Lecture 4
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Lecture 4

Course Number: CH 432, Fall 2009

College/University: Colby

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Pericyclic Reactions ! ! ! Carey & Sundberg: Part A; Chapter 11 Carey & Sundberg: Part B; Chapter 6 Fleming, Chapter 4 Pericyclic Reactions Introduction/Definitions A pericyclic reaction is characterized as a change in bonding relationships that takes place as a continuous, concerted reorganization of electrons. The term "concerted" species that there is one single transition state and...

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Reactions ! ! ! Carey Pericyclic & Sundberg: Part A; Chapter 11 Carey & Sundberg: Part B; Chapter 6 Fleming, Chapter 4 Pericyclic Reactions Introduction/Definitions A pericyclic reaction is characterized as a change in bonding relationships that takes place as a continuous, concerted reorganization of electrons. The term "concerted" species that there is one single transition state and therefore no intermediates are involved in the process. To maintain continuous electron ow, pericyclic reactions occur through cyclic transition states. More precisely: The cyclic transition state must correspond to an arrangement of the participating orbitals which has to maintain a bonding interaction between the reaction components throughout the course of the reaction. Major Categories of Pericyclic Reactions (1) ELECTROCYCLIC RING CLOSURE/RING OPENING: An electrocyclic ring closure is the creation of a new !-bond at the expense of the terminal p orbitals of a conjugated "-system. There is a corresponding reorganization of the conjugated "# system. We usually classify the reaction according to the number of electrons involved. Examples: A 4 e- electrocyclic reaction A 6 e- electrocyclic reaction $ or h% Cyclobutene Butadiene $ or h% 1,3,5-Hexatriene 1,3-Cyclohexadiene (2) CYCLOADDITION REACTIONS/CYCLOREVERSION REACTIONS: A cycloaddition reaction is the union of two smaller, independent " systems. Sigma bonds are created at the expense of "#bonds. A cycloaddition can occur in an intramolecular sense, but it must be between two independent " systems. Cycloaddition reactions are referred to as [m + n] additions when a system of m conjugated atoms combines with a system of n conjugated atoms. A cycloreversion is simply the reverse of a cycloaddition. Examples: + O [2+2] O h% A 2+2 cycloaddition. The Paterno-Bchi reaction. [4+2] + $ A 4+2 cycloaddition. The Diels-Alder reaction. Major Categories of Pericyclic Reactions (3) CHELETROPIC REACTIONS: Cheletropic reactions are a special group of cycloaddition/cycloreversion reactions. Two bonds are formed or broken at a single atom. The nomenclature for cheletropic reactions is the same as for cycloadditions. Examples: O + [4+1] S O S O O + C O [4+1] O + CR2 [2+1] R R (4) SIGMATROPIC REARRANGEMENTS: A sigmatropic rearrangement is the migration of a !-bond from one position in a conjugated system to another position in the system, accompanied by reorganization of the connecting "-bonds. The number of " and ! bonds remains constant. The rearrangement is an [m,n] shift when the !