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Rearrangements and Reactive Intermediates [email protected] 1 Rearrangements and Reactive Intermediates Hilary Term 2018 1A Organic Chemistry Handout 1 Me Me 1 7 2 7 2 3 H 3 1 Me HO 6 5 4 Me 4 6 5 Me 8 8 isoborneol camphene http://burton.chem.ox.ac.uk/teaching.html ◼ Polar Rearrangements, Oxford Chemistry Primer no. 5; L. M. Harwood ◼ Organic Chemistry J. Clayden, N. Greeves, S. Warren – Chapters 36-41 ◼ Reactive Intermediates, Oxford Chemistry Primer no. 8; C. J. Moody, G. H. Whitham ◼ Mechanism and Theory in Organic Chemistry, T. H. Lowry, K. S. Richardson ◼ Advanced Organic Chemistry, F. A. Carey, R. A. Sundberg ◼ Modern Physical Organic Chemistry; E. Anslyn, D. Docherty Rearrangements and Reactive Intermediates 2 Synopsis ◼ Carbocations and carbanions NMR spectroscopy and X-ray structures of carbocations; aggregation and pyramidal inversion of carbanions. Reactivity, including SE1, redox, hydride elimination and rearrangements: Wagner–Meerwein, pinacol, semi-pinacol. ◼ Rearrangement of anions and carbocations Orbital theory; Is 3c-2e structure TS or HEI? Stepwise versus concerted rearrangements; non-classical carbocations (carbonium ions), transannular hydride shifts. Carbanions: Favorskii, Ramberg-Bäcklund, Stevens and Wittig rearrangements. ◼ Carbenes Structural features that influence stability. Methods of making them; carbenes versus carbenoids. General classification of the types of reaction that these species undergo. Rearrangements: Wolff, cyclopropanation, C-H insertion. ◼ Rearrangements to electron-deficient nitrogen and oxygen Structure of nitrenes; structural features that influence stability. Methods of making them. Types of reaction: aziridination, C–H insertion. Nitrene versus non-nitrene mechanisms. Rearrangements to electron-deficient nitrogen (Beckmann, Neber, Hoffmann, Curtius, Schmidt, Lossen). Baeyer–Villiger rearrangement. ◼ Introduction to radicals Structure; stability. General types of reaction involving radicals: homolysis, recombination, redox, addition, β-scission, substitution, disproportionation. ◼ Problem class relating to lectures 1–4. ◼ Case studies Elucidating mechanisms of rearrangements. Evidence for currently accepted mechanisms for the Baeyer– Villiger, Beckmann and Favorskii rearrangements. ◼ Problem class relating to lectures 5 and 7. Rearrangements and Reactive Intermediates 3 Types of High Energy Intermediates ◼ Electron Rich Anions reactive towards Carbanion (8 electrons) a) electrophiles ◼ Electron Deficient Cations reactive towards b) acids Two classes of carbocations a) nucleophiles c) oxidising agents b) bases R R • Carbenium ion (6 electrons) c) reducing agents R R • R R R R R R R R ◼ Electron Rich Anions Radical Anion Carbonium ion (8 electrons) H H H H H H e.g. CH5 • Radical cation H H H H H H H H H H H H • ◼ Neutral species • + Radical (7 electrons) H H H H reactive towards H H R a) electrophiles or nucleophiles • b) other high energy agents ◼ Neutral species R R c) oxidising or reducing agents Carbenes (6 electrons) R • R ◼ Neutral species ◼ Neutral species R R • R • • ketenes arynes R R R R R R singlet triplet • O R Rearrangements and Reactive Intermediates 4 Stuctures of Carbocations ◼ Crystal structure of an adamantyl carbocation 110° 1.44 Å 118° 99° 1.53 Å ° δC 38 ppm 1.62 Å 