http://www.courses.fas.harvard.edu/~chem206/ Ph Ph OO O CO2Me CO2Me H H CO2Me MeO2C H H O O O Ph Ph Chem 206D. A. Evans Matthew D. Shair Monday, Columbus Day, October 14, 2002 a73 Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11Concerted Pericyclic Reactions Pericyclic Reactions: Part–2 Chemistry 206 Advanced Organic Chemistry Lecture Number 12 Pericyclic Reactions–2 a73 Electrocyclic Reactions a73 Cheletropic Reactions a73 Sigmatropic Rearrangements: [1,2], [1,3], [1,5] a73 Other Reading Material: Fleming: Chapter 4Thermal Pericyclic Reactions a73 Woodward-Hoffmann Theory R. B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry, Verlag Chemie, Weinheim, 1970. a73 Frontier Molecular Orbital Theory I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John-Wiley and Sons, New York, 1976. a73 Dewar-Zimmerman Theory T. H. Lowry and K. S. Richardson, Mechanism and Theory in Organic Chemistry, 3rd Ed., Harper & Row, New York, 1987. a73 General Reference R. E. Lehr and A. P. Marchand, Orbital Symmetry: A Problem Solving Approach, Academic Press, New York, 1972. a73 Problems of the Day: Huisgen, TL, 1964, 3381. Predict the stereochemical outcome of this reaction. a68 a68heat Suggest a mechanism for the following reaction. heat Bloomfield, TL, 1969, 3719. Houk, et. al. Acc. Chem. Res. 1996, 29, 471-477. Houk, et. al. JOC. 1996, 61, 2813-2825. H Ph Ph OO O Ph Ph OO O R R R R R R R R H HOMO O O O Ph Ph O O O Ph Ph LUMO LUMO HOMO Evans, Breit Electrocyclic Processes-1 Chem 206 Electrocyclic Reaction - Selection Rules Ground State(Thermal process) Excited State(Photochemical Process) 4n pi e- (n = 1,2...) 4n+2 pi e- (n = 0,1,2...) conrotatory disrotatory disrotatory conrotatory Controtation and on to the indicated bonding and anti-bonding orbitals of cyclobutene: Con Con 42 29 45 27 Criegee, Chem. Ber. 1968, 101, 102. Activation Energy (kcal/mol)for electrocyclic ring opening Huisgen, TL, 1964, 3381. Activation Energy (kcal/mol)for electrocyclic ring opening Ground State Excited State Conrotatory Disrotatory Disrotatory Conrotatory Conrotatory Disrotatory Disrotatory Conrotatory Conrotatory Disrotatory Conrotatory Disrotatory Disrotatory Conrotatory Examples Con Con Sterically favored R CN Me CH2OBn H H CHO R H R H R Me CN CH2OBn CHO R Me CN R CH2OBn CHO A R H H H H H H H R H H H H H H H H H H H R H H H H H B Evans, Breit Electrocyclic Processes-2: Torquoselectivity Chem 206 con con in out Torquoselectivilty is defined as the predisposition of a given R substituent for a given conrotatory motion con + R = Me R = CHO only none none only con + ratio: >20:1 con + ratio: 4:1 Houk et al. Acc. Chem. Res 1996, 29, 471 Examples: Donor substituents prefer con–out modePi acceptor substituents prefer con–in mode HOMO + p LUMO + p Inward Motion HOMO + p Outward Motion LUMO + p How do we explain? Donor substituents prefer con–out modePi acceptor substituents prefer con–in mode View the 2 conrotatory modes by looking at the breaking sigma bond from this perspective destabilizing 4 electron interation for donor substituents stabilizing 2 electron interation for acceptor substituents As conrotation begins the energy ofthe breaking sigma bond rises steeply. Hyperconjugation with a pi* orbital, while possible in both A & B , is better in B. (Houk) + + Ψ3 Ψ1 Ψ2 A H R H A R A H A H CR A H H A X R R R R X R R LUMO C C R A H H A A A R H H R R HOMO LUMO LUMO X X H TsO X C CR H Me Me H C CR Me H H Me X HOMO HOMO –X– –X– H TsO MeMe H H H +X– R Me H H Me H TsO HH Me Me R H Me Me H X +X– Electrocyclic Processes-3: 3-Atom Electrocyclizations Chem 206 Sterically favored Dis Favored for R = ring Dis Three-Atom Electrocyclizations (2 electrons) Con??Dis?? Dis Note that there are two disrotatory modes Dis ++ Evans, Breit nonbonding cation anion Solvolysis of Cyclopropyl Derivatives slow fast slow Does solvolysis proceed via cation 1 followed by rearrangement to 2 (Case 1), or does it proceed directly to 2 (Case 2)? 