DOCSLIB.ORG

Possible Chemical Warfare Nerve Agents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Possible Chemical Warfare Nerve Agents Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2013, vol. 82(1), p. 2-24 ISSN 0372-7025 DOI: 10.31482/mmsl.2013.001 REVIEW ARTICLE BINDING OF QUATERNARY AMMONIUM SALTS TO ACETYLCHOLINE RECEPTORS: POSSIBLE CHEMICAL WARFARE NERVE AGENTS James C. Ball 1083 Jewell Road, Milan, MI 48160, USA Received 22 th January 2013. Revised 12 th February 2013. Published 8 th March 2013. Summary Classical chemical nerve agents are organophosphate based compounds such as Sarin, Soman, Tabun, VX and others. These compounds inhibit acetylcholinesterases in the synapses of nerve junctions. Instead of inactivating acetylcholinesterases, compounds, quaternary amines, can block nerve transmission by binding primarily to the acetylcholine receptor sites. The U.S. Patent Office has published 23 unique patents or invention registrations on the synthesis of compounds that can bind to muscarinic and nicotinic acetylcholine receptors. It is likely that some of these compounds could serve as either polarizing or nonpolarizing nerve agents that bind to the acetylcholine receptor and block binding of acetylcholine. This paper has systematically reviewed a series of bisquaternary amines that could be potentially deadly nerve agents. Analogous tertiary amines, based on the structure of the parent bisquaternary amines, have been proposed as compounds that might be more soluble in membranes making them more bioavailable and toxic. Finally, methods have been discussed that could identify this class of compounds using a bioassay for binding to the acetylcholine receptor. A tool in the identification of these compounds, the Hofmann elimination reaction, has been proposed as a novel method for helping to establish that quaternary or tertiary amines are functional groups of the nerve agent. Key words: Quaternary ammonium salts; nerve agents; chemical warfare; acetylcholine receptor INTRODUCTION AND BACKGROUND the skin as well as through inhalation and oral expo - sure. These compounds act on acetylcholinesterases Classical chemical nerve agents are organophos - in the synapses of nerve junctions. The mode of ac - phate based compounds such as Sarin, Soman, tion of these agents involves phosphorylation Tabun, VX and others. These agents have properties of the active site of acetylcholinesterase followed by that make them uniquely suitable as chemical warfare “aging” in some compounds, a chemical reaction in - agents including high toxicity by all routes of expo - volving the spontaneous formation of a stable cova - sure. The hydrophobic nature of these chemicals lent bond in the active site of the enzyme. In a typical makes them susceptible to absorption through nerve conduction scenario, acetylcholine is released from the nerve terminus of the synaptic junction and rapidly diffuses across the synaptic cleft 1083 Jewell Road, Milan, MI 48160, USA to the postjunctional membrane where it binds [email protected] to acetylcholine receptors. When two acetylcholine (734) 429-1280 molecules bind to their respective sites within a re - Ball: Quaternary Ammonium Salts – Possible Chemical Agents ceptor, a conformational change occurs in the recep - receptors and opens the channel for the migration tor proteins allowing the opening of a channel with of cations. Thus, succinylcholine acts to depolarize the influx of Na +/Ca 2+ and efflux of K + [1]. the neuromuscular endplate. Succinylcholine is not The movement of cations through the channel causes hydrolyzed by the usual acetylcholinesterase but is the nerve to become depolarized; the nerve repolar - hydrolyzed by butyrylcholinesterase – a slower izes once the acetylcholine has diffused away from enzyme. The development of nondepolarizing the receptor causing the channel to