D. A. Evans Pericyclic Reactions: Part-2 Chem 206 ■ Other Reading Materia: http://www.courses.fasharvardedu/-chem206/ aWoodward-Hoffmann Theory R. B. Woodward and R Hoffmann. The Conservation of orbital Symmetry, Verlag Chemie, Weinheim, 1970 Chemistry 206 a Frontier Molecular Orbital Theory Fleming, Frontier Orbitals and Organic Chemical Reactions, Advanced Organic Chemistry John-Wiley and Sons, New York, 1976 IDewar-Zimmerman Theory T. H Lowry and K. S. Richardson, Mechanism and Theory in Lecture number 12 Organic Chemistry, 3rd Ed, Harper&Row, New York, 1987 ■ General Reference R.E. Lehr and A P Marchand, Orbital Symmetry: A Problem Pericyclic Reactions-2 Solving Approach, Academic Press, New York, 1972 ■ Electrocyclic ■ Problems of the Day a Cheletropic Reactions I Sigmatropic Rearrangements: [1, 2 [1,3,[1,5] Predict the stereochemical outcome of this reactio 0 Reading Assignment for week Carey Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Huisgen, TL, 1964, 3381 Fleming: Chapter 4 Thermal Pericyclic Reactions Houk, et al. Acc. Chem. Res. 1996, 29, 471-477 Suggest a mechanism for the following reaction Houk,et.a.JoC.1996,61,28132825 Meo2C Matthew d shair October 14
http://www.courses.fas.harvard.edu/~chem206/ Ph Ph O O O CO2Me CO2Me H H CO2Me MeO2C H H O O O Ph Ph D. A. Evans Chem 206 Matthew D. Shair Monday, Columbus Day, October 14, 2002 ■ Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Pericyclic Reactions: Part–2 Chemistry 206 Advanced Organic Chemistry Lecture Number 12 Pericyclic Reactions–2 ■ Electrocyclic Reactions ■ Cheletropic Reactions ■ Sigmatropic Rearrangements: [1,2], [1,3], [1,5] ■ Other Reading Material: Fleming: Chapter 4 Thermal Pericyclic Reactions ■ Woodward-Hoffmann Theory R. B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry, Verlag Chemie, Weinheim, 1970. ■ Frontier Molecular Orbital Theory I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John-Wiley and Sons, New York, 1976. ■ Dewar-Zimmerman Theory T. H. Lowry and K. S. Richardson, Mechanism and Theory in Organic Chemistry, 3rd Ed., Harper & Row, New York, 1987. ■ General Reference R. E. Lehr and A. P. Marchand, Orbital Symmetry: A Problem Solving Approach, Academic Press, New York, 1972. ■ Problems of the Day: Huisgen, TL, 1964, 3381. Predict the stereochemical outcome of this reaction. ❉ heat ❉ 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
Evans. Breit Electrocyclic Processes-1 Chem 206 Electrocyclic Reaction-Selection Rules Controtation , and y2 on to the indicated bonding and anti-bonding orbitals of cyclobutene Ground st Excited state ermal pro (Photochemical Proces 4nπe (n=12…) 4n+2πe (n=0, 1, 2.)disrotatory conrotatory Examples Ground state Excited state LUMO HOMO onto ration Energy(kcal/mol) ctivation Energy(kcal electrocyclic ring opening for electrocyclic ring op conrotatory Disrotato Criegee, Chem. Ber. 1968, 101. 102 Disrotatory 0~00 Disrotatory Connotate Ph Sterically favored Huisgen, TL, 1964, 3381
H Ph Ph O O O Ph Ph O O 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 p e- (n = 1,2...) 4n+2 p 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
Evans. Breit Electrocyclic Processes-2: Torquoselectivity Chem 206 Torquoselectivilty is defined as the predisposition of a given R substituent for a given conrotatory motion How do we explain? Donor substituents prefer con-out mode Pi acceptor substituents prefer con-in mode Houk et al. Acc. Chem. Res 1996.29. 471 View the 2 conrotatory modes by looking at R the breaking sigma bond from this perspective con Examples Donor substituents prefer con-out mode Pi acceptor substituents prefer con-in mode Outward motion Inward Motion CO R=Me one H R=CHo none H LUMO +p LUMO+ p CH2OBn CH20Bn CHO A H ratio: >20: 1 HOMO+ p HOMO + p M destabilizing 4 electron interation for donor As conrotation begins the energy of substituents the breaking sigma bond rises steeply. Hyperconjugation with a pi orbital, while possible in both a&B stabilizing 2 electron is better in B. Houk) interation for acceptor substituents
