DOCSLIB.ORG

Experimental and Computational Investigations Into the Benzyl-Claisen Rearrangement

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Experimental and Computational Investigations Into the Benzyl-Claisen Rearrangement Experimental and Computational Investigations into the Benzyl-Claisen Rearrangement Jed M. Burns B.Sc. (Hons I) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 School of Chemistry and Molecular Biosciences i Abstract Being a prime example of a [3,3]-sigmatropic process, the Claisen rearrangement is an essential reaction at the core of modern organic chemistry. Its undisputed value is derived not only from its reliable and predictable application to the synthesis of complex molecules but, also, in being a reaction of longstanding interest in the field of computational organic chemistry, contributing to our theoretical understanding of pericyclic reactions. A long-standing shortcoming of the Claisen rearrangement is that while allyl-vinyl and allyl-phenyl ethers are viable substrates for the reaction, applications to benzyl-vinyl ethers have rarely been reported. To date, a very limited number of benzylic substrates have been investigated, with the few successful reactions typically requiring harsh conditions. Herein, we report the optimisation of a procedure for Claisen rearrangements of benzyl- vinyl ethers (referred to here as the “Benzyl-Claisen” rearrangement) based on a previous literature procedure and, for the first time, investigate the scope of such a process. Benzyl ketene acetals were generated in a short two-step procedure by bromoacetalisation of the requisite benzyl alcohol followed by elimination of HBr. Heating the ketene acetals in refluxing DMF smoothly converted the substrates to the product tolylacetates, which were saponified and isolated as their carboxylic acid derivatives. In the course of the reaction optimisation, a pronounced solvent effect was observed: DMF led to the [3,3]-rearranged product, whereas conducting the reaction in xylene led to a mixture of radical dissociation-recombination products. Electron-donating and electron-neutral substituents (–Me, –Ph, –Cl, –Br, –OMe and –SMe) gave the highest yields in the Benzyl-Claisen rearrangement (24–50%) whereas substrates derived from electron-poor aromatic systems (–NO2, – CN, –COOBn, –SO2Me or –CF3) tended to decompose under the reaction conditions. Claisen rearrangements conducted on meta-substituted systems were observed, unexpectedly, to preferentially generate products via rearrangement “towards” the meta substituent, leading to sterically crowded 1,2,3-trisubstituted tolylacetates. By analogy to the aromatic Claisen rearrangement, it was expected that the Benzyl-Claisen rearrangement should proceed through a dearomatised isotoluene intermediate. A benzyl ketene acetal possessing a terminal alkene was observed to form a ring-closed product via a facile Alder- ene reaction when submitted to the standard reaction conditions. This supports the formation of a dearomatised isotoluene intermediate along the reaction pathway and therefore the operation of the [3,3]-sigmatropic rearrangement. ii The mechanism of the Benzyl-Claisen rearrangement was investigated using computational methods. The activation free energy for rearrangement of benzyl vinyl ether calculated with the high-accuracy CBS-QB3 method was 40.1 kcal/mol, which is 10.2 kcal/mol higher than that of the aliphatic Claisen rearrangement of allyl vinyl ether at the same level of theory. The C-2 alkoxy substituent on the ketene acetal was shown to be essential in making the process both thermodynamically and kinetically favourable, lowering the barrier by 10.2 kcal/mol and stabilising the intermediate isotoluene by 18.0 kcal/mol. As a general rule, substitution of the aromatic systems with an electron-donor group was calculated to lower the barrier for the reaction whilst electron- withdrawing substituents were calculated to raise it. The para-OMe substituent was calculated to lower the activation free energy by 1.4 kcal/mol whereas the para-CN substituent raised the barrier by 0.9 kcal/mol. The regiochemical preference for rearrangement “towards” existing meta- substituents was confirmed in silico with 1,2,3-substituted product being favoured by 0.7 kcal/mol for the cyano substituent and 0.6 kcal/mol for the methoxy substituent. The results were rationalised as being due to the interaction of the frontier molecular orbitals of the system, with the preferred site on the aromatic ring possessing larger orbital coefficients. The computational results support the operation of a [3,3]-sigmatropic process and provide direction for the further development of the Benzyl-Claisen rearrangement. iii Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. Publications during candidature No publications. Publications included in this thesis No publications included. Contributions by others