111 δ 29 ppm Me Me C 1.52 Å F5SbFSbF5 adamantane Me ◼ C-C σ to empty p Me Me Me Me Me Me Me Me Me δ 294 ppm F C C-C sp3-sp3 1.54 Å δC 71 ppm 3 2 C-C sp -sp 1.50 Å 2SbF5 δC 90 ppm 2 2 C-C sp -sp 1.46 Å Me Me SO2 Me Me δC 30 ppm C=C 1.34 Å Me Me δC 49 ppm ◼ Bond lengths and bond angles provide evidence of hyperconjugation (T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349). Rearrangements and Reactive Intermediates 5 ◼ Crystal structure of a t-butyl carbocation H H H C-C sp3-sp3 1.54 Å 1.44 Å C-C sp3-sp2 1.50 Å H H C-C sp2-sp2 1.46 Å C=C 1.34 Å H H H H 120° F5SbFSbF5 δC = 335 ppm O F CH3 2SbF5 2SbF5 δC = 94 ppm H3C F H C CH3 3 SO2 H3C CH3 SO2 H3C CH3 δ = 28 ppm CH3 δC = 171 ppm C δ = 47 ppm C δH = 4.35 ppm (adamantyl acid fluoride) δC = 320 ppm F H δ = 13.5 ppm SbF5 H H3C CH3 SO2 H3C CH3 δH = 5 ppm δC = 51.5 ppm ◼ Bond lengths provide evidence of hyperconjugation (T. Laube, J. Am. Chem. Soc. 1993, 115, 7240). Rearrangements and Reactive Intermediates 6 ◼ Hyperconjugation donation of C-H σ-bond (or C-C σ- bond) electrons into empty p orbital empty p-orbital H filled σ C-H orbital CH3 H CH H 3 energy of the bonding electrons reduced system stabilised ◼ greater number of C-H (or C-C) σ-bonds the greater the extent of hyperconjugation and the greater stabilisation tertiary secondary primary ◼ carbenium ion stability therefore goes in the order: R R R R R > > R ◼ conjugation with alkenes, arenes and lone pairs, also stabilises carbenium ions ◼ most carbocations are fleeting reaction intermediates – the triphenylmethyl (trityl) cation persists - crystal structure of trityl cation demonstrates all the phenyl groups are twisted out of plane ◼ Ph3C BF4 is a commercially available crystalline solid HSO4 Ph H2SO4 Ph OH Ph CH2Cl2 δC = 212 ppm B(CN)4 Rearrangements and Reactive Intermediates 7 Structures of Carbanions ◼ generally aggregated in the solid state and in solution ◼ methyllithium is a tetramer (MeLi)4 with CH3 groups sitting above each face of a Li4 tetrahedron — overall a distorted cube ◼ tert-butyllitium is also tetrameric in the solid state (X-ray crystal structures below) Li C C Li C Li Li C t-butyllithium methyllithium idealised arrangement of (t-BuLi)4 (MeLi)4 lithium and carbon atoms (H-atoms removed for clarity) ◼ in coordinating solvents e.g. THF, Et2O most organolithiums become less aggregated and hence more reactive Rearrangements and Reactive Intermediates 8 ◼ stability of carbanions is related to the pKa of their conjugate acids H H H H H H increasing pKa of conjugate acid, 16 24 41 43 44 increasing reactivity, decreasing stability H H H H H H aromatic sp-hybridised conjugated sp2-hybridised sp2-hybridised CH3 CH3CH2 (CH3)2CH (CH3)3C H increasing pKa of conjugate acid, 46 48 50 51 53 increasing reactivity, decreasing stability H H H H Me H Me Me H H Me Me Me sp3-hybridised sp3-hybridised sp3-hybridised sp2-hybridised sp3-hybridised electron donating electron donating electron donating alkyl group alkyl groups alkyl groups Rearrangements and Reactive Intermediates 9 3 ◼ pyramidal inversion is generally fast for sp hybridised carbanions (they are isoelectronic with NH3) and hence chiral carbanions generally undergo rapid racemisation. ‡ fast R'' R'' R R R'' R R' R' R' ◼ vinyl anions and cyclopropyl anions are the exceptions and are generally considered configurationally