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1971 Schreck, Nonlinear Hammett Relationships.Pdf
James 0. Schreck University of Northern Colorado Nonlinear Hammett Relationships Greeley, Colorado 80631 The Haminett equation is a well-known empirical relationship for correlating structure and re- activity. Specifically, it relates structure to both equilibrium and reaction rate constants for reactions of met* and para-substituted benzene derivatives. When the Hammett equation is written in the form log (k/ko) = .P (1) k and ko are the rate (or equilibrium) constants for the " reaction of the substituted and unsubstituted com- S!h$tttuent Cmrtant. 0 pounds, respectively; u is the substituent constant, and Figure 1. Types of lineor ond nonlinear Hammoll curves. p is the reaction constant. The substituent constant is a measure of the ability of the substitueut to change reaction such as the electron density at the reaction site and is indepen- dent of the reaction involved; whereas, the reaction con- stant is a measure of the sensitivity of the reaction series to changes in electron density at the reaction site. In shows how changes in structure which affect principally most cases the equation is valid only for substituents the second step can result in a nonlinear structure-re- in the meta- or para-positions of the benzene ring. (In activity correlation (6). In this case the rate control- a recent article, however, the relative chemical shifts ling step of the reaction changes from the first step to of OH in ortho-substituted phenols in DMSO are the second step due to the greater effect of changes in correlated excellently with ortho-substituents (I).) structure on the second step of the reaction. -
Strategic Applications of Tandem Reactions in Complex Natural Product Synthesis
Strategic Applications of Tandem Reactions in Complex Natural Product Synthesis: Rapid Access to the (Iso)Cyclocitrinol Core Christopher W. Plummer Submitted in partial fulfillment of the Requirement for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences Columbia University 2012 © 2012 Christopher Wainwright Plummer All Rights Reserved Abstract Strategic Applications of Tandem Reactions in Complex Natural Product Synthesis: Rapid Access to the (Iso)Cyclocitrinol Core Christopher W. Plummer This thesis describes the efforts of Professor James Leighton and myself toward the synthesis of the tetracyclic core of a class of steroidal natural products known as the cyclocitrinols. Our initial work in this area was performed on racemic model systems in order to validate our ring contraction-Cope rearrangement strategy. Novel chemistry was then identified to access the functionalized core in enantio-enriched form. Finally, in line with our efforts to probe the transition state of our key tandem Claisen-Cope reaction, additional substrates were prepared supporting our proposed transition state and improving the efficiency of this transformation. Table of Contents Chapter I. Background………………………………………………………....……………1 1.1: Isolation and Characterization of the Cyclocitrinols 1 1.2: Biosynthesis and Previous Synthetic Approach 2 1.3: Retrosynthetic Analysis 5 1.4: Previous Synthetic Efforts in the Leighton Laboratory 9 Chapter II. Model Studies……………………………………………………………….….13 2.1: 1st Generation Macrolactone Approach 13 2.2: -
Hydrogen Bond-Directed Stereospecific Interactions in (A) General Synthesis of Chiral Vicinal Diamines and (B) Generation of Helical Chirality with Amino Acids
HYDROGEN BOND-DIRECTED STEREOSPECIFIC INTERACTIONS IN (A) GENERAL SYNTHESIS OF CHIRAL VICINAL DIAMINES AND (B) GENERATION OF HELICAL CHIRALITY WITH AMINO ACIDS by Hyunwoo Kim A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Chemistry University of Toronto © Copyright by Hyunwoo Kim, 2009 Hydrogen Bond-Directed Stereospecific Interactions in (A) General Synthesis of Chiral Vicinal Diamines and (B) Generation of Helical Chirality with Amino Acids Hyunwoo Kim Doctor of Philosophy 2009 Department of Chemistry University of Toronto ABSTRACT Hydrogen bonding interactions have been applied to the synthesis of chiral vicinal diamines and the generation of helical chirality. A stereospecific synthesis of vicinal diamines was developed by using the diaza-Cope rearrangement reaction driven by resonance-assisted hydrogen bonds (RAHBs). This process for making a wide variety of chiral diamines requires only a single starting chiral diamine, 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN) and aldehydes. Experimental and computational studies reveal that this process provides one of the simplest and most versatile approaches to preparing chiral vicinal diamines including not only C2 symmetric diaryl and dialkyl diamines but also unsymmetrical alkyl-aryl and aryl-aryl diamines with excellent yields and enantiopurities. Weak forces affecting kinetics and thermodynamics of the diaza-Cope rearrangement were systematically studied by combining experimental and computational approaches. These forces include hydrogen bonding effects, electronic effects, steric effects, and oxyanion effects. As an example of tuning diamine catalysts, a vicinal diamine-catalyzed synthesis of warfarin is described. Detailed mechanistic studies lead to a new mechanism involving diimine intermediates. -