1 2 2 Case 2 Case 1 relative rate 1 4 40,000 Dis DePuy, Accts. Chem. Res. 1967, 1, 33 fast fast H2C H2C CH2TsO H H H H TsO H H O Cl H TsO O– Cl H TsO MeMe H H TsO H H H H TsO H H –Cl– O– H TsO H H Me Me O Ψ3 Ψ1 Ψ2 A H R H A CR B A B A NAr CO2Me CO2Me H H NAr CO2Me H H MeO2C CR A H H A MeO2C N MeO2C Ar CC CR B A B A N MeO2C Ar CO2Me A A R H H Electrocyclic Processes-3: 3-Atom Electrocyclizations Chem 206 Three-Atom Electrocyclizations (4 electrons) Con??Dis?? Evans, Breit nonbonding cation anion Observation ?? ?? (–)(+) ?? (–)(+) Con Con Con ?? ?? relative rate 1 4 40,000 Solvolysis Summary favorableUnfavorable Ring-fused Cyclopropyl Systems When the cis substiltutents on the cyclopropyl ring are tied together in a ring the following observsations have been made dis-in dis-in dis-out dis-out favored disavored relative rate: > 10+6 Revisiting the Favorski rearrangement: (Carey, Part A, pp 506-8) base dis-in 3-exo-tet disallowed products R A A R A A R A A O A A O +H+ +H+ OH A A C C A H A HA A HOMO LUMO C C H H A AA A A A AA O –H+ O A A A A Electrocyclic Processes-3 Chem 206 Eight-Atom Electrocyclizations (8 electrons) ?? Five-Atom Electrocyclizations (4 electrons) a70 Con??Dis?? nonbonding Cation Anion a70a70 Con Pentadienyl Cation + Dis Pentadienyl Anion – a71 a71 a71 Con??Dis?? Let's use the "Ready" shortcut to find the homo: Nodes will appear at single bonds symmetry of homo Closure should be conrotatory Evans, Breit Denmark, S. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5; pp 751. The Nazarov Reaction predict stereochemistry a66 a66 a66 a66 X Y Z C R R C R R C Y Z C Me Me Y Z Me Me HOMO HOMO SO2 C C C O C C X Y Z C N N N N O R RR R X Y Z X Y Z HOMO HOMO R R C C C C R R S OOS O O C RR Cheletropic Processes-1 Chem 206 2 + 1 CheletropicReaction: Olefins + Singlet CarbeneCHELETROPIC REACTIONS: [n+1] Cycloadditions (or Cycloreversions) Concerted processes in which 2 σ-bonds are made (or broken) which terminate at a single atom. + [4+2] + [4+1] General pi-s yst em Reversion Addition pi-sy ste m + Singlet-CarbeneAddition (and Reversion) Cycloreversion only Reversion and Addition Frontier Orbitals E ω2 ω0 p (empty) sp2 (filled) 0 2 Linear Approach: 2 HOMO-LUMO Interactions LUMO LUMO Nonlinear Approach: 2 HOMO-LUMO Interactions LUMO Carry out the analysis of the indicated hypothetical transformation Evans, Breit predict approach geometry of carbene LUMO Question: what is orientation of carbene relative to attacking olefin?? HOMO LUMO HOMO LUMO Me Me Me Me S O O S O O filled filled empty (LUMO) S O O S O O S O O S O O Me Me S O O Me Me S O O filled S O O empty S O O S O O R1 X S R2O O R1 R2 filled + SO2 empty (LUMO) S O O– S O O– S R1 R2 O O S R1 R2 O O -SO2 -SO2 S R1 R2 O O R1 R2 R2R1 S O O– S O O– Cheletropic Processes-2 Chem 206 Let's now consider SO2 as the one-atom component 4e– in pi system reactions are:stereospecific & reversible Key step in the Ramberg B?cklund Rearrangement base E Z base suprafacial Evans, Breit Clough, J. M. The Ramberg-Backlund Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 861. "The Ramberg-Backlund Rearrangement.", Paquette, L. A. Org. React. (N.Y.) 