field Chairman, Departmental Committee on Graduate Students ARCHIVES: This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: -/ Professor Gregory C. Fu: " Ch Chair Professor Stephen L. Buchwald Thesis Supervisor Professor Timothy M. Swager: , -L i \ O 2 The Development and Application of Metal-Catalyzed Processes for Organic Synthesis by Edward J. Hennessy Submitted to the Department of Chemistry on May 19, 2005 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the Massachusetts Institute of Technology ABSTRACT Chapter 1. Copper-Catalyzed Arylation of Stabilized Carbanions A mild, general catalytic system for the synthesis of a-aryl malonates has been developed. Aryl iodides bearing a variety of functional groups can be effectively coupled to diethyl malonate in high yields using inexpensive and widely available reagents, making this a superior method to those previously described that employ copper reagents or catalysts. The functional group tolerance of the process developed makes it complementary to analogous palladium-catalyzed couplings. Importantly, a set of mild reaction conditions has been developed that minimize product decomposition, a problem that had not been addressed previously in the literature. -
Nucleophilic Aromatic Substitution
NUCLEOPHILIC AROMATIC SUBSTITUTION Ms. Prerana Sanas M.Pharm (Pharmceutical Chemistry) Asst.Professor, NCRD’s Sterling Institute of Pharmacy Nerul Navi Mumbai Nucleophilic aromatic substitution results in the substitution of a halogen X on a benzene ring by a nucleophile (:Nu– ). Aryl halides undergo a limited number of substitution reactions with strong nucleophiles. NAS occurs by two mechanisms i) Bimoleccular displacement (Addition –Elimination) ii) Benzyne Formation( Elimination –Addition) 7/5/2019 Ms.Prerana Sanas 2 Bimolecular displacement (Addition – Elimination) Aryl halides with strong electron-withdrawing groups (such as NO2) on the ortho or para positions react with nucleophiles to afford substitution products. For example, treatment of p-chloronitrobenzene with hydroxide (– OH) affords p-nitrophenol by replacement of Cl by OH. Nucleophilic aromatic substitution occurs with a variety of strong nucleophiles, including – OH, – OR, – NH2, – SR, and in some cases, neutral nucleophiles such as NH3 and RNH2 . 7/5/2019 Ms.Prerana Sanas 3 Mechanism…… The mechanism of these reactions has two steps: Step i) Addition of the nucleophile (:Nu– ) forms a resonance-stabilized carbanion with a new C – Nu bond—three resonance structures can be drawn. • Step [1] is rate-determining since the aromaticity of the benzene ring is lost. In Step ii) loss of the leaving group re-forms the aromatic ring. This step is fast because the aromaticity of the benzene ring is restored. 7/5/2019 Ms.Prerana Sanas 4 Factors affecting Bimolecular displacement Increasing the number of electron-withdrawing groups increases the reactivity of the aryl halide. Electron-withdrawing groups stabilize the intermediate carbanion, and by the Hammond postulate, lower the energy of the transition state that forms it. -
The Total Synthesis of Securinine and Other Methodology Studies
University of Windsor Scholarship at UWindsor Electronic Theses and Dissertations Theses, Dissertations, and Major Papers 2010 The total synthesis of securinine and other methodology studies Bhartesh Dhudshia University of Windsor Follow this and additional works at: https://scholar.uwindsor.ca/etd Recommended Citation Dhudshia, Bhartesh, "The total synthesis of securinine and other methodology studies" (2010). Electronic Theses and Dissertations. 8275. https://scholar.uwindsor.ca/etd/8275 This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. The Total Synthesis of Securinine and Other Methodology Studies by Bhartesh Dhudshia A Dissertation Submitted to the Faculty of Graduate Studies through the Department of Chemistry and Biochemistry in Partial Fulfillment of the Requirements -
Organic Synthesis: New Vistas in the Brazilian Landscape