-bond migrates across m atoms of one system and n atoms of the second system. Examples: 2 2 3 1 [1,3]-shift 2 3 1 3 4 5 1 R1 R2 [1,5]-shift R2 R1 H R 1 2 3 3' 2' R 1 2 3 3' 2' X R 1' [3,3]-shift X R 1' X=CR2, Cope rearrangement X=O, Claisen rearrangement Major Categories of Pericyclic Reactions (5) GROUP TRANSFER REACTIONS: In a group transfer reaction one or more groups get transferred to a second reaction partner. Examples: Hydrogen Transfer: R H + R H H R + H H H N N H + R N N R' H H R H N2 R' + R R' H H Ene Reaction: + H H H Analysis of Pericyclic Processes Some factors to consider in our analysis: The number of electrons involved has a profound influence on reactivity: heat rarely observed 4 electrons heat often observed 6 electrons Pericyclic reactions are stereospecific: A A A A heat A A heat A A Reactions behave differently depending on the conditions used (i.e. thermal versus photochemical conditions): A A A heat A h! A A Electrocyclic Reactions Electrocyclic ring closing: heat (#) or light (h$) heat (#) or light (h$) a conjugated !-system a ring with one less !-bond and one additional "-bond Electrocyclic ring opening: heat (#) or light (h$) heat (#) or light (h$) Electrocyclic Ring Closing/Opening The Stereochemical issues: Ring closure can occur in two distinct ways. This has consequences with regard to: ! The orbital lobes that interact ! The disposition of substituents on the termini Conrotatory Closure: The termini rotate in the same direction A B A B B A A B B A B A Disrotatory Closure: The termini rotate in opposite directions A B A B A B A B A B B A Electrocyclic Reactions: Stereochemical Considerations Me H Me H h" ! Me H H Me Me H H Me disrotatory conrotatory Me H H Me h" ! Me Me Me H Me H conrotatory disrotatory It was noted that butadienes undergo conrotatory closure under thermal conditions, while hexatrienes undergo disrotatory closure under thermal conditions. The microscopic reverse reactions also occur with the same rotational sense (i.e. cyclobutenes open in a conrotatory sense when heated, and cyclohexadienes open in a disrotatory sense when heated.) Molecular Orbitals in Conjugated Systems antibonding 4 p-orbitals 3 p-orbitals 2 p-orbitals !3 "# 6 p-orbitals 5 p-orbitals !4 !3 C nonbonding !2 nonbonding C !2 " !1 !1 bonding There are no nodal planes in the most stable bonding MO. With each higher MO, one additional nodal plane is added. The more nodes, the higher the orbital energy. FMO Treatment of Electrocyclic Reactions ! Examine the interactions that occur in the HOMO as the reaction proceeds. ! If the overlap is constructive (i.e. of the same phase) then the reaction is "allowed." ! If the overlap is destructive (i.e. of different phases) then the reaction is "forbidden." Thermal Activation: Conrotatory Closure: (Allowed and observed) Constructive overlap Me H H Me Me H H Me Me H H Me !2 (diene HOMO) Disrotatory Closure: (Forbidden and not observed) H Me H H Me Me Destructive overlap H Me H Me H Me !2 (diene HOMO) FMO Treatment of Electrocyclic Reactions Photochemical activation: When light is used to initiate an electrocyclic rxn, an electron is excited from 2 to 3. Treating 3 as the HOMO now shows that disrotatory closure is