Anion Relay Cyclopropanation and Aryl Vinyl Cyclopropane Cope Rearrangements By
Anion Relay Cyclopropanation and Aryl Vinyl Cyclopropane Cope Rearrangements By Kevin Michael Allegre B.Sc., The University of Kansas, 2013 Submitted to the graduate degree program in Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Chair: Jon A. Tunge Paul R. Hanson Helena Malinakova Michael Rubin Ryan A. Altman Date Defended: 18 July 2019 The dissertation committee for Kevin M. Allegre certifies that this is the approved version of the following dissertation: Anion Relay Cyclopropanation and Aryl Vinyl Cyclopropane Cope Rearrangements Chair: Jon A. Tunge Date Approved: 24 July 2019 ii Abstract Kevin M. Allegre and Jon A. Tunge Department of Chemistry, July 2019 University of Kansas Anion Relay Chemistry is a powerful tool for the rapid development of molecular complexity in an operationally simple manner. Much of the work in this field has been pioneered and developed by the Smith group, whose work has primarily focused on silicon and phosphorus Brook rearrangements to effect anion relay. Presented herein is the development of a retro-Claisen condensation protocol to effect anion relay in the synthesis of vinyl cyclopropanes, and subsequent aromatic Cope rearrangement of those vinyl cyclopropanes. This protocol provides a supplementary method of anion relay utilizing readily accessible nucleophiles, which obviates the need for synthesis of alkyl silanes or phosphines as starting materials. Chapter 1 is a review of anion relay chemistry, which focuses on through-space anion relay over 3 or more bonds. It covers both new developments and applications to total synthesis of through-space anion relay more than three bonds since the field was last reviewed by Smith in 2008. -
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. -
Synthesis and Reactions of 4,5-Homotropone and 4,5-Dimethylenetropone Richard Anthony Fugiel Iowa State University
Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1974 Synthesis and reactions of 4,5-homotropone and 4,5-dimethylenetropone Richard Anthony Fugiel Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Organic Chemistry Commons Recommended Citation Fugiel, Richard Anthony, "Synthesis and reactions of 4,5-homotropone and 4,5-dimethylenetropone " (1974). Retrospective Theses and Dissertations. 5986. https://lib.dr.iastate.edu/rtd/5986 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORIVIATIOIM TO USERS This material was produced from a microfilm copy of the original document. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the original submitted. The following explanation of techniques is provided to help you understand markings or patterns which may appear on this reproduction. 1.The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. When an image on the film is obliterated with a large round black mark, it is an indication that the photographer suspected that the copy may have moved during exposure and thus cause a blurred image. -
Gold Catalysis in Organic Synthesis
SCI Review Meeting 2010 Gold Catalysis in Organic Synthesis Paul Davies [email protected] School of Chemistry University of Birmingham November 2010 111 Why use gold catalysis for organic synthesis? • Gold catalysed reactions show several characteristics that render them synthetically attractive: – Significant increases in molecular complexity; – Diverse set of reactions; – Mild reaction conditions (often room temperature); – Au(I) generally tolerant of oxygen; – Minimal use of additives; – Excellent chemoselectivity; – Asymmetric control possible; – Straightforward work-ups; – Robust readily accessible precatalysts; – Orthogonal reactivity to many other TM catalysed processes; – Au(I), Au(III) do not readily cycle between oxidation states (though see final section). 2 Talk Overview This talk is intended to give an overview of the breadth and depth of gold catalysis in the development of methodology for organic synthesis and its implementation. The talk is loosely broken down into sub-sections concerning particular types of overall reactivity: 1. Gold as a π–acid 2. X-H addition across π–systems 3. Indirect X-H addition 4. C-H addition across π–systems 5. Gold Intermediates 6. C-X addition across π–systems 7. Cycloadditions 8. Enyne cycloisomerisations 9. Propargylic carboxylates 10.Preparation of gold carbenoids 11.Recent advances in gold redox cycles 333 Gold as a π-acid catalyst • A diverse range of transformations have been developed based on the activation of alkynes by gold (and platinum) salts and complexes: • π-acids: – Metal fragments that bind to a C-C multiple bond – Deprive multiple bonds of a part of their electron density – Induce positive charge onto multiple bonds – “soft” counterparts to conventional Lewis acids • More electron density is lost than is gained through back donation, rendering the π- system electrophilic Reviews: Relativistic Effects: D. -