stable ◼ lithium halogen exchange with alkenyl iodides and bromides is a stereospecific process tBu Li Br Ph Ph R Br Li Ph R Br tBuLi R Br Li R Ph Ph Ph 2 Br Li CO2H ◼ sp hybridisation at transition state for Me BuLi Me CO2 Me pyramidal inversion ◼ ideal 120 ° angles only ca. 60° for cyclopropane Ph Ph Ph Ph Ph Ph ◼ transition state highly strained (S) ‡ retention therefore slow rate of inversion R Rearrangements and Reactive Intermediates 10 Reactions of Carbocations and Carbanions ◼ Generic reaction map of carbocations and carbanions hydride loss reaction with nucleophile reduction E carbocation deprotonation Nu rearrangement X R R H H R R R + 2e - H Nu - H electrophilic ionisation SET substitution + e X - X + e - X X R R R R R • SN1 or E1 - e - e SE1 single electron - H transfer (SET) E - H R E R R R reaction with R electrophile electrophile carbanion deprotonation hydride loss reaction addition Rearrangements and Reactive Intermediates 11 ⊕ ◼ most common reaction of carbanions is reaction with electrophiles (e.g. RLi or RMgBr plus E ) which is amply covered elsewhere ◼ some other reactions are shown below SE1 – Subsitution Electrophilic Unimolecular - formally related to a carbanion as SN1 is to a carbocation ◼ generic mechanism X - X E E R R R SE1 ◼ examples O O O O OH Br Br H Br Ph Ph Ph Ph R R R - N2 ROH N H R N R R O O HO O O P OH, H O Ph P P P H Ph 2 HO Ph + Ph Ph Ph O Ph + heat Ph Rearrangements and Reactive Intermediates 12 ◼ β-hydride elimination from carbanions common for transition metals ◼ reverse reaction is hydrometallation – well known from hydroboration chemistry H H H PdX + HPdX BR2 BR2 ◼ not a common reaction for Grignard reagents or organolithiums; however, β-hydride elimination is a decomposition pathway for organolithiums and tert-butyllithium can act as a source of hydride Li Me Me H + LiH Me Me ◼ redox reactions – Single Electron Transfer - SET MgBr Cl H + Cl + H • H H dimerisation SET of Ph• Cl Cl • Cl SET + • Cl • Rearrangements and Reactive Intermediates 13 ◼ rearrangement of carbocations ◼ the neopentyl system Me Me Me Me Me Me AgNO3, water Me HO + not Me Me I Me Me Me OH Ag H2O then - H - H Me 1,2- shift Me Me ◼ the 1,2 shift is a Wagner- Me Meerwein rearrangement Me Me ◼ as an aside, remember that neopentyl systems, although primary, are unreactive under SN2 conditions as the nucleophile is severely hindered from attacking the necessary carbon atom Me Me ‡ Me Me Me Me Me Me (-) (-) Me Nu Nu H LG Nu LG R'' LG H R' H H ◼ staggered conformation requires nucleophile to approach passed one of the methyl groups Rearrangements and Reactive Intermediates 14 ◼ Wagner-Meerwein rearrangements exemplified Me 1 Me 7 7 2 7 2 1 - H 2 3 H 3 Me 3 1 Me HO 6 5 ◼ overall red bond is broken and 4 4 6 Me Me 5 4 6 5 Me 8 blue bond is formed isoborneol camphene 8 Me 8 H ◼ in general alkyl shifts occur to rotate yield a more stable carbocation Me 1 Me Me Me Me 1 Me Me 1 1 Me 2 2 Me 7 2 7 8 7 2 5 3 3 5 3 6 6 6 best orbital overlap is also H2O 6 ◼ 5 4 5 4 4 rotate 7 Me Me 8 Me 3 important in determining which 8 4 8 group migrates ◼ secondary ◼ tertiary carbocation carbocation Me poor orbital overlap 1 Me Me 1 Me Me 1 Me migration Me Me for migration 2 2 2 7 7 3 3 3 would lead to 1 6 6 7 5 4 5 4 6 4-membered 5 Me Me Me 5 2 8 8 4 ring 8 best orbital overlap H Me 8 for migration (ca.