allowed and conrotatory closure is forbidden. !4 !3 !2 !1 h" Me H H Me Photon Me absorption H H !4 !3 Me !2 !1 !2 (HOMO) !3 (HOMO) Disrotatory Closure: (Allowed and observed) H Me H H Me Me Constructive overlap H Me H Me H Me !3 (new HOMO) Conrotatory Closure: (Forbidden and not observed) Me Me H H Me Me H H Me Me H H !3 (new HOMO) Destructive overlap The principle of microscopic reversiblity says that if the reaction is allowed in one direction, it must be allowed in the other direction we do not have to analyze the ring opening reactions separately. Sigmatropic Rearrangements The Stereochemical issues: The migrating group can migrate across the conjugated !-system in one of two ways. If the group migrates on the same side of the system, it is said to migrate suprafacially with respect to that system. If the group migrates from one side of the !-system to the other, it is said to migrate antarafacially with respect to that system. Suprafacial migration: The group moves across the same face. B A B A A B A B A B A B Antarafacial migration: The group moves from one face to the other. A B A B A B A B A B A B Sigmatropic Rearrangements: FMO Analysis For complex systems, we must imagine the two pieces fragmenting into a cation/anion pair, (or a pair of radicals) and examine the HOMO/LUMO interaction. If the overlap is constructive at both termini then the reaction is allowed. If the overlap is destructive at either terminus then the reaction is forbidden. Sigmatropic Rearrangements [1,2] Sigmatropic Rearrangements: CH3 X Y X CH3 Y X Y CH3 [1,3] Sigmatropic Rearrangements: CH3 X Y X CH3 CH3 Y X Y We will construct the transition state by considering an allyl anion and the methyl cation [1,5] Sigmatropic Rearrangements: Y CH3 X X Y CH3 Y H3C X We will construct the transition state by considering a butadienyl anion and the methyl cation [1,2] Sigmatropic Rearrangements [1,2] Concerted sigmatropic rearrangements to cationic centers allowed (A Wagner-Meerwein shift) R R + + LUMO R+ HOMO transition state [1,2] Concerted sigmatropic rearrangements to carbanionic centers not observed R !! !! R X LUMO R+ antibonding HOMO transition state Sigmatropic Rearrangements X [1,3] Sigmatropic rearrangement R ! R X X [1,5] Sigmatropic rearrangement H ! X H [2,3] Sigmatropic rearrangement R X Y: ! R :X Y X [3,3] Sigmatropic rearrangement X ! Sigmatropic Rearrangements D R Me ! [1,3] R D Me R D Me R ! [1,5] D Me D R R D Me Me R H Me H D antarafacial D R H D R H Me Me H suprafacial D R H Me H D R H Me R R D Me X antarafacial suprafacial R H D Me X D Me Sigmatropic Rearrangements 2p on Carbon 2p on Carbon [1,3]: H C H H bonding H C H H antibonding bonding bonding X H H Y !2 (allyl anion HOMO) X H H Y !3 (allyl anion HOMO - excited state) Thermal Process: Suprafacial on allyl fragment Forbidden Photochemical Process: Suprafacial on allyl fragment Allowed 2p on Carbon 2p on Carbon H C H H bonding H C H H antibonding bonding [1,5]: bonding X H Y !3 (pentadienyl anion HOMO) X H Y !4 (pentadienyl anion HOMO - excited state) Thermal Process: Suprafacial on allyl fragment Allowed Photochemical Process: Suprafacial on allyl fragment Forbidden Examples of Sigmatropic