PDF (Appendix 2: the Cope Rearrangement)
65 APPENDIX TWO The Cope Rearrangement A2.1 The Cope Rearrangement In 1940, Arthur Cope discovered a thermal rearrangement of 1,5-diene 137a to a more conjugated isomeric 1,5-diene (137b, Scheme A2.1.1).1 Cope postulated that his rearrangement was an all-carbon analogue of the Claisen rearrangement,2 and was intramolecular. He speculated that the reaction proceeded through a six-membered transition state. Cope published these hypotheses 25 years before Woodward and Hoffman3 disclosed the first papers on conservation of orbital symmetry, a theory that explained the molecular orbital basis for synchronous Cope rearrangements, calling them [3,3] sigmatropic rearrangements. Scheme A2.1.1 The Cope rearrangement 150–160 °C NC NC Me 4 h Me EtO2C EtO2C Me Me 137a 137b A2.2 Transition State Geometry in Concerted Cope Rearrangements4 Thermal [3,3] sigmatropic rearrangements occur with suprafacial–suprafacial geometries3 through a six-membered cyclic transition state in either a chair or boat conformation. In 1962, Doering and Roth5 determined that in simple cases, the Cope rearrangement proceeded through a chair-like transition state (Scheme A2.2.1). On the basis of product ratios, Doering and Roth estimated that ΔΔG‡ (boat–chair) for meso 66 138a was 5.7 kcal/mol. Subsequent experiments by Hill excluded the twist (helix) arrangement,6 which had not been considered by Doering and Roth. Scheme A2.2.1 Feasible transition states for the Cope rearrangement Me Me Me Me ! Me Me Me Me (99.7% yield) 138b Me Me Me Me ! ! Me Me Me Me Me Me (0.3% yield) 138a 138c Me Me Me Me ! Me Me Me Me 138d While simple Cope rearrangements employ a chair transition state, the boat transition state is used when molecules are geometrically constrained, as is the case with 1,2-divinyl cyclopropanes in which the vinyl groups are nearly elipsed.7 Most 1,2- divinylcyclobutanes also proceed through boat transition states,8,9 but their larger ring size accompanies greater structural flexibility. -
Organic Chemistry Lecture Outline Chapter 16: Chemistry of Benzene: Electrophilic Aromatic Substitution
Organic Chemistry Lecture Outline Chapter 16: Chemistry of Benzene: Electrophilic Aromatic Substitution I. ELECTROPHILIC AROMATIC SUBSTITUTION (EAS) A. There are five general types of electrophilic aromatic substitution reactions. 1. Halogenation of benzene with Br2, Cl2 or I2 occurs through the same mechanism. a. Bromination of benzene occurs upon treatment with Br2 and FeBr3. b. Chlorination of benzene occurs upon treatment with Cl2 and FeCl3. c. Iodination of benzene occurs upon treatment with I2 and CuCl2. + 2. Nitration of benzene occurs through treatment with a nitronium ion, NO2. a. The nitronium ion can be generated from nitric acid and sulfuric acid. b. The nitronium ion can be generated from nitronium tetrafluoroborate. c. Nitration of benzene occurs through the same mechanism as halogenation. 3. Sulfonation of benzene occurs through treatment with fuming sulfuric acid. The reaction is reversible and products depend on the reaction conditions. a. In strong acid, sulfonation is favored. b. In hot, dilute acid, desulfonation is favored. c. Sulfonation of benzene occurs through the same mechanism as halogenation & nitration. 4. Alkylation (Friedel-Crafts Alkylation) of benzene involves substituting a hydrogen atom on a benzene ring with an alkyl group. This reaction occurs by treatment of benzene with a stable carbocation and aluminum trichloride. There are a number of problems with alkylation of an aromatic ring using the Friedel-Crafts reaction. a. Only alkyl halides can be used to generate the carbocation. b. Benzene rings substituted with electron-withdrawing groups are not reactive. c. The monosubstituted product initially formed is more reactive than the starting material d. Rearrangements can occur with unstable carbocations. -
HYDROLYSIS 2016.Pdf