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    Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones By Ming-Hsiu Yang Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chairperson Ryan A. Altman Michael D. Clift Apurba Dutta Michael F. Rafferty Jon A. Tunge Date Defended: April 26, 2017 The Dissertation Committee for Ming-Hsiu Yang certifies that this is the approved version of the following dissertation: Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones Chairperson Ryan A. Altman Date Approved: April 26, 2017 ii Abstract Ming-Hsiu Yang Department of Medicinal Chemistry, April 2017 The University of Kansas Fluorine plays an important role in drug design, because of some unique features imparted by fluorine. The incorporation of fluorine into small molecules can modulate molecular physicochemical properties, metabolic stability, lipophilicity, and binding affinity to the target proteins. However, few fluorinated molecules are biosynthesized by enzymes. This means incorporating fluorine into the molecules relies on synthetic methods. Thus, efficient synthetic strategies to access the molecules bearing a variety of privileged fluorinated moieties are important for drug discovery. Fluoroalkenes are an isopolar and isosteric mimic of an amide bond with distinct biophysical properties, including decreased H-bond donating and accepting abilities, increased lipophilicity, and metabolic stability. Moreover, fluoroalkenes can also serve as probes for conducting conformational analyses of amides. These potential applications require the development of efficient methods to access fluoroalkenes. In chapter 2, a Shapiro fluorination strategy to access peptidomimetic fluoroalkenes is demonstrated.
  • Catalytic Cyclopropanation of Polybutadienes

    Catalytic Cyclopropanation of Polybutadienes

    Erschienen in: Journal of Polymer Science, Part A: Polymer Chemistry ; 48 (2010), 20. - S. 4439-4444 https://dx.doi.org/10.1002/pola.24231 Catalytic Cyclopropanation of Polybutadienes JUAN URBANO,1 BRIGITTE KORTHALS,2 M. MAR DI´AZ-REQUEJO,1 PEDRO J. PE´ REZ,1 STEFAN MECKING2 1Laboratorio de Cata´ lisis Homoge´ nea, Departamento de Quı´mica y Ciencia de los Materiales, Unidad Asociada al CSIC, Centro de Investigacio´ n en Quı´mica Sostenible, Campus de El Carmen s/n, Universidad de Huelva, 21007 Huelva, Spain 2Department of Chemistry, University of Konstanz, 78464 Konstanz, Germany ABSTRACT: Catalytic cyclopropanation of commercial 1,2- or 1,4- bonyl-cyclopropene)]. Catalytic hydrogenation of residual dou- cis-polybutadiene, respectively, with ethyl diazoacetate catalyzed ble bonds of partially cyclopropanated polybutadienes provided by [TpBr3Cu(NCMe)] (TpBr3 ¼ hydrotris(3,4,5-tribromo-1-pyrazo- access to the corresponding saturated polyolefins. Thermal lyl)borate) at room temperature afforded high molecular weight properties are reported. 5 À1 (Mn > 10 mol ) side-chain or main-chain, respectively, carbox- yethyl cyclopropyl-substituted polymers with variable and con- trolled degrees of functionalization. Complete functionalization KEYWORDS: carbene addition; catalysis; functionalization of poly- of 1,4-cis-polybutadiene afforded poly[ethylene-alt-(3-ethoxycar- mers; organometallic catalysis; polar groups; polybutadienes INTRODUCTION Catalytic insertion polymerization of ethyl- polypropylene.6 Examples of catalytic post-polymerization ene and propylene is employed for the production of more reactions on saturated polyolefins are rare. The oxyfunction- than 60 million tons of polyolefins annually.1 These poly- alization of polyethylenes and polypropylenes by metal- mers are hydrocarbons, without any heteroatom-containing based catalysts can afford hydroxyl groups.7 We have functional groups, such as for example ester moieties.