close. Acetyl - compounds as an adjunct to anesthesia and used as choline is prevented from continually binding to a tool to relax muscles during surgery has resulted the receptor by rapid hydrolysis in a reaction catalyzed in the identification of several bisquaternary by acetylcholinesterase. If this enzyme is inactivated, ammonium compounds such as pancuronium as happens with the binding of the phosphorus-based (Figure 3), vercuronium (Figure 4) and tubocurarine nerve agents, the levels of acetylcholine do not dimin - (Figure 1) [3]. ish, the channel remains open and the nerve remains polarized; nerve conduction ceases to exist because the nerve cannot repolarize. Nicotinic acetylcholine O receptors are cholinergic receptors (responsive O H + to acetylcholine) found in the central nervous system, + N peripheral nervous systems and skeletal muscles. N H H O H OH O O + N O Figure 3. Pancuronium Cation [(2 S,3 S,5 S,8 R,9 S,10 S,13 S,14 S,16 S,17 R)- 17-acetyloxy- O 10,13-dimethyl-2,16-bis(1-methyl-3,4,5,6-tetrahydro-2 H- pyridin-1-yl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetra- + OH N decahydro-1 H-cyclopenta[ a]phenanthren-3-yl] acetate H O Figure 1. d-Tubocurarine 6,6’-dimethoxy-2,2,2’,2’-tetramethyltubocuraran-2,2’- O diium-7’,12’-diol O + H N N + OO+ H N N H O OO H Figure 2. Succinylcholine Cation O 2,2'-[(1,4-dioxobutane-1,4-diyl)bis(oxy)]bis( N,N,N - Figure 4. Vercuronium Cation trimethylethanaminium) [(2 S,3 S,5 S,8 R,9 S,10 S,13 S,14 S,16 S,17 S)-17-acetyloxy- 10,13-dimethyl-16-(1-methyl-3,4,5,6-tetrahydro-2 H-pyridin -1-yl)-2-(1-piperidyl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17- Tubocurarine was the first compound identified tetradecahydro-1 H-cyclopenta[a]phenanthren-3-yl] acetate to cause muscle paralysis via binding to the nicotinic acetylcholine receptor. This compound was identified from curare, an extract of a South American plant A key feature of nondepolarizing compounds Pareira, Chondrodendron tomentosum [2]. is that they form a rigid molecular framework. Tubocurarine is a compound with two quaternary Decamethonium (Figure 5), with two quaternary ammonium functional groups (Figure 1) that binds to ammonium centers separated by 10 methylene (-CH 2-) the nicotinic acetylcholine receptor and blocks groups, is sufficiently flexible that both sites for the binding of acetylcholine. The binding of this acetylcholine binding are bound resulting in the compound does not open the membrane channel. nerve becoming depolarized [4, 5]. Two broad Succinylcholine (Figure 2, basically two classes of compounds that bind to acetylcholine acetylcholine molecules joined back to back) binds to receptors are the competitive inhibitors that block both acetylcholine binding sites in the acetylcholine binding of the acetylcholine neurotransmitters, but 3 Ball: Quaternary Ammonium Salts – Possible Chemical Agents do not activate the ion channel and compounds that The development of new agents, which do not bind tightly to both sites in the acetylcholine receptor depend on the inactivation of acetylcholinesterase, causing depolarization of the nerve. Depolarization would make the use of these three countermeasures of the nerve allows initial transmission of the nerve mute. New agents would also significantly delay impulse to the muscle resulting in twitching the forensic identification of the agent and its origin. of the muscles (fasciculations) followed by paralysis An example of potential new nerve agents comes of the affected muscles. from an examination of the U.S. Patent Office which has published 23 unique patents or invention Phosphorus-based nerve agents were first registrations on the synthesis of compounds that can synthesized by German chemists prior to and during block nerve transmission by binding to muscarinic World War II and were, fortunately, never used and nicotinic acetylcholine