to the thesis Dr Ross McGeary and Dr Elizabeth Krenske have both had significant input into the conception and design of the project, as well as editing of the thesis iv Statement of parts of the thesis submitted to qualify for the award of another degree None. v Acknowledgements Firstly, I would like to thank Dr Ross McGeary for being my supervisor over the course of the PhD. For the ideas, helpful conversations and endless support, thank you. Synthetic methodology is my dream, and for the past 3 years I have been able to wake up every day and do what I love. I appreciate that at times I’ve been given an enviable degree of freedom in choosing the direction of my research (more than enough rope to hang myself) and for that I am truly grateful. To my second supervisor, Dr Elizabeth Krenske, thank you for introducing me to the strange and magical world that is computational chemistry. Chemistry, for me, has always been about trying to uncover “the rules” that govern the dim and murky realm of atoms and molecules. The knowledge you have given me (over many patient hours, thoroughly complicated by my confusion) means that that other-world is now in sharper relief. I have you to blame for the “superpower” that is the ability to do chemistry at 1 o’clock in the morning. I would also like to thank all the people in the SCMB who have made up the colourful fabric of our research community. My fellow group members for the short witticisms and long conversations (and free food!). Dr Tri Le and Graham MacFarlane for help with characterisation data, which was totally superfluous to the news and gossip I could catch up on. The tutors, staff and students on level 5 who allowed me to take a holiday, once a week, to teach. The other honours and PhD students for the opportunities to shoot the breeze, complain bitterly about the state of the art and, of course, drink coffee (or beer). Finally, to my family (Ma and Jess), and my beautiful soon-to-be wife Raichelle, thank you so much for providing me with the love and support that I needed throughout my PhD experience. I know deep in my heart that without the comfort, conversation and care that you offer I wouldn’t have made it. This thesis is for you. I love you all. P.S. To my dear colour-blind readers, I apologise in advance for the HSQC/HMBC spectra present in the experimental section and the free energy and HOMO/LUMO diagrams present in the computational section. Unfortunately, there are only a limited number of pigments which work on white backgrounds. vi Keywords Claisen rearrangement, Benzyl-Claisen, ketene acetal, computational chemistry, density functional theory Australian and New Zealand Standard Research Classifications (ANZSRC) ANZSRC code: 030503, Organic Chemical Synthesis, 70% ANZSRC code: 030701, Quantum Chemistry, 30% Fields of Research (FoR) Classification FoR code: 0305, Organic Chemistry, 70% FoR code: 0307, Theoretical and Computational Chemistry, 30% vii Table of Contents Abstract ..................................................................................................................................... ii Declaration by author ................................................................................................................iv Publications during candidature ................................................................................................iv
Load more

Recommended publications
  • Download Answer
    Question #72514, Chemistry / Organic Chemistry Explain the electrocyclic and sigmatropic reaction in detail. Answer: In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. The Diels-Alder reaction is a common example. The especially interesting thing about this reaction is its stereochemistry. When performing an electrocyclic reaction, it is often desirable to predict the cis/trans geometry of the reaction's product. The first step in this process is to determine whether a reaction proceeds through conrotation or disrotation. Reactions can be either photochemical or thermal and their mexanisms are different. Mechanism of thermal reactions: Correlation diagrams, which connect the molecular orbitals of the reactant to those of the product having the same symmetry, can then be constructed for the two processes. Mechanism of photochemical reactions: If the ring opening of 3,4-dimethylcyclobutene were carried out under photochemical conditions the resulting electrocyclization would be occur via a disrotatory mode instead of a conrotatory mode as can be seen by the correlation diagram for the allowed excited state ring opening reaction. A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular process. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement [3,3] sigmatropic shifts are well studied sigmatropic rearrangements. The Woodward– Hoffman rules predict that these six electron reactions would proceed suprafacially, via a Huckel topology transition state.