Anais da Academia Brasileira de Ciências (2018) 90(1 Suppl. 1): 895-941 (Annals of the Brazilian Academy of Sciences) Printed version ISSN 0001-3765 / Online version ISSN 1678-2690 http://dx.doi.org/10.1590/0001-3765201820170564 www.scielo.br/aabc | www.fb.com/aabcjournal Organic Synthesis: New Vistas in the Brazilian Landscape RONALDO A. PILLI and FRANCISCO F. DE ASSIS Instituto de Química, UNICAMP, Rua José de Castro, s/n, 13083-970 Campinas, SP, Brazil Manuscript received on September 11, 2017; accepted for publication on December 29, 2017 ABSTRACT In this overview, we present our analysis of the future of organic synthesis in Brazil, a highly innovative and strategic area of research which underpins our social and economical progress. Several different topics (automation, catalysis, green chemistry, scalability, methodological studies and total syntheses) were considered to hold promise for the future advance of chemical sciences in Brazil. In order to put it in perspective, contributions from Brazilian laboratories were selected by the citations received and importance for the field and were benchmarked against some of the most important results disclosed by authors worldwide. The picture that emerged reveals a thriving area of research, with new generations of well-trained and productive chemists engaged particularly in the areas of green chemistry and catalysis. In order to fulfill the promise of delivering more efficient and sustainable processes, an integration of the academic and industrial research agendas is to be expected. On the other hand, academic research in automation of chemical processes, a well established topic of investigation in industrial settings, has just recently began in Brazil and more academic laboratories are lining up to contribute. -
Reactions of Aromatic Compounds Just Like an Alkene, Benzene Has Clouds of Electrons Above and Below Its Sigma Bond Framework
Reactions of Aromatic Compounds Just like an alkene, benzene has clouds of electrons above and below its sigma bond framework. Although the electrons are in a stable aromatic system, they are still available for reaction with strong electrophiles. This generates a carbocation which is resonance stabilized (but not aromatic). This cation is called a sigma complex because the electrophile is joined to the benzene ring through a new sigma bond. The sigma complex (also called an arenium ion) is not aromatic since it contains an sp3 carbon (which disrupts the required loop of p orbitals). Ch17 Reactions of Aromatic Compounds (landscape).docx Page1 The loss of aromaticity required to form the sigma complex explains the highly endothermic nature of the first step. (That is why we require strong electrophiles for reaction). The sigma complex wishes to regain its aromaticity, and it may do so by either a reversal of the first step (i.e. regenerate the starting material) or by loss of the proton on the sp3 carbon (leading to a substitution product). When a reaction proceeds this way, it is electrophilic aromatic substitution. There are a wide variety of electrophiles that can be introduced into a benzene ring in this way, and so electrophilic aromatic substitution is a very important method for the synthesis of substituted aromatic compounds. Ch17 Reactions of Aromatic Compounds (landscape).docx Page2 Bromination of Benzene Bromination follows the same general mechanism for the electrophilic aromatic substitution (EAS). Bromine itself is not electrophilic enough to react with benzene. But the addition of a strong Lewis acid (electron pair acceptor), such as FeBr3, catalyses the reaction, and leads to the substitution product. -
AROMATIC NUCLEOPHILIC SUBSTITUTION-PART -2 Electrophilic Substitution
Dr. Tripti Gangwar AROMATIC NUCLEOPHILIC SUBSTITUTION-PART -2 Electrophilic substitution ◦ The aromatic ring acts as a nucleophile, and attacks an added electrophile E+ ◦ An electron-deficient carbocation intermediate is formed (the rate- determining step) which is then deprotonated to restore aromaticity ◦ electron-donating groups on the aromatic ring (such as -OH, -OCH3, and alkyl) make the reaction faster, since they help to stabilize the electron-poor carbocation intermediate ◦ Lewis acids can make electrophiles even more electron-poor (reactive), increasing the reaction rate. For example FeBr3 / Br2 allows bromination to occur at a useful rate on benzene, whereas Br2 by itself is slow). In fact, a substitution reaction does occur! (But, as you may suspect, this isn’t an electrophilic aromatic substitution reaction.) In this substitution reaction the C-Cl bond breaks, and a C-O bond forms on the same carbon. The species that attacks the ring is a nucleophile, not an electrophile The aromatic ring is electron-poor (electrophilic), not electron rich (nucleophilic) The “leaving group” is chlorine, not H+ The position where the nucleophile attacks is determined by where the leaving group is, not by electronic and steric factors (i.e. no mix of ortho– and para- products as with electrophilic aromatic substitution). In short, the roles of the aromatic ring and attacking species are reversed! The attacking species (CH3O–) is the nucleophile, and the ring is the electrophile. Since the nucleophile is the attacking species, this type of reaction has come to be known as nucleophilic aromatic substitution. n nucleophilic aromatic substitution (NAS), all the trends you learned in electrophilic aromatic substitution operate, but in reverse. -