receptors [8-32]. It is in combat [6]. There has been little research likely that some of these compounds could serve as published on the development of new nerve agents either polarizing or nonpolarizing nerve agents that and it is difficult to determine the extent to which any bind to the acetylcholine receptor and block binding country has developed new and novel nerve agents. of acetylcholine. There are a number of motivations why countries would pursue such research. For example, some The primary purpose of this paper is to report on of the phosphorous-based nerve agents can be an investigation of the open literature for clues to counteracted three ways: possible new classes of chemical weapons, or in this case, a new class of nerve agents. This paper will 1) through the use of agents that reactivate endeavor to review some of the physical properties acetylcholinesterase (2-PAM, 2-pyridine aldoxime (e.g. solubility, hydrophobicity) and potential methyl chloride; Figure 6); toxicities of a new class of nerve agents and their potential for use in chemical warfare. There are 2) by protection of the enzyme from attack several objectives of this study: (pyridostigmine; Figure 7) [4]; 1) to understand the structure, properties and 3) or by replacement of inactivated possible modes of action of a “second class” of nerve acetylcholinesterase by the intravenous injection agents that does not involve the inhibition of (i.v.) of human butyrylcholinesterase [7]. acetylcholinesterase, a mechanism common to the phosphorous based nerve agents – the original class of nerve agents, + + N N 2) review structural characteristics of these compounds that appear to be important Figure 5. Decamethonium Cation in the structure-toxicity relationship, Trimethyl-(10-trimethylammoniodecyl)ammonium 3) review characteristics of quaternary ammonium compounds that optimize their binding + to the nicotinic or muscarinic acetylcholine receptors, N OH N 4) discuss the possibility that more potent nerve
Load more

Recommended publications
  • Open PS Thesis - Clara Capparelli
    The Pennsylvania State University The Graduate School Department of Material Science and Engineering INFLUENCE OF CARBON SPACERS AND ALKYL PENDANT CHAINS ON THE STABILITY OF QUATERNARY AMMONIUM CATIONS FOR ANION EXCHANGE MEMBRANES A Thesis in Material Science and Engineering by Clara Capparelli 2015 Clara Capparelli Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science August 2015 The thesis of Clara Capparelli was reviewed and approved* by the following: Michael A. Hickner Associate Professor of Materials Science and Engineering Thesis Advisor James Runt Professor of Polymer Science T.C. Mike Chung Professor of Material Science and Engineering Suzanne Mohney Professor of Material Science and Engineering and Electrical Engineering Chair, Intercollege Graduate Degree Program in Material Science and Engineering *Signatures are on file in the Graduate School iii ABSTRACT Proton and anion exchange membranes are of great importance in the function of fuel cells, one of the most promising technologies for renewable energy conversion. Proton exchange membrane fuel cells (PEMFC) have been studied extensively in the past couple of decades, and there have been tremendous advances in the development of these systems, especially in industries such as automotive and portable power. Anion exchange membranes (AEM) have caught the attention of scientists because they would allow for the development of fuel cells without costly precious metal catalysts, among other advantages. Efforts are being made in developing long-lived and high performance AEMs for fuel cell applications. Primarily, the focus in AEM research has been membrane stability. It has been observed that AEMs are not as stable as the state-of-the-art NAFION® PEM and demonstrations of cell performance beyond 1000 hours is rare.