    [Show full text]
  • Synthesis of Y,Δ-Unsaturated Amino Acids by Claisen Rearrangement - Last 25 Years
    The Free Internet Journal Review for Organic Chemistry Archive for Arkivoc 2021, part ii, 0-0 Organic Chemistry to be inserted by editorial office Synthesis of y,δ-unsaturated amino acids by Claisen rearrangement - last 25 years Monika Bilska-Markowska,a Marcin Kaźmierczak,*a,b and Henryk Koroniaka aFaculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland bCentre for Advanced Technologies, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 10, 61-614 Poznań, Poland Email: [email protected] In dedication to Professor Zbigniew Czarnocki on the occasion of his 66th anniversary Received mm-dd-yyyy Accepted mm-dd-yyyy Published on line mm-dd-yyyy Dates to be inserted by editorial office Abstract This mini review summarizes achievements in the synthesis of y,δ-unsaturated amino acids via Claisen rearrangements. The multitude of products that can be obtained using the discussed protocol shows that it is one of the most important reactions in organic synthesis. Moreover, many Claisen rearrangement products are building blocks in the synthesis of more complex molecules with potential biological activity. Keywords: y,δ-Unsaturated amino acids, Claisen rearrangement, fluorine-containing γ,δ-unsaturated amino acids, diastereoselectivity, optically active compounds DOI: https://doi.org/10.24820/ark.5550190.p011.335 Page 1 ©AUTHOR(S) Arkivoc 2021, ii, 0-0 Bilska-Markowska, M. et al. Table of Contents 1. Introduction 2. Chelated Claisen Rearrangement 3. Related Versions of Claisen Rearrangement for γ,δ-Unsaturated Amino Acids 4. Application of Claisen Rearrangement to the Synthesis of Fluorine-containing γ,δ-Unsaturated Amino Acids 5.
    [Show full text]
  • Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo- Philes
    SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 3035–3068 short review 3035 en Syn thesis E. M. Budynina et al. Short Review Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo- philes Ekaterina M. Budynina* Konstantin L. Ivanov Ivan D. Sorokin Mikhail Ya. Melnikov Lomonosov Moscow State University, Department of Chemistry, Leninskie gory 1-3, Moscow 119991, Russian Federation [email protected] Received: 06.02.2017 Accepted after revision: 07.04.2017 Published online: 18.05.2017 DOI: 10.1055/s-0036-1589021; Art ID: ss-2017-z0077-sr Abstract Ring opening of donor–acceptor cyclopropanes with various N-nucleophiles provides a simple approach to 1,3-functionalized com- pounds that are useful building blocks in organic synthesis, especially in assembling various N-heterocycles, including natural products. In this review, ring-opening reactions of donor–acceptor cyclopropanes with amines, amides, hydrazines, N-heterocycles, nitriles, and the azide ion are summarized. 1 Introduction 2 Ring Opening with Amines Ekaterina M. Budynina studied chemistry at Lomonosov Moscow 3 Ring Opening with Amines Accompanied by Secondary Processes State University (MSU) and received her Diploma in 2001 and Ph.D. in Involving the N-Center 2003. Since 2013, she has been a leading research scientist at Depart- 3.1 Reactions of Cyclopropane-1,1-diesters with Primary and Secondary ment of Chemistry MSU, focusing on the reactivity of activated cyclo- Amines propanes towards various nucleophilic agents, as well as in reactions
    [Show full text]