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 mode Pi 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 mode Pi 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 of the breaking sigma bond rises steeply. Hyperconjugation with a pi* orbital, while possible in both A & B , is better in B. (Houk)
Evans. Breit Electrocyclic Processes-3: 3-Atom Electrocyclization Chem 206 Three-Atom Electrocyclization (2 electrons Solvolysis of Cyclopropyl Derivatives Does solvolysis proceed via cation 1 followed by rearrangement to 2 ( Case 1), or does it proceed directly to 2( Case 2)? Con?? fast Case 2 nonbonding Me tso 000 cation relative rate 40,000 LUMO DePuy, Accts. Chem. Res. 1967, 1, 33 X LUMO HOMO Note that there are two disrotatory modes HOMO RDis LUMO X Sterically favored Favored for R=ring HOMO
+ + Y3 Y1 Y2 A H R H A R A H A H R C 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 C R H Me Me H C C R Me H H Me X HOMO HOMO –X– –X– H TsO Me Me H H H +X– R Me H H Me H TsO H H 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) Dis?? Con?? 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
Evans. Breit Electrocyclic Processes-3: 3-Atom Electrocyclization Chem 206 dis-out Solvolysis Summary Three-Atom Electrocyclization (4 electrons) Unfavorable favorable TsO Me D22 Con?? relative rate 1 Ring-fused Cyclopropyl Systems 0Q0 When the cis substiltutents on the cyclopropyl ring are tied together 00 in a ring the following observations have been made nonbond Tso favored nIon elative rate:>10 H2c 仓CH disavowed dis-out Observation COmE COm Con Revisiting the Favorski rearrangement: (Carey, Part A, pp 506-8) MeO2C / COmE MeO2C (+)…(
H2C H2C CH2 TsO H H H H TsO H H O Cl H TsO O– Cl H TsO Me Me H H TsO H H H H TsO H H –Cl– O– H TsO H H Me Me O Y3 Y1 Y2 A H R H A R C B A B A Ar N CO2Me CO2Me H H Ar N CO2Me H H MeO2C R C A H H A MeO2C N MeO2C Ar C C R C 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) Dis?? Con?? Evans, Breit nonbonding cation anion Observation ·· ·· (–) (+) ·· (–) (+) Con Con Con ·· ·· relative rate 1 4 40,000 Solvolysis Summary Unfavorable favorable 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
Evans. Breit Electrocyclic Processes-3 Chem 206 Five-Atom Electrocyclizations(4 electrons) The Nazarov Reaction R 八 +H Denmark, S E In Comprehensive Organic Synthesis: Trost, B M Fleming, I, Eds. Pergamon Press: Oxford, 1991; Vol. 5: pp 751 wQ0.9 mbo predict 0000 Eight-Atom Electrocyclization(8 electrons) 1 00000 Pentadienyl Cation LUMO 2 Let's use the"Ready"shortcut to find the homo: Nodes will appear at single bonds syr Pentadienyl Anion Closure should be conrotatory
R A A R A A R A A O A A O +H+ +H+ OH A A C C A H A A H A HOMO LUMO C C H H A A A A A A A A O –H+ O A A A A Electrocyclic Processes-3 Chem 206 Eight-Atom Electrocyclizations (8 electrons) ·· Five-Atom Electrocyclizations (4 electrons) Dis?? ❋ Con?? nonbonding Cation Anion ❋ ❋ Con Pentadienyl Cation + Dis Pentadienyl Anion – ● ● ● Dis?? Con?? 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 ❇ ❇ ❇ ❇
Evans. Breit Cheletropic Processes-1 Chem 206 CHELETROPIC REACTIONS: [n+1] Cycloadditions(or Cycloreversions 2+1 CheletropicReaction: Olefins Singlet Carbene Concerted processes in which 2 a-bonds are made(or broken)which terminate at a single atom R Linear Approach: 2 HOMO-LUMO Interactions General HOMO LUMO LUMO HOMO Y Reversion Nonlinear Approach: 2 HOMO-LUMO Interactions Addition 8 LUMO Addition (and Rev and Addition HOMO LUMO HOMO Frontier Orbitals p(empty) Carry out the analysis of the indicated hypotheti Question: what is orientation of carbene relative to attacking olefin?? try of carbene
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 R R R X Y Z X Y Z HOMO HOMO R R C C C C R R S O O S O O C R R Cheletropic Processes-1 Chem 206 2 + 1 CheletropicReaction: Olefins + Singlet Carbene CHELETROPIC REACTIONS: [n+1] Cycloadditions (or Cycloreversions) Concerted processes in which 2 s-bonds are made (or broken) which terminate at a single atom. + [4+2] + [4+1] General p-system Reversion Addition p-system + Singlet-Carbene Addition (and Reversion) Cycloreversion only Reversion and Addition Frontier Orbitals E w 2 w 0 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??