    [Show full text]
  • Subject Index
    455 Subject Index Aminohydroxylation, 364 a-Aminoketone, 281 4-Aminophenol, 18 A Aminothiophene, 158 Abnormal Claisen rearrangement, 1 a-Aminothiophenols, 184 Acrolein, 378 Ammonium ylide, 383 2-(Acylamino)-toluenes, 245 Angeli-Rimini hydroxamic acid Acylation, 100, 145, 200 synthesis, 9 Acyl azides, 98 ~-Anomer, 225 Acylium ion, 145, 149, 175, 177 Anomeric center, 211 a-Acyloxycarboxamides, 298 Anomeric effect, 135 a-Acyloxyketones, 17 ANRORC mechanism, 10 a-Acyloxythioethers, 327 Anthracenes, 51 Acyl transfer, 17, 42, 228, 298, 305, Anti-Markovnikov addition, 219 327,345 Amdt-Eistert homologation, 11 AIBN, 22, 23, 415 Aryl-acetylene, 66 Alder ene reaction, 2 Arylation, 253 Alder's endo rule, Ill 0-Aryliminoethers, 67 Aldol condensation, 3, 14, 26, 34, 2-Arylindoles, 38 69, 130, 147, 172, 305, Aryl migration, 31 340,396,412 Autoxidation, 69, 115, 118 Aldosylamine, 8 Auwers reaction, 13 Alkyl migration, 16, 132, 315, 443 Axial, 347 Alkylation, 144, 145 Azalactone, I 00 N-Aikylation, 162 Azides, 125, 330 Alkylidene carbene, 151 Azirine, 6, 7, 281 Allan-Robinson reaction, 4, 228 Azulene, 310 Allene, 119 1t-Allyl complex, 414 B Allylation, 213, 414 Baeyer-Drewson Allylstannane, 213 indigo synthesis, 14 Allylsilanes, 349 Baeyer-Villiger oxidation, 16, 53 Alper carbonylation, 6 Baker-Venkataraman Alpine-borane®, 262 rearrangement, 17 Aluminum phenolate, 149 Balz-Schiemann reaction, 354 Amadori rearrangement, 8 Bamberger rearrangement, 18 Amide acetal, 74 Bamford-Stevens reaction, 19 Amides, 28, 67,276,339, 356 Bargellini reaction, 20 Amidine,
    [Show full text]
  • Solvating Alkylamine Hofmann Elimination in Zeolites Through Cooperative Adsorption Han Chen† and Omar A
    Solvating Alkylamine Hofmann Elimination in Zeolites Through Cooperative Adsorption Han Chen† and Omar A. Abdelrahman †,‡* † Department of Chemical Engineering, University of Massachusetts Amherst, 686 N. Pleasant Street, Amherst, MA 01003, USA ‡ Catalysis Center for Energy Innovation, University of Delaware, 150 Academy Street, Newark, DE 19716, USA *Corresponding Author: [email protected] Abstract. A kinetic investigation of the vapor phase Hofmann elimination of tert-butylamine over H- ZSM-5 reveals a carbocation mediated E1-like mechanism, where isobutene and ammonia are exclusively produced over Brønsted acid sites. Hofmann elimination kinetics are found to be insensitive to Al content or siting, varying only with alkylamine carbocation stability (rtertiary > rsecondary > rprimary). Under conditions of complete tert-butylamine surface coverage, experimentally measurable apparent kinetics are directly equivalent to the intrinsic kinetics of the rate determining unimolecular surface elimination. The direct measurement of elementary step kinetics served as a water-free reactive probe, providing a direct measurement of the impact of water on solid Brønsted acid catalyzed chemistries at a microscopic level. Over a range of temperatures (453‒513 K) and tert-butylamine partial pressures (6.8×10-2‒6.8 kPa), water reversibly inhibits the rate of Hofmann elimination. Despite expected changes in aluminosilicate hydrophobicity, the water-induced inhibition is found to be insensitive to Al content, demonstrated to be due to one water molecule per Brønsted acid site. Regardless of the significant reduction in the rate of Hofmann elimination, kinetic interrogations and operando spectroscopic measurements reveal that the coverage of TBA adsorbed on H-ZSM-5 is unaltered in the presence of water.