  • Catalyzed Claisen Rearrangement of Allenyl Vinyl Ethers: a Synthetic and Mechanistic Approach Kassem M
    Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2011 Gold (I)-Catalyzed Claisen Rearrangement of Allenyl Vinyl Ethers: A Synthetic and Mechanistic Approach Kassem M. Hallal Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES GOLD (I)-CATALYZED CLAISEN REARRANGEMENT OF ALLENYL VINYL ETHERS; A SYNTHETIC AND MECHANISTIC APPROACH By KASSEM M. HALLAL A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Spring Semester, 2011 The members of the committee approve the dissertation of Kassem M. Hallal defended on March 18, 2011. _______________________________________ Marie E. Krafft Professor Directing Dissertation _______________________________________ Thomas C. S. Keller III University Representative _______________________________________ Robert A. Holton Committee Member _______________________________________ Gregory B. Dudley Committee Member _______________________________________ William T. Cooper Committee Member Approved: ____________________________________________________________ Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry The Graduate School has verified and approved the above-named committee members. ii This work is dedicated To My soul mate, lovely wife zeinab, My baby Mohammad And also to my parents Mohammad & Kamela And to My brothers and lovely sister Youssef, Hamzeh and Fatima & My Great professor Prof. Marie E. Krafft iii ACKNOWLEDGEMENTS Starting my PhD career at Florida State University was one of the most important stages in my life. Throughout the past five years, I learned a lot of things about chemistry and science, however, the most important thing which I learned was the chemistry of life.
    [Show full text]
  • R. B. Woodward Precipitation of Barium in the Copper-Tin Group Of
    HETEROCYCLES, Vol. 7, No. 1. 1977 R. B. Woodward Precipitation of barium in the copper-tin group of qualitative analysis. W.J.Hal1 and RBW, -Ind. Eng. Chem., Anal. Ed., 6, 478 (1934). A new pressure regulator for vacuum distillation. R.L.Emerson and RBW, g.,2, 347 (1937). The Staling of coffee. II. S.C.Prescott, R.L.Emerson, RBW, and R. Heggie, Food Re- --search, 2, 165 (1937). Pyrolysis of organomagnesium compounds. I. A new agent for the reduction of bemophenone. D.B.Clapp, and RBW, 1. ---Am. Chem. Soc., -60, 1019 (1938). The direct introduction of the angular methyl group. RBW, Ibid., 62, 1208 (1940). Experiments on the synthesis of oestrone. I. 2-(8-phenylethy1)-furans as components in the diene synthesis. RBW, Ibid., 62, 1478 (1940). The formation of Reissert's compounds in non-aqueous media. RBW, Ibid., 62, 1626 (1940). A new optically active reagent for carbonyl compounds. The resolution of -dl-camphor. RBW, T. P. Kohman, and G. C. Harris, Ibid., 63, lu) (1941). The isolation and properties of 1, 1-dineopentylethylene, a component of triisobutylene. P.D.Bartlett, G.L. Fraser, and RBW, x.,3, 495 (1941). Structure and absorption spectra of a,p-unsaturated ketones. RBW, Ibid., 3, 1123 (1941). 5 Structure and absorption spectra. II. 3-Acetoxy-A -(6)-~cholestene-7-carboxylicacid. RBW, and A.F.Clifiord, -Ibid., -63, 2727 (1941). The structure of cantharidine and the synthesis of desoxycantharidine. RLW, and R.B. Loftfield, Ibid., 3, 3167 (1941). -t-Butyllithium. P.D.Bardett, C .G.Swain, and RBW, --Ibid., 63, 3229 (1941).