Aryl Halides
Block 3 Aromatic Hydrocarbons and Halogen Derivatives UNIT14 ARYL HALIDES Structure 14.1 Introduction Electophilic Substitution Reactions Expected Learning Outcomes 14.2 Structure and Reactivity Reactions due to C−X bond 14.5 Reactivity and Relative 14.3 Preparation of Aryl Halides Strength of C−X Bonds in 14.4 Reaction of Aryl Halides Halogen Derivatives Nucleophilic Substitution by 14.6 Summary Addition-Elimination 14.7 Terminal Questions Nucleophilic Substitution via 14.8 Answers Benzene Intermediate 14.1 INTRODUCTION In Unit 13, we have pointed out that there is a difference in the nature of C−X bond of aryl halides and aryl halides. Because of this aryl halides differ from the alkyl halides in their preparation and properties. In this Unit, we will study the unique chemistry of aryl halides. First, we shall take up the structure and reactivity of aryl halides, which is followed by their preparations and properties. At the end of the unit we shall compare the reactivity and relative strength of C−X bond in different type of halogen derivatives. Expected Learning Outcomes After studying this unit, you should be able to: explain why aryl halides are less reactive than alkyl halides, outline the methods of preparation of aryl halides, describe the reactions of aryl halides, and explain the difference in structure and reactivity of alkyl, alkenyl and aryl halides towards nucleophilic substitution reactions. 94 Unit 14 Aryl Halides 14.2 STRUCTURE AND REACTIVITY Before going into the details of the preparations and properties of aryl halides let us take a look at the structure and reactivity of these compounds so that we can understand why their reactions are different from alkyl halides. -
Aromatic Substitution Reactions: an Overview
Review Article Published: 03 Feb, 2020 SF Journal of Pharmaceutical and Analytical Chemistry Aromatic Substitution Reactions: An Overview Kapoor Y1 and Kumar K1,2* 1School of Pharmaceutical Sciences, Apeejay Stya University, Sohna-Palwal Road, Sohna, Gurgaon, Haryana, India 2School of Pharmacy and Technology Management, SVKM’s NMIMS University, Hyderabad, Telangana, India Abstract The introduction or replacement of substituent’s on aromatic rings by substitution reactions is one of the most fundamental transformations in organic chemistry. On the basis of the reaction mechanism, these substitution reactions can be divided into electrophilic, nucleophilic, radical, and transition metal catalyzed. This article also focuses on electrophilic and nucleophilic substitution mechanisms. Introduction The replacement of an atom, generally hydrogen, or a group attached to the carbon from the benzene ring by another group is known as aromatic substitution. The regioselectivity of these reactions depends upon the nature of the existing substituent and can be ortho, Meta or Para selective. Electrophilic Aromatic Substitution (EAS) reactions are important for synthetic purposes and are also among the most thoroughly studied classes of organic reactions from a mechanistic point of view. A wide variety of electrophiles can effect aromatic substitution. Usually, it is a substitution of some other group for hydrogen that is of interest, but this is not always the case. For example, both silicon and mercury substituent’s can be replaced by electrophiles. The reactivity of a particular electrophile determines which aromatic compounds can be successfully substituted. Despite the wide range of electrophilic species and aromatic ring systems that can undergo substitution, a single broad mechanistic picture encompasses most EAS reactions. -
JUN 1 51998 Science