    [Show full text]
  • Organic Seminar Abstracts
    L I B RA R.Y OF THE UN IVE.R.SITY Of ILLI NOIS 547 l£6s \ 954/55 PV Return this book on or before the Latest Date stamped below. University of Illinois Library Llf.1—H41 Digitized by the Internet Archive in 2012 with funding from University of Illinois Urbana-Champaign http://archive.org/details/organicsemi195455univ \7^ — SEMINAR TOPICS CHEMISTRY 435 I Semester 1954-55 The Quinolizinium Ion and Some of its Derivatives Harvey M. Loux, September 24 1 The Stereochemistry of Atropine and Cocaine Ho E . Knipmeyer, September 24 4 Recent Developments in the Chemistry of Cinnoline Derivatives Roger H. Kottke , October 1 8 Interpretation of Electrophiiic Aromatic Substitution and Solvolysis of Allylic and Benzhydryl Chlorides in Terms of Hyperconjugation Robert D. Stolow, October 1 11 The Decahydronaphtholic Acids and Their Relationship to the Decalols and the Decalylamines Robert J. Harder, October 8 14 Bis-Cyclopentadienyl Metal Compounds Edwin L. DeYoung, October 8 17 Ion-Pairs as Intermediates in Solvolysis Reactions Arthur H. Goldkamp, October 15 21 Synthesis of Morphine Mohan D. Nair, October 15 24 Structural and Geometrical Isomerism in the Oxidation of Azo Compounds D. F. Morrow, October 22 27 Stereochemical Aspects of Thermochromism John W. Johnson, Jr., October 22 30 A New Method for the Preparation of Olefins --The Pyrolysis of Sulfites F. M. Scheidt, October 29 33 Recent Studies of Macrocyclic Ring Systems: Cyclophanes Fred P. Hauck, Jr., October 29 36 Mechanism of the Para-Claisen Rearrangement Hugh H . Gibbs , November 5 40 A Proposed Mechanism for Basic c is -Dehydrohalogenat ion Robert M.
    [Show full text]
  • Elimination Reactions Are Described
    Introduction In this module, different types of elimination reactions are described. From a practical standpoint, elimination reactions widely used for the generation of double and triple bonds in compounds from a saturated precursor molecule. The presence of a good leaving group is a prerequisite in most elimination reactions. Traditional classification of elimination reactions, in terms of the molecularity of the reaction is employed. How the changes in the nature of the substrate as well as reaction conditions affect the mechanism of elimination are subsequently discussed. The stereochemical requirements for elimination in a given substrate and its consequence in the product stereochemistry is emphasized. ELIMINATION REACTIONS Objective and Outline beta-eliminations E1, E2 and E1cB mechanisms Stereochemical considerations of these reactions Examples of E1, E2 and E1cB reactions Alpha eliminations and generation of carbene I. Basics Elimination reactions involve the loss of fragments or groups from a molecule to generate multiple bonds. A generalized equation is shown below for 1,2-elimination wherein the X and Y from two adjacent carbon atoms are removed, elimination C C C C -XY X Y Three major types of elimination reactions are: α-elimination: two atoms or groups are removed from the same atom. It is also known as 1,1-elimination. H R R C X C + HX R Both H and X are removed from carbon atom here R Carbene β-elimination: loss of atoms or groups on adjacent atoms. It is also H H known as 1,2- elimination. R C C R R HC CH R X H γ-elimination: loss of atoms or groups from the 1st and 3rd positions as shown below.
    [Show full text]
  • Chapter 8: Alkenes: Structure and Preparation Via Elimination Reactions
    with cyanide anion affords a . N C: + H3C-H2C-H2C-H2C Br H3C-H2C-H2C-H2CC N + KBr K . with azide anion affords alkyl azides Br N3 + NaBr NN N + SN2 Na . with an thiols or thiolate ions affords a . – R–S + H3CH2C–Cl + H3CH2C– S–R + KCl S 2 + N Li 165 Chapter 8: Alkenes: Structure and Preparation via Elimination Reactions 8.1 Introduction to Elimination Reactions – Nucleophiles are Lewis bases. They can also promote elimination reactions of alkyl halides or sulfonates rather than substitution. SN2 – H3C-O Br OCH3 H H elimination + HOCH3 – H3C-O Br OH2 elimination + H O+ H 3 Br SN1 166 OH 83 8.2 Alkenes in Nature and in Industry (please read) 8.3 Nomenclature of Alkenes (please read and understand) Prefix-Parent-Suffix Suffix for alkenes: -ene Many of the same rules for alkanes apply to alkenes 1. Name the parent hydrocarbon by locating the longest carbon chain that contains the double bond and name it according to the number of carbons with the suffix -ene. H3C CH2 H C CH 3 2 C CH2 C CH 2 H C CH CH 3 2 2 H3C CH2 CH2 Parent = pentene not hexene (does not contain double bond) 2a. Number the carbons of the parent chain so the double bond carbons have the lowest possible numbers. Indicate the double bond by the number of the first alkene carbon. H3C CH2 CH2 CH CH CH3 123456 167 2-hexene 2b. If the double bond is equidistant from each end, number so the first substituent has the lowest number.