Rearrangements/Shifts R [1,7a]-shift Me D OH Me D OH + Me D OH R R Me Me Me JACS 1987, 109, 4690; 1988, 110,, 973. Me 250 C [1,5s]-shift Me H Me [1,5s]-shift Me Me Me D Me Me heat D R R Me Me D + R Me Me D D D Berson and Willcott, JACS, 1965, 87, 2751; 1966, 88, 2494. Sigmatropic Rearrangements X [1,3] Sigmatropic rearrangement R ! R X X [1,5] Sigmatropic rearrangement H ! X H [2,3] Sigmatropic rearrangement ! R X Y: R :X Y X [3,3] Sigmatropic rearrangement X ! [2,3] Sigmatropic Rearrangements R2 R X Y: R3 R X R2 R3 Y R2 R :X Y R3 Representative X-Y Pairs: NO (amine oxides) SC (sulfur ylids) OC (Wittig rearrangement) NC (nitrogen ylids) SS (disulfides) SP, SN, SO (sulfoxides) OP (phosphites) +C (haloium ylids) NN, Cl PC, CC (homoallylic anions). [2,3] Sigmatropic Rearrangements R2 R X Y: R3 R X R2 R3 Y R2 R :X Y R3 Note that because the breaking and forming bond on the XY pair do not interact, the process will always be allowed stereoelectronically However, there will be steric considerations in the possible transition states. Examples of [2,3] Sigmatropic Rearrangements Wittig Rearrangement: Me O Ph Sulfonium Ylide Rearrangement: Me BuLi Me O Me Li+ [2,3] Me LiO Me Ph Ph Baldwin, JACS 1971, 93, 3556 BuLi [2,3] S S S Li+ S S S Ammonium Ylide Rearrangement: BuLi Me N Me Me [2,3] H CH2 NMe2 base CH2 N Me Me Me NMe2 R2 R1 Me N Me CN + R2 R3 BuLi R1 Me N Me CN + R2 R3 [2,3] R1 Me2N R3 CN Coupled [2,3] Sigmatropic Rearrangement/ Reductive Cleavage Meisenheimer Rearrangement R2 R1 Me N O Me + R2 R3 R1 Me N Me O R3 R2 Zn HOAc R1 R3 OH Tanabe, Tet Let. 1975, 3005 Favors Starting Material Sulfoxide Rearrangement R2 R1 Ar ! R2 R3 R1 S Ar ! R2 R3 PPh3 (or other thiophile) R1 ! R3 + S O O OH Evans, Accts. Chem. Res. 1974, 7, 147 R2 R1 ! R2 R3 BuLi PhSCl R1 S Ar ! R3 R2 R1 Ar ! R3 O OH O + S [2,3] Sigmatropic Rearrangements: Transition State Structures Starting olefin: Trans favored Ra X Y: Rb X Y H Ra Rb H Ra :X Y Rb Ra Rb H disfavored Y H X Rb Ra Y :X Ra & Rb prefer to orient in pseudo-equatorial positions during rearrangement; nevertheless, this is a delicately balanced situation Starting olefin: Cis favored Ra X Y: Rb X Y H Ra H Ra :X Y Rb Rb highly disfavored Y X Rb Ra H Rb Ra Y :X H Conclusions ! Product olefin geometry can be either (E) or (Z) from (E) starting material ! Product olefin geometry will be (E) from (Z) starting material [2,3] Sigmatropic Rearrangements in Synthesis + ! N Me N S Me O Ph OMe HO Na2S, MeOH O S Ph O MeO HO N cepharamine Me N Me Tandem [ 4+2 ] & [ 2,3 ] Process: Evans, Bryan, Sims J. Am. Chem. Soc. 1972, 2891. Sigmatropic Rearrangements X [1,3] Sigmatropic rearrangement R ! R X X [1,5] Sigmatropic rearrangement H ! X H [2,3] Sigmatropic rearrangement R X Y: ! R :X Y X [3,3] Sigmatropic rearrangement X ! [3,3] Sigmatropic Rearrangements The Cope Rearrangement: ! The Claisen Rearrangement: O ! O What is the three-dimensional transition state? [3,3] Sigmatropic Rearrangements The Doering/Roth experiments [Tetrahedron 18, 67, (1962)]: The Geometry of the transltion state (boat vs chair) can be analyzed via the rearrangement of substituted 1,5-dienes: Me Me Me Me Me Me Me Me Me Chiral isomer Me Meso isomer Predictions: Chiral isomer: H Me Me H Me H less favored H Me H disfavored H Me H Me H Me Me Me H H Me H H Me Predictions: Meso isomer: Me Me H H Me disfavored H H H H favored Me Me trans-trans favored H H Me Me trans-cis cis-cis Me Me trans-trans trans-cis [3,3] Sigmatropic Rearrangements Predictions: Results: Chiral isomer: H Me Me H Me H less favored H Me H disfavored H Me H Me H Me Me Me H Me H Me H H H Me Chiral isomer: favored favored Me H Me H less favored H Me H Me H H Me Me Me Me Me trans-trans trans-trans: 90% cis-cis cis-cis: 10% H Me H disfavored trans-cis H Me H H Me trans-cis: < 1% Meso isomer: Me Me H H Me H H Me Me Meso isomer: Me Me H H H Me Me Me trans-trans H H H H H Me favored Me trans-cis favored H H Me Me trans-cis: 99.7% !!G ~ 5.7 kcal/mol Me disfavored disfavored H H Me trans-trans: 0.3% [3,3] Sigmatropic Rearrangements The Reaction Energetics Goldstein, JACS 1972, 94, 7147 X X E !G523 = 46.3 !G523 = 40.5 X X X CHAIR Relative Energy !!G: 0 BOAT + 5.8 kcal/mol [3,3] Sigmatropic Rearrangements Ring Strain can be employed to drive the Cope process: H 5-20 C H Brown Chem. Commun. 1973, 319 H 120 C H Vogel Annalen 1958, 615, 1 H 60 C H Reese Chem. Commun. 1970, 1519 equilibrium stongly favors this isomer [3,3] Sigmatropic Rearrangements A fluxional molecule, W. von E. Doering's Bullvalene: ! ! ! At 100 C one carbon is observed in the 13C NMR spectrum Tautomerism can drive a reversible cope process: H 220 C 3h keq ~ 10+5 OH Energetically, how much does tautomerization give you? OH 90% keq ~ 10+5 O !G = 1.4(pKeq) = 1.4X(-5) = -7 kcal/mmol Marvell, Tet. Lett. 1970, 509 Complex Total Synthesis; An Introduction O O O O Me Me Me Me Periplanone-B A potent female cockroach sex attractant 200 g was isolated from 75,000 virgin female cockroaches Schreiber, JACS, 1984, 106, 4038. Complex Total Synthesis; An Introduction O O O Me Me Periplanone-B O O ? Me Me Me Me Complex Total Synthesis; An Introduction O O O Me Me Periplanone-B CH2 O CH2 Me O , h! H H Me [2+2] Me Me Complex Total Synthesis; An Introduction O O O Me Me Periplanone-B CH2 O CH2 Me O , h! H H Me [2+2] Me Me ? OH H H Me Me Complex Total Synthesis; An Introduction O O O Me Me Periplanone-B CH2 O CH2 Me O , h! H H Me [2+2] Me Me MgBr OH H H Me Me Complex Total Synthesis; An Introduction O O O Me Me Periplanone-B OH OH [3.3] Me ! Me Me Me O tautomerize Me H Me OH Me Me Complex Total Synthesis; An Introduction O O O Me Me Periplanone-B O O " Me H Me electrocyclic ring opening X O O O photoisomerization (h!) 8 steps O Me Me Me Me Periplanone-B The Claisen Rearrangement O R # O R #H ~ 20 kcal mol-1 There is good thermodynamic driving force for this reaction. Bonds Broken: C-C! (65 kcal mol-1) & C-O" (85 kcal mol-1) Bonds Made: C-O! (85 kcal mol-1) and C-C" (85 kcal mol-1) ! Themodynamics of Claisen Variants: X O O X Substituent X=H X = OH X = NH2 #H (kcal mol-1) 16 31 30 (estimates) H ~ 30 O O OR ~ 20 H ~ 20 kcal/mol O ~ 30 kcal/mol OR O Heteroatom substitution at the indicated position increases exothermicity as well as reaction rate Traditional Claisen Rearrangements O 180-200 oC O H OH tautomerization 77% [3,3] O [3,3] N OH 65% N O [3,3] O [3,3] H O Claisen Cope OH tautomerization 91% E:Z = 6.7:1 The