    [Show full text]
  • A New Reaction Mechanism of Claisen Rearrangement Induced by Few-Optical-Cycle Pulses: Demonstration of Nonthermal Chemistry by Femtosecond Vibrational Spectroscopy*
    Pure Appl. Chem., Vol. 85, No. 10, pp. 1991–2004, 2013. http://dx.doi.org/10.1351/PAC-CON-12-12-01 © 2013 IUPAC, Publication date (Web): 13 August 2013 A new reaction mechanism of Claisen rearrangement induced by few-optical-cycle pulses: Demonstration of nonthermal chemistry by femtosecond vibrational spectroscopy* Izumi Iwakura1,2,3,‡, Atsushi Yabushita4, Jun Liu2, Kotaro Okamura2, Satoko Kezuka5, and Takayoshi Kobayashi2 1Innovative Use of Light and Materials/Life, PRESTO, JST, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan; 2University of Electro-Communications, 1-5-1 Chofugaoka, Chofu, Tokyo 182-8585, Japan; 3Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Yokohama 221-8686, Japan; 4Department of Electrophysics, National Chiao-Tung University, Hsinchu 300, Taiwan; 5Department of Applied Chemistry, School of Engineering, Tokai University, 1117 Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan Abstract: Time-resolved vibration spectroscopy is the only known way to directly observe reaction processes. In this work, we measure time-resolved vibration spectra of the Claisen rearrangement triggered and observed by few-optical-cycle pulses. Changes in molecular structure during the reaction, including its transition states (TSs), are elucidated by observ- ing the transient changes of molecular vibration wavenumbers. We pump samples with visi- ble ultrashort pulses of shorter duration than the molecular vibration period, and with photon energies much lower than the minimum excitation energy of the sample. The results indicate that the “nonthermal Claisen rearrangement” can be triggered by visible few-optical-cycle pulses exciting molecular vibrations in the electronic ground state of the sample, which replaces the typical thermal Claisen rearrangement.
    [Show full text]
  • Robert Burns Woodward 1917–1979
    NATIONAL ACADEMY OF SCIENCES ROBERT BURNS WOODWARD 1917–1979 A Biographical Memoir by ELKAN BLOUT Any opinions expressed in this memoir are those of the author and do not necessarily reflect the views of the National Academy of Sciences. Biographical Memoirs, VOLUME 80 PUBLISHED 2001 BY THE NATIONAL ACADEMY PRESS WASHINGTON, D.C. ROBERT BURNS WOODWARD April 10, 1917–July 8, 1979 BY ELKAN BLOUT OBERT BURNS WOODWARD was the preeminent organic chemist Rof the twentieth century. This opinion is shared by his colleagues, students, and by other distinguished chemists. Bob Woodward was born in Boston, Massachusetts, and was an only child. His father died when Bob was less than two years old, and his mother had to work hard to support her son. His early education was in the Quincy, Massachusetts, public schools. During this period he was allowed to skip three years, thus enabling him to finish grammar and high schools in nine years. In 1933 at the age of 16, Bob Woodward enrolled in the Massachusetts Institute of Technology to study chemistry, although he also had interests at that time in mathematics, literature, and architecture. His unusual talents were soon apparent to the MIT faculty, and his needs for individual study and intensive effort were met and encouraged. Bob did not disappoint his MIT teachers. He received his B.S. degree in 1936 and completed his doctorate in the spring of 1937, at which time he was only 20 years of age. Immediately following his graduation Bob taught summer school at the University of Illinois, but then returned to Harvard’s Department of Chemistry to start a productive period with an assistantship under Professor E.
    [Show full text]
  • Rearrangement Reactions
    Rearrangement Reactions A rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. 1, 2-Rearrangements A 1, 2-rearrangement is an organic reaction where a substituent moves from one atom to another atom in a chemical compound. In a 1, 2 shift the movement involves two adjacent atoms but moves over larger distances are possible. In general straight-chain alkanes, are converted to branched isomers by heating in the presence of a catalyst. Examples include isomerisation of n-butane to isobutane and pentane to isopentane. Highly branched alkanes have favorable combustion characteristics for internal combustion engines. Further examples are the Wagner-Meerwein rearrangement: and the Beckmann rearrangement, which is relevant to the production of certain nylons: Pericyclic reactions A pericyclic reaction is a type of reaction with multiple carbon-carbon bonds making and breaking wherein the transition state of the molecule has a cyclic geometry and the reaction progresses in a concerted fashion. Examples are hydride shifts [email protected] and the Claisen rearrangement: Olefin metathesis Olefin metathesis is a formal exchange of the alkylidene fragments in two alkenes. It is a catalytic reaction with carbene, or more accurately, transition metal carbene complexintermediates. In this example (ethenolysis, a pair of vinyl compounds form a new symmetrical alkene with expulsion of ethylene. Pinacol rearrangement The pinacol–pinacolone rearrangement is a method for converting a 1,2-diol to a carbonyl compound in organic chemistry. The 1,2-rearrangement takes place under acidic conditions.