HYDROLYSIS Hydrolysis reactions of organic substrates are ubiquitous (common) in the environment. Hydrolysis is an important degradation reaction in surface, ground, fog and porewaters and can be a dominant pathway in biological systems as well. In general, hydrolysis occurs via one of two classes of mechanisms; 3 i) Nucleophilic Substitution (SN1 and SN2), generally occurs when the leaving group is attached to sp hybridized carbon centre, such as alkyl halides, epoxides and phosphate esters. X Nu: + Nu + X: And ii) Addition – Elimination, generally occurs when the leaving group is attached to sp2 hybridized acyl carbon centre, such as with carboxylic acid derivatives including esters, anhydrides, amides, carbamates and ureas. O O O Nu: + + X: X X Nu Nu tetrahedral intermediate Kinetics Hydrolysis rates are generally first order or pseudo first order under most environmental conditions (where the pH is generally buffered) with an overall observed hydrolysis rate constant kh. The half life can therefore be expressed as; ln 2 t1/2 kh Hydrolysis reactions are generally enhanced by both acids and bases and three independent reaction mechanisms account for neutral, acid and base hydrolysis. Therefore, the overall hydrolysis kinetics has three contributing components. Rate of hydrolysis = kh [RX] + - where, kh = kA[H ] + kN + kB[OH ] NUCLEOPHILIC SUBSTITUTION/ELIMINATION MECHANISM HALOGENATED HYDROCARBONS The hydrolysis of halogenated hydrocarbons leads to alcohols (or poly alcohols, which rapidly equilibrate to corresponding carbonyl compounds). The reaction is often accompanied by competing elimination to form alkene products, which can be more environmentally persistent and hazardous. In general, hydrolysis products predominant under neutral conditions, whereas elimination products are often more significant under basic conditions. -
Progress Toward the Total Synthesis of Paclitaxel (Taxol®)
PROGRESS TOWARD THE TOTAL SYNTHESIS OF PACLITAXEL (TAXOL®) DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Matthew M. Kreilein, M.S. * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Professor Leo A. Paquette, Advisor Professor David J. Hart Professor T.V. RajanBabu _____________________________ Advisor Professor Pui-Kai Li Chemistry Graduate Program ABSTRACT Described herein is the continuation of efforts focused towards the synthesis of Taxol utilizing a route that is amenable to novel analog formation from advanced Taxol precursors. Elaboration of (1S)-(+)-10-camphorsulfonic acid to a highly functionalized taxane skeleton has been achieved in a total of twenty-two synthetic operations. Highlighting the brevity and efficiency of this series is the fact that only five operations thus far are protecting group manipulations, which tend to significantly increase the length and complexity of a synthetic route. Entry to a completed D-ring has been made by prevous researchers in a six-step sequence. After the revelation that formation of the densly functionalized A-ring in the presence of a completed D-ring was not possible, the focus became one of elaboration of the A-ring using the very useful diosphenol intermediate 3.1. Two areas of research have been explored and are described. First, the route to the bridge-migrated taxane 1.85 was reviewed and problems existing in the key alkenyl iodide coupling, dihydroxylation, C2 oxygenation, and bridge migration were investigated and resolved. ii With an efficient synthesis of 1.85 in hand, attention was focused on completion of the A-ring beginning with routes originating from 1.85. -
A Theoretical Study of the Relationship Between the Electrophilicity Ω Index and Hammett Constant Σp in [3+2] Cycloaddition Reactions of Aryl Azide/Alkyne Derivatives
molecules Article A Theoretical Study of the Relationship between the Electrophilicity ! Index and Hammett Constant σp in [3+2] Cycloaddition Reactions of Aryl Azide/Alkyne Derivatives Hicham Ben El Ayouchia 1, Hafid Anane 1, Moulay Lahcen El Idrissi Moubtassim 1, Luis R. Domingo 2, Miguel Julve 3 and Salah-Eddine Stiriba 1,3,* 1 Laboratoire de Chimie Analytique et Moléculaire, Faculté Polydisciplinaire de Safi, Université Cadi Ayyad, Safi 46010, Morocco; [email protected] (H.B.E.A.); ananehafi[email protected] (H.A.); [email protected] (M.L.E.I.M.) 2 Departamento de Química Orgánica, Universidad de Valencia, Avda. Dr. Moliner 50, Burjassot 46100, Valencia, Spain; [email protected] 3 Instituto de Ciencia Molecular/ICMol, Universidad de Valencia, C/Catedrático José Beltrán No. 2, Paterna 46980, Valencia, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-96-354-4445; Fax: +34-96-354-7223 Academic Editor: James W. Gauld Received: 14 August 2016; Accepted: 21 October 2016; Published: 27 October 2016 Abstract: The relationship between the electrophilicity ! index and the Hammett constant σp has been studied for the [2+3] cycloaddition reactions of a series of para-substituted phenyl azides towards para-substituted phenyl alkynes. The electrophilicity ! index—a reactivity density functional theory (DFT) descriptor evaluated at the ground state of the molecules—shows a good linear relationship with the Hammett substituent constants σp. The theoretical scale of reactivity correctly explains the electrophilic activation/deactivation effects promoted by electron-withdrawing and electron-releasing substituents in both azide and alkyne components. Keywords: [2+3] cycloaddition reactions; arylazides; arylalkynes; substituent effects; electrophilicity index; Hammett constants 1.