Claisen Rearrangement in Cyclic Systems Stereochemical outcome is syn and controlled by hydroxyl stereocenter 1 O X R 2 O R R X O 1 O X R 2 R Control of stereocenter 2 evolves into a decision how to establish the hydroxyl-bearing stereocenter X O Synthesis of Allyl Vinyl Ethers Hg(OAc)2 OH OEt (solvent) AcOHg O OEt 75% O Watanabe, Conlon, JACS 1957, 79, 2828 Bronsted acids can also serve as catalysts O Ph O Cp2Ti CH2 AlMe2 Cl 96% Ph CH2 O CH2 Cp2Ti Cl The Tebbe Reagent AlMe2 Think of as: Cp2Ti CH2 Other Claisen Variants Johnson Orthoester Claisen OEt OH Me C OEt OEt MeCO2H (cat) ! Me EtO O OEt O OEt O OEt Johnson, Faulkner, Peterson, JACS 1970, 92, 741. Eschenmoser-Claisen Xylene, 150oC OH Me Et2N OMe OMe O NEt2 Et BF4- + O Et Synthesis of Eschenmoser's Reagent O Me NMe2 Et2O Me OEt NaOEt NMe2 EtOH + EtO Me OEt NMe2 Et O Et2N OMe O Eschenmoser, A. Helv. Chem. Acta 1964, 47, 2425; Helv. Chim.Acta 1969, 52, 1030. NEt2 Me Et OH Me Et2N OMe OMe Et Me Me2N O Et Me Xylene, 110oC NMe2 High yield, E:Z = 99:1 H via: NMe2 Et O Me Et O H NMe2 Me Other Claisen Variants Ireland-Enolate Claisen O O Me LDA Me3SiCl OTMS O t1/2 (32oC) = 3.5 h OTMS O H2O O OH 66% Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868 Introduction to Retrosynthesis Et Me O Et Me CO2Me Cecropia Juvenile Hormone Introduction to Retrosynthesis Et Me O Et Me CO2Me HO Me Et Et Me CO2Me Cecropia Juvenile Hormone OH Introduction to Retrosynthesis Et Me O Et Me CO2Me HO Me Et Et Me CO2Me HO Me Et 2 1O 3 4 Et 5 Me CO2Me 6 Cecropia Juvenile Hormone OH Introduction to Retrosynthesis Et Me O Et Me CO2Me HO Me Et Et Me CO2Me HO Me Et 2 1O 3 4 Et 5 Me CO2Me 6 Cecropia Juvenile Hormone OH Et 5 Me 6 Et Me CO2Me OH 4 3 2 CO2Me O 1 Et OR Me Introduction to Retrosynthesis Et Me O Et Me CO2Me HO Me Et Et Me CO2Me HO Me Et 2 1O 3 4 Et 5 Me CO2Me 6 Cecropia Juvenile Hormone OH Et 5 Me 6 Et 2 1O 3 4 Me 5 Et CO2Me 6 Me CO2Me OH 4 3 2 CO2Me O 1 Et OR Me Me 5 4 3 6 CO2Me The Faulkner Juvenile Hormone Synthesis: JACS 1973, 95, 553 Me CO2Me OH Et O 1 2 Starting Material Introduction to Retrosynthesis Et Me Et Me CO2Me O Cecropia Juvenile Hormone Me CO2Me OH OMe 1 H+ 6 Me 2 85-90% (E) 3 CO2Me O 4 Et 5 4 O 6 1 Me 2 CO2Me 3 + Et NaBH4 Et Me CO2Me OH 110 C 5 Et Et Me CO2Me OH OMe OMe Me + Et OR Me H+ 110 C 1 6 Et Et 2 Me 3 O 4 CO2Me HO Me 4 Et 5 O 6 1 Et 2 Me CO2Me 3 5 OR Me The Faulkner Juvenile Hormone Synthesis: JACS 1973, 95, 553 Introduction to Retrosynthesis Et Me O Et Me CO2Me Cecropia Juvenile Hormone HO Me Et 3 Et Me CO2Me 6 NaBH4 HO Me Et Et Me CO2Me 1O OH TsCl, pyridine Et Me O Et Me CO2Me MeONa HO Me Et Et Me CO2Me OTs Acyclic Chirality Transfer in the Claisen Rearrangement OEt OH R2 ! OEt O R1 R2 ! R1 MeC(OEt)3 R1 H+ R2 O ! R2 R1 O H H R2 O R1 favored R2 ! R1 X X R2 O X disfavored R2 H X R1 H R1 O X O Note that chirality transfer is coupled to olefin geometry in product. Acyclic Chirality Transfer in the Claisen Rearrangement R2 ! R1 MeC(OEt)3 H+ R2 H H R1 O R2 ! R1 CO2Et OH Na/NH3 H2 Pd CaCO3 R2 OEt ! R1 OH ! R1 MeC(OEt)3 H+ H R1 O R2 H R2 ! R1 CO2Et R2 OH OEt Since stereoselection in reduction of acetylenes is >98%, either product accessible
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