    [Show full text]
  • The Mechanism of the Para-Claisen Rearrangement
    THE MECHANISM OF TIlE PARA-CLAISEN REARRANGEME NT by ROY TERANISHI A THESIS submitted to OREGON STAT COLLEGE in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY June 1954 APPROVED: Assistant Professor of Chemistry In Charge of Major Chairman of Chemistry Department Chairman of School Graduate Conimittee Dean of Graduate School ,-:, Date thesis is presented _ ?/, fgr'/ Typed by Mary Willits TABLE OF CONTENTS Page Introduction. e . e . i History ........ e s e s . 3 Dicuson ...... 9 Experimental ..... 19 Tables. * ...... 22 Summary ........ s s s . 27 13 i bi i ogr aphy ........ 28 THE MECHANISM OF THE PARA-CLAISEN REARRANGEMENT INTRODUCTION The mechanism of the Claisen rearrangement to the para position has not been satisfactorily explained or proved, although that postulated for the rearrangement to the ortho position is in good agreement with experimental data. D. Stanley Tarbell (22, p.497) sug:ested that the rearrangement to the para position involved a dissociation of the allyl group, either as an ion or a radical, although he mentions that serious objections can be raised to both. liurd and Pollack (10, p.550) have suggested that rearrange- ment to the para position might go by two steps: first, a shift of the allyl group to the ortho position with inver- sion, as described for the ortho rearrangement, followed by another shift to the para position with inversion. Very recently, in view of new data presented, there has been a tendency to accept this mechanism. In this mochanism,first postulated by Hurd and Pollack (lo, p.550), the intermediate formed in the first step would be a dienone, III.
    [Show full text]
  • The Claisen Rearrangement (Transition State Analog/Monoclonal Antibody/Chorismate Mutase Model) DONALD HILVERT*, STEPHEN H
    Proc. Natl. Acad. Sci. USA Vol. 85, pp. 4953-4955, July 1988 Chemistry Catalysis of concerted reactions by antibodies: The Claisen rearrangement (transition state analog/monoclonal antibody/chorismate mutase model) DONALD HILVERT*, STEPHEN H. CARPENTER, KAREN D. NARED, AND MARIA-TERESA M. AUDITOR Department of Molecular Biology, Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, La Jolla, CA 92037 Communicated by Emil Thomas Kaiser, March 28, 1988 (receivedfor review March 15, 1988) ABSTRACT Monoclonal antibodies were prepared against The oxabicyclic compound 4a, which mimics the putative a transition state analog inhibitor of chorismate mutase (EC transition state structure, is the best known inhibitor of 5.4.99.5). One ofthe antibodies catalyzes the rearrangement of chorismate mutase (13). It binds approximately 100 times chorismate to prephenate with rate accelerations of more than more tightly to the enzyme than does chorismate (13). We 2 orders of magnitude compared to the uncatalyzed reaction. have synthesized a derivative of4a and used it as a hapten to Saturation kinetics were observed, and at 250C the values of elicit monoclonal antibodies. Having completed a prelimi- k,.t and Km were 1.2 x 1O-3 S-' and 5.1 x 10-5 M respec- nary screen of 15 ofthe 46 resulting antibodies, we report that tively. The transition state analog was shown to be a compet- one of these significantly accelerates the rearrangement of itive inhibitor of the reaction with Ki equal to 0.6 JIM. These chorismate to prephenate. results demonstrate the feasibility of using rationally designed immunogens to generate antibodies that catalyze concerted MATERIALS AND METHODS reactions.