    [Show full text]
  • Named Organic Reactions
    Named Organic Reactions Thomas Laue and Andreas Piagens Technical University, Braunschweig, Germany Translated into English by Dr. Claus Vogel Universität Magdeburg, Germany JOHN WILEY & SONS Chichester • New York • Weinheim • Brisbane • Singapore • Toronto Contents Introduction ix Acyloin Ester Condensation 1 Aldol Reaction 4 Alkene Metathesis 10 Arbuzov Reaction 12 Arndt-Eistert Synthesis 13 Baeyer-Villiger Oxidation 16 Bamford-Stevens Reaction 19 Beckmann Rearrangement 22 Benzidine Rearrangement 24 Benzilic Acid Rearrangement 26 Benzoin Condensation 27 Bergman Cyclization 29 Birch Reduction 33 Blanc Reaction 36 Bucherer Reaction 37 Cannizzaro Reaction 40 Chugaev Reaction 42 Claisen Ester Condensation 45 Claisen Rearrangement 48 Clemmensen Reduction 52 Cope Elimination Reaction 54 Cope Rearrangement 56 Corey-Winter Fragmentation 59 Curtius Reaction 61 1,3-Dipolar Cycloaddition 64 [2 + 2] Cycloaddition 67 Darzens Glycidic Ester Condensation 71 Delepine Reaction 73 Diazo Coupling 74 Diazotization 77 Diels-Alder Reaction 78 vi Contents Di-7r-Methane Rearrangement 86 Dötz Reaction 88 Elbs Reaction 92 Ene Reaction 93 Ester Pyrolysis 97 Favorskii Rearrangement 100 Finkelstein Reaction 102 Fischer Indole Synthesis 103 Friedel-Crafts Acylation 106 Friedel-Crafts Alkylation 110 Friedländer Quinoline Synthesis 114 Fries Rearrangement 116 Gabriel Synthesis 120 Gattermann Synthesis 123 Glaser Coupling Reaction 125 Glycol Cleavage 127 Gomberg-B achmann Reaction 129 Grignard Reaction 132 Haloform Reaction 139 Hantzsch Pyridine Synthesis 141 Heck Reaction
    [Show full text]
  • So Many Hof(F)Man(N)S 5/10/2008
    Baran Group Meeting I.S. Young So Many Hof(f)man(n)s 5/10/2008 Hof(f)man(n)s Discussed Hof(f)man(n) #2 (Many contributions to chemistry) - K. A. Hofmann and J. Sand (Paper from 1900, no other info available) - studied under Justus von Liebig (University of - oxymercuration of alkenes Giessen) - taught in Bonn, London and Berlin August Wilhelm von Hofmann (1818-1892) - many named reaction and aniline dyes - first to use molecular models (colors still conserved) Felix Hoffmann (1868-1946) - invented many named reactions - first useful synthesis of aspirin and heroin August Wilhelm Albert Hofmann (1906-2008) von Hofmann - his student (Perkin) responsible for aniline dyes - father of LSD and first synthesis of psilocybin Roald Hoffmann (Cornell University) Hofmann Rearrangement (Ber. 1881, 14, 2725.) - organic and inorganic chemist, 1981 Nobel Prize (orbital symmetry) O For base sensitive substrates Br2 O H2O C can use hypervalent iodine or Robert V. Hoffman (Professor Emeritus, New Mexico State University) R R-NH2 R NH2 NaOH N -CO lead tetraacetate - chemistry of N-sulfonyloxy compounds 2 Example from Recent Literature (J. Am. Chem. Soc. 1998, 120, 8259) Reinhard W. Hoffmann (Professor at University of Marburg, Germany) - natural product synthesis and reactive organometallic compounds OMe OMe OMe PMPO MOMO PMPO MOMO HO H. Martin R. Hoffmann (Professor at Hannover University, Germany) O Br2 O NaOMe - chiral allyl cations, chemistry of cinchona alkaloids, natural product Steps O synthesis O MeOH O HO MeO O N N H N Hof(f)man(n) #1 (not much known on this one) 2 O Me O (K.