1977, 25, 1. suprafacial Analysis of the Suprafacial SO2 Extrusion (nonlinear) Similar to carbene geometry X H H C XH R C RHX C Me H 1 3 R X Y:– X X R X H ? ? ? ? YHX H X H Y H X Y X Y ? H X X R Y–:X X R X H Y MeH HX H Y D Y CH3 X ? ? YHX H Y H3C X Me H Y CH3 X D Sigmatropic Rearrangements-1 Chem 206D. A. Evans Bridging distance too great for antarafacial migration. Antarafacial GeometrySuprafacial Geometry bonding Ψ2 (allyl HOMO) antibondingbonding bonding a73 Construct TS by uniting an allyl and H radical: Consider the orbitals needed to contructthe transition state (TS). ? consider the 1,3-migration of H a73 [1,3] Sigmatropic Rearrangements (H migration) [3,3] Sigmatropic rearrangement [2,3] Sigmatropic rearrangement [1,3] Sigmatropic rearrangement [1,5] Sigmatropic rearrangement Sigmatropic rearrangements are those reactions in which a sigma bond(& associated substituent) interchanges termini on a conjugated pi system a73 Examples: Sychronous bonding to both termini is possible from this geometry a203 The stereochemical constraints on the suprafacial migration of carbonwith inversion of configuration is highly disfavored on the basis of strain. bonding bonding Inversion at carbon Suprafacial on allyl fragment Retention at carbon Sychronous bonding to both termini cannot be achieved from this geometry bonding a73 [1,3] Sigmatropic Rearrangements (C migration) consider the 1,3-migration of Carbon ?Consider the orbitals needed to contruct the transition state (TS). a203 Construct TS by uniting an allyl and Me radicals: antibonding Suprafacial on allyl fragment ? 1 3 These rearrangements are only seen in systems that are highly strained,an attribute that lowers the activation for rearrangement. 120 °C 3 1 no observed scrambling of labels a54a54 [1,3]-Sigmatropic rearrangements are not common R R R RR H H R R R H H Me Me H H R H H H H R Me Me H H H R H H R HH Me Me Sigmatropic Rearrangements-2 Chem 206D. A. Evans a73 [1,5] Sigmatropic Rearrangements (C migration) [1s,5s] alkyl shift ? RETENTION SIGMATROPIC REACTIONS - FMO-Analysis 1 2 3 ?/hν R = H, CR3 4 5 1 2 3 4 5 [1a,5a] alkyl shift ? INVERSIONa73 [1,5] Sigmatropic Rearrangements (H migration) disfavored a73 [1,5] (C migration): Stereochemical Evaluation 230-280°C RETENTION [1,5s]H- shift[1,5s]C- shift nonbonding thermal hν photochemical pentadienyl radical View as cycloadditon between following species: pentadienyl radical + either, or suprafacial preferred Dewar–Zimmerman Analysis: Retention 0 phase inversions ? Huckel toplogy 6 electrons therefore, allowed thermally a71 a71 a71 R R R R R R R R O R C O O R Li R H BuLi O R Li O Li C O R H OLi R O Li R Sigmatropic Rearrangements-3 Chem 206D. A. Evans a73 [1,2] Sigmatropic Rearrangements: Carbon + + consider as cycloaddition C–R homoylsis transition state a71 a71 olefin radical cation a71 + [1,2] Concerted sigmatropic rearrangements to cationic centers allowed [1,2] Concerted sigmatropic rearrangements to carbanionic centers not observed consider as cycloaddition a71a71 a71a71stepwise C–R homoylsis a71 olefin radical anion a71a71 a71 a71a71 a71 antibonding transition state The Wittig Rearrangement [1,2] "[2,3]-Wittig Sigmatropic Rearrangements in Organic Synthesis.", Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885. Marshall, J. A. The Wittig Rearrangement.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 975. a71 Ra71This 1,2-sigmatropic rearrangement is non-concerted The Wittig Rearrangement [2,3] C–R homoylsis Allyl radical ketyl radical a71a71 Allyl radical a71a71