    [Show full text]
  • Pericyclic Reactions Notes
    - 1 - PERICYCLIC REACTIONS NOTES Pericyclic reactions cannot be treated adequately by “curly-arrow” formalisms and a knowledge of molecular orbital theory is crucial to their understanding. They are reactions in which “all first order changes in bonding relationships takes place in concert on a closed curve” (Woodward & Hoffmann). More simply, the term “pericyclic” covers all concerted reactions involving a cyclic flow of electrons through a single transition state. Pericyclic reactions can be predicted and controlled to a great degree, which makes them very useful in synthesis. There are broadly four classes of pericyclic reaction: Sigmatropic – These are unimolecular isomerisations, and involve the movement of a σ-bond from one position to another. An illustration would be the first step of the Claisen Rearrangement: Note the nomenclature of this reaction, being described as a [i,j] shift. For example, this following is a [1,7] shift: Electrocyclic – These are unimolecular. They are characterised by ring opening or closing with a σ- bond forming at one end. Ring closing is more common, since this is formation of a σ-bond at the expense of a π-bond, but ring strain can lead to opening. Two examples are: Cycloaddition – This is the largest class of pericyclic reaction. It is characterised by two fragments coming together to form two new σ-bonds in a ring. Some examples are Diels-Alder and Ozonolysis reactions, which are described below. Chelotropic reactions are a specific type of cycloaddition, where the two bonds are made or broken at the same atom. The classic example of this is carbene addition to a double bond.
    [Show full text]
  • Arynes in Synthesis; New Reaction and Precursor Development
    ARYNES IN SYNTHESIS; NEW REACTION AND PRECURSOR DEVELOPMENT A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences 2014 By Donald McAusland School of Chemistry 2 Contents Abstract 11 Declaration 12 Copyright 13 Acknowledgements 14 1 Introduction 15 1.1 Generationofbenzyne ............................ 17 1.2 Reactionsofbenzyne............................. 19 1.2.1 Pericyclicreactions. 19 1.2.2 Nucleophilicadditiontoarynes . 21 1.2.3 Transition-metal-catalysed reactions . 26 1.3 Selectivitywithsubstitutedarynes . ..... 28 1.4 (Trimethylsilyl)phenyl triflates and related aryne precursors . 32 1.4.1 ortho-Lithiation ........................... 33 1.4.2 [4+2]Cycloaddition . 34 1.4.3 Oxidative para-triflation of acetanilides . 34 1.4.4 Commerciallyavailableprecursors . 35 1.4.5 Precursors for the synthesis of polyaromatic structures...... 35 1.4.6 Other functionalised Kobayashi precursors . ..... 37 1.4.7 Relatedaryneprecursors. 39 1.5 Arynesinsynthesis.............................. 41 1.5.1 Indolesyntheses ........................... 42 2 The Benzyne Fischer Indole Reaction 46 2.1 Introduction.................................. 46 2.1.1 Buchwaldmodification. 47 Contents 3 2.1.2 The arylation of hydrazones with benzyne . 52 2.2 Application of aryne electrophiles to the Fischer indole synthesis . 52 2.2.1 Aryne reactions of other hydrazones . 55 2.2.2 BenzyneFischerindolescope . 58 2.2.3 Substitutedarynes . 60 2.2.4 Miscellaneoustosylhydrazones. 66 2.3 Conclusions .................................. 67 3 Synthesis and Applications of New Aryne Precursors 68 3.1 Introduction.................................. 68 3.1.1 Palladium cross-coupling chemistry . 68 3.1.2 TheSuzukireaction ......................... 69 3.1.3 Organoboronreagents . 71 3.1.4 Chemoselectivity in Suzuki couplings . 74 3.2 Aims.....................................
    [Show full text]