    [Show full text]
  • The Emergence of the Structure of the Molecule and the Art of Its Synthesis
    Total Synthesis DOI: 10.1002/anie.200((will be filled in by the editorial staff)) The Emergence of the Structure of the Molecule and the Art of Its Synthesis K. C. Nicolaou* At the core of the science of chemistry lie the structure of the molecule, the art of its synthesis, and the design of function within it. These attributes elevate chemistry to an essential, indispensable, and powerful discipline whose impact on the life and materials sciences is paramount, undisputed, and expanding. Indeed, today the combination of structure, synthesis, and function is driving many scientific frontiers forward, including drug discovery and development, biology and biotechnology, materials science and nanotechnology, and molecular devices of all kinds. What connects structure and function is synthesis, whose flagship is total synthesis, the art of constructing the molecules of nature and their derivatives. The power of chemical synthesis at any given time is reflected and symbolized by the state of the art of total synthesis, and as such the condition and sophistication of the latter needs to be continuously nourished and advanced. In this review the understanding of the structure of the molecule, the emergence of organic synthesis, and the art of total synthesis are traced from the nineteenth century to the present day. 1. Introduction other sciences, technologies, and engineering, and how did it come to be so advanced and enabling? The power of chemistry is The celebration of Angewandte Chemie’s 125th anniversary in primarily derived from its ability to understand molecular structure, 2013 gives us the opportunity to reflect on both the past and the synthesize it, and build function within it through molecular design future of the central, and yet universal and ubiquitous, science of and synthesis.
    [Show full text]
  • Method Development for the Stereoselective Synthesis of Medium-Sized Cyclic Ethers and Application to Natural Product Synthesis: Part I
    Method Development for the Stereoselective Synthesis of Medium-Sized Cyclic Ethers and Application to Natural Product Synthesis: Part I. Organocatalytic Oxa-Conjugate Addition for α,α´-trans-Oxepanes Part II. Gold(I)-Catalyzed Alkoxylation for α,α´-cis - Oxocenes Part III. Studies toward the Synthesis of (+)-Intricenyne by Megan L. Lanier Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Jiyong Hong, Supervisor ___________________________ Ross A. Widenhoefer ___________________________ Qiu Wang ___________________________ Katherine J. Franz Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2015 ABSTRACT Method Development for the Stereoselective Synthesis of Medium-Sized Cyclic Ethers and Application to Natural Product Synthesis: Part I. Organocatalytic Oxa-Conjugate Addition for α,α´-trans-Oxepanes Part II. Gold(I)-Catalyzed Alkoxylation for α,α´-cis - Oxocenes Part III. Studies toward the Synthesis of (+)-Intricenyne by Megan L. Lanier Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Jiyong Hong, Supervisor ___________________________ Ross A. Widenhoefer ___________________________ Qiu Wang ___________________________ Katherine J. Franz An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2015 Copyright by Megan L. Lanier 2015 Abstract Medium-sized cyclic ethers are challenging synthetic targets due to enthalpic and entropic barriers. Methods for the stereoselective synthesis of α,α΄-disubstituted medium- sized cyclic ethers began to appear with the discovery of naturally-occurring, ladder- shaped polycyclic ethers, such as brevetoxin B, and monocyclic ethers, such as (+)- laurencin.