Efforts Toward the Syntheses of Natural Products: Part A: Paeoniflorin Part B: (+)-Taxusin A thesis presented by Rebecca J. Carazza B.S. Chemistry University of Massachusetts, Amherst, 1993 Submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry at the Massachusetts Institute of Technology June 1998 © 1998 Massachusetts Institute of Technology. All rights reserved. SinatureofAuthor: SignatureT- -~- -- .. -uof -Author: -- I- ----- D4pdrtment o('ihemistry May 26, 1998 Certified by: ,Scott C. Virgil Thesis Advisor Acceuted bv: Dietmar Seyferth Chairman, Departmental Committee on Graduate Students O-V .Z\ . JUN 1 51998 Science UR PAES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Rick L. Danheiser - Chairman Professor Scott C. Virgil / Th/sis Supervisor Professor Peter H. Seeberger Efforts Toward the Syntheses of Natural Products: Part A: Paeoniflorin Part B: (+)-Taxusin by Rebecca J. Carazza Submitted to the Department of Chemistry on May 26, 1998 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry Massachusetts Institute of Technology ABSTRACT Part A Efforts toward the synthesis of the monoterpene glycoside paeoniflorin (1) are discussed. Optimization of the previous synthetic route was successful. Synthesis of the key cc-diazo intermediate 30 was achieved and the construction of the carbocyclic frame was completed. Key reactions of the strategy involve a ring contraction via a Wolff rearrangement, and formation of the lactone 78 which undergoes diisobutylaluminum hydride reduction followed by acid catalyzed cyclization to the paeoniflorin ring system 80. A new synthetic strategy was initiated to prepare the key [3.2.1]bicyclooctanone 81 using a palladium mediated olefin cyclization of the acyloin substrate 82. -
Syntheses of Morphine and Codeine (1992 – 2002): Templates for Exploration of Synthetic Tools
Current Organic Synthesis, 2006, 3, 99-120 99 Syntheses of Morphine and Codeine (1992 – 2002): Templates for Exploration of Synthetic Tools L. M. Mascavage#, M. L. Wilson and D. R. Dalton* Department of Chemistry (016-00), Beury Hall, 13th and Norris Streets, Temple University, Philadelphia, PA 19122, USA and Department of Chemistry, Arcadia University, Glenside, PA, 19038, USA Abstract: Morphine (1) and its O-methylated analogue codeine (2), analgesic alkaloids of the opium poppy (Papaver Somniferium), have been targets of organic chemists engaged in synthetic activities for at least half a century. The “first” (Gates) and “most efficient” (Rice) syntheses of morphine (1) and codeine (2) are well known and have been reviewed and analyzed extensively numerous times. However, syntheses of the same two alkaloids that have been reported since 1992 and which have been used as devices to advance the art of organic synthesis are not as widely recognized and they have not been as thoroughly reviewed. Here they are analyzed in the spirit of the use of these two compounds as templates. Further, since both racemic and enantiospecific syntheses are important and since all eight (8) approaches (since 1992) are sufficiently different so as to warrant more tha n superficial examination, they are all considered. H HO 7 H 8 15 6 H H 6 14 N 5 CH3 H 13 NCH3 HO 14 13 9 16 9 O 16 12 15 10 O 10 4 4 11 1, R = H 2, R = CH 1 1 3 RO 3 RO 3 2 2 It is nearly two hundred years since the initial report the ubiquitous standard opium poppy or with cultivars that (1806) of the isolation of morphine (1, R = H) from the might be subsequently generated through genetic unripe seed pods of the opium poppy, Papever somniferum, manipulations so as to maximize production of these or by Friedrich Wihelm Adam Setürner [1], seventy five years related bases. -
Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates
1158 J. Org. Chem. 2000, 65, 1158-1174 Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates John P. Wolfe,† Hiroshi Tomori, Joseph P. Sadighi,‡ Jingjun Yin, and Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Received October 29, 1999 Palladium complexes supported by (o-biphenyl)P(t-Bu)2 (3)or(o-biphenyl)PCy2 (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 °C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination. Owing to the many important applications of aniline derivatives, and the limitations of most methods for their synthesis, a considerable amount of effort has been recently devoted to the development of catalysts that are capable of effecting the cross-coupling of amines with aryl halides and sulfonates.1 However, the proper choice of catalyst (Pd source, ligand choice) is crucial for the success of these reactions.