Evans. Breit Cheletropic Processes-2 Chem 206 Let's now consider SO2 as the one-atom component Key step in the Ramberg Backlund Rearrangement E 0⊙ base R1 4e- in pi system p2 filled 3 empty Z suprafacial Clough, J M. The Ramberg-Backlund Rearrangement. Trost, B M. and Fleming, I Pergamon Press: Oxford, 1991; VoL. 3, pp 861 The Ramberg-Backlund Rearrangement. Paquette, L. A. Org. React.(NY) 1977, reactions are 25,1 stereospecific reversible Analysis of the Suprafacial So Extrusion(nonlinear) suprafaci HOMO HOMO p3 empty(LUMO) y3 empty(LUMO) LUMO LUMO 2 y, filled milar to carbene geometry
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 R 1 X S R 2 O O R 1 R 2 filled + SO2 empty (LUMO) S O O – S O O – S R 1 R 2 O O S R 1 R 2 O O -SO2 -SO2 S R 1 R 2 O O R 1 R 2 R 2 R 1 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 Bäcklund 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
D. A. Evans Sigmatropic Rearrangements-1 Chem 206 Sigmatropic rearrangements are those reactions in which a sigma bond a[1, 3] Sigmatropic Rearrangements(C migration) ( associated substituent interchanges termini on a conjugated pi system consider the 1, 3-migration of Carbon [1,3] Sigmatropic rearrangement H3 Consider the orbitals needed to contruct the transition state (Ts) [2, 3]Sigmatropic rearrangement 0 Construct TS by uniting an allyl and Me radicals R Retention at carbon Inversion at carbol [3, 3 Sigmatropic rearrangement R Suprafacial on allyl fragment Suprafacial on allyl fragment a[1, 3]Sigmatropic Rearrangements(H migration Sychronous bonding to Sychronous bonding to both termi cannot be achieved from this geometry is possible from this geometry consider the 1, 3-migration of H o The stereochemical constraints on the suprafacial migration of carbon H Consider the orbitals needed to contruct with inversion of configuration is highly disfavored on the basis of strain the transition state (TS) [1, 3F-Sigmatropic rearrangements are not common a Construct TS by uniting an ally l and H radical no observed scrambling of labels bonding -Y 2(allyl HOMO Suprafacial Geometry Antarafacial Geometry Bridging distance too great for antarafacial migration These rearrangements are only seen in systems that are highly strained, an attribute that lowers the activation for rearrangemer
X H H C H X R C R H X C Me H 1 3 R X Y:– X X R X H D D D D Y X H H X H Y H X Y X Y D H X X R Y –:X X R X H Y Me H H X H Y D Y CH3 X D D Y X H H Y H3 C X Me H Y CH3 X D D. A. Evans Sigmatropic Rearrangements-1 Chem 206 Bridging distance too great for antarafacial migration. Suprafacial Geometry Antarafacial Geometry bonding Y2 (allyl HOMO) antibonding bonding bonding ■ Construct TS by uniting an allyl and H radical: Consider the orbitals needed to contruct the transition state (TS). ‡ consider the 1,3-migration of H ■ [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 ■ Examples: Sychronous bonding to both termini is possible from this geometry ❐ The stereochemical constraints on the suprafacial migration of carbon with 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 ■ [1,3] Sigmatropic Rearrangements (C migration) consider the 1,3-migration of Carbon ‡ Consider the orbitals needed to contruct the transition state (TS). ❐ 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 ✻ ✻ [1,3]-Sigmatropic rearrangements are not common
D. A. Evans Sigmatropic Rearrangements-2 Chem 206 SIGMATROPIC REACTIONS-FMO-Analysis [1, 5] Sigmatropic Rearrangements(C migration) Why R=H, CR3 [1s, 5s]alkyl shift= RETENTION [1, 5]Sigmatropic Rearrangements(H migration [1a, 5a] alkyl shift INVERSION disfavored a [1, 5](C migration: Stereochemical Evaluation 中3 RETENTION 1, 5s H-shift Dewar-Zimmerman Analysis: Retention 00000 thermal photochemic R View as cycloadditon between following species suprafacial preferred 0 phase inversions Huckel toplogy 6 electrons therefore. allowed thermally either, or ntadienyl radical y3 ntadienyl radical 3
R R R R R 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 H H Me Me D. A. Evans Sigmatropic Rearrangements-2 Chem 206 ■ [1,5] Sigmatropic Rearrangements (C migration) [1s,5s] alkyl shift Þ RETENTION SIGMATROPIC REACTIONS - FMO-Analysis 1 2 3 D/hn R = H, CR3 4 5 1 2 3 4 5 ■ [1,5] Sigmatropic Rearrangements (H migration) [1a,5a] alkyl shift Þ INVERSION disfavored ■ [1,5] (C migration): Stereochemical Evaluation 230-280°C RETENTION [1,5s]H- shift [1,5s]C- shift nonbonding thermal hn photochemical pentadienyl radical View as cycloadditon between following species: pentadienyl radical + either, or suprafacial preferred Dewar–Zimmerman Analysis: Retention 0 phase inversions Þ Huckel toplogy 6 electrons therefore, allowed thermally