    [Show full text]
  • Chapter 9 Formation of Alkenes and Alkynes
    (2/94)(5-8/96)(7,8/01)(1,2/02)(10-12/03) Neuman Chapter 9 Chapter 9 Formation of Alkenes and Alkynes. Elimination Reactions from Organic Chemistry by Robert C. Neuman, Jr. Professor of Chemistry, emeritus University of California, Riverside [email protected] <http://web.chem.ucsb.edu/~neuman/orgchembyneuman/> Chapter Outline of the Book ************************************************************************************** I. Foundations 1. Organic Molecules and Chemical Bonding 2. Alkanes and Cycloalkanes 3. Haloalkanes, Alcohols, Ethers, and Amines 4. Stereochemistry 5. Organic Spectrometry II. Reactions, Mechanisms, Multiple Bonds 6. Organic Reactions *(Not yet Posted) 7. Reactions of Haloalkanes, Alcohols, and Amines. Nucleophilic Substitution 8. Alkenes and Alkynes 9. Formation of Alkenes and Alkynes. Elimination Reactions 10. Alkenes and Alkynes. Addition Reactions 11. Free Radical Addition and Substitution Reactions III. Conjugation, Electronic Effects, Carbonyl Groups 12. Conjugated and Aromatic Molecules 13. Carbonyl Compounds. Ketones, Aldehydes, and Carboxylic Acids 14. Substituent Effects 15. Carbonyl Compounds. Esters, Amides, and Related Molecules IV. Carbonyl and Pericyclic Reactions and Mechanisms 16. Carbonyl Compounds. Addition and Substitution Reactions 17. Oxidation and Reduction Reactions 18. Reactions of Enolate Ions and Enols 19. Cyclization and Pericyclic Reactions *(Not yet Posted) V. Bioorganic Compounds 20. Carbohydrates 21. Lipids 22. Peptides, Proteins, and α−Amino Acids 23. Nucleic Acids ************************************************************************************** *Note: Chapters marked with an (*) are not yet posted. 0 (2/94)(5-8/96)(7,8/01)(1,2/02)(10-12/03) Neuman Chapter 9 9: Formation of Alkenes and Alkynes. Elimination Reactions Preview 9-3 9.1 Elimination Reactions 9-3 Common Features of Elimination Reactions (9.1A) 9-3 General Equations.
    [Show full text]
  • The Quest for Quinine: Those Who Won the Battles and Those Who Won the War Teodoro S
    Reviews T. S. Kaufman and E. A. Rfflveda Natural Products Synthesis The Quest for Quinine: Those Who Won the Battles and Those Who Won the War Teodoro S. Kaufman* and Edmundo A. Rfflveda Keywords: alkaloids · asymmetric synthesis · history of chemistry · quinine · structural determination Angewandte Chemie 854 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200400663 Angew. Chem. Int. Ed. 2005, 44, 854 – 885 Angewandte Quinine Synthesis Chemie For a long time, the synthesis of quinine constituted an From the Contents elusive target. In 2004, which marked the 60th anniver- sary of the publication of the approach used by Wood- 1. Introduction 855 ward and Doering to synthesize quinine, two new ster- 2. Quina: Bark from the New World That Cures eocontrolled total syntheses of the natural product were Malaria 856 accomplished. Together with the well-publicized first stereocontrolled total synthesis of quinine by Stork in 3. The Search for the Active Component in the 2001, these publications evidence the revival of interest of Cinchona Bark 857 organic chemists in the synthesis of this compound, once 4. The First Synthetic Approach to Quinine: Birth considered a miracle drug. The recently disclosed of a New Industry 858 syntheses of quinine also testify in a remarkable manner the huge progress made by organic synthesis during the 5. The Structure of Quinine 860 last three decades since the first series of partially 6. Rabe Provides the First Steps and the Synthesis controlled syntheses of quinine by the group of Usko- of Quinine Seems To Become Simpler 864 kovic. Following an account of the historical importance of quinine as an antimalarial drug and a brief description 7.
    [Show full text]