http://www.courses.fas.harvard.edu/~chem206/ Ph Ph OO O CO2Me CO2Me CO2Me MeO2C H H O O O Ph Ph Chem 206D. A. Evans, T. B. Dunn Matthew D. Shair Friday, October 11, 2002 a73 Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11Concerted Pericyclic Reactions Pericyclic Reactions: Part–1 Chemistry 206 Advanced Organic Chemistry Lecture Number 11 Pericyclic Reactions–1 a73 Introduction to Pericyclic Reactions a73 Electrocyclic Reactions a73 Sigmatropic Reactions a73 Cycloaddition Reactions 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. Chem 206D. A. Evans, B. Breit, T. B. Dunn Pericyclic Reactions: Introduction The Five Major Categories of Pericyclic Reactions (1) ELECTROCYCLIC RING CLOSURE/RING OPENING: Cyclobutene Butadiene 1,3,5-Hexatriene 1,3-Cyclohexadiene Examples: An electrocyclic ring closure is the creation of a new sigma bond at the expense of the terminal p orbitals of a conjugated pi system. There is a corresponding reorganization of the conjugated pi system. We usually classify the reaction according to the number of electrons involved. Pericyclic Reactions - Introduction/Definitions A pericyclic reaction is characterized as a change in bonding relationships thattakes place as a continuous, concerted reorganization of electrons. The term "concerted" specifies that there is one single transition state and therefore no intermediates are involved in the process. To maintain continuous electron flow, pericyclic reactions occur through cyclictransition states. More precisely: The cyclic transition state must correspond to an arrangementof the participating orbitals which has to maintain a bonding interaction between the reaction components throughout the course of the reaction. Pericyclic reactions are stereospecific: A A AA A A Reactions behave differently depending on the conditions used (i.e. thermal versus photochemical conditions): A The number of electrons involved has a profound influence on reactivity: 4 electrons rarely observed 6 electrons oftenobserved Some factors to consider in our analysis: The Theories:Three theories are commonly used to explain and predict pericyclic reactions. We will only concern ourselves with two of these theories. 1) Fukui: Frontier Molecular Orbital Interactions Much easier to use than the original orbital symmetry arguments HOMO/LUMO interactions 2) Dewar-Zimmerman: Aromatic Transition States The easiest to apply for all reaction types, but it is not as easy to understand why it it valid Aromatic or antiaromatic transition states a73 a73 a73 a73 On the three methods: "There are several ways of applying the orbital-symmetry principle to cycloaddition reactions, three of which are used more frequently than others. Of these three, we will discuss two: the frontier-orbital method and the M?bius-Hückel method. The third, called the correlation diagram method, is less convenient to apply than the other two." Jerry March in "Advanced Organic Chemistry" A 4 e- electrocyclic reaction A 6 e- electrocyclic reaction A A A A A A A ? or hν ? or hνhν First theory to explain and predict the outcome of many reactions Correlation diagrams 3) Woodward-Hoffmann: Conservation of Orbital Symmetry a73 a73 heat heat heatheat heat [4+1] [4+1] [2+1] R R R1 R2 O O S OO O CR2 R R C O S O O X R X R R H H R N N H H R R' N2 H H ? H H H R H R' R1 H R2 Chem 206D. A. Evans, B. Breit, T. B. Dunn Pericyclic Reactions: Major Classes (2) CYCLOADDITION REACTIONS/CYCLOREVERSION REACTIONS: + [2+2] + [4+2] A cycloaddition reaction is the union of two smaller, independent pi systems. Sigma bonds are created at the expense of pi bonds. A cycloaddition can occur in an intramolecular sense, but it must be between two independent pi 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: A 2+2 cycloaddition.The Paterno-Büchi reaction. A 4+2 cycloaddition.The Diels-Alder reaction. (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: (4) SIGMATROPIC REARRANGEMENTS: 1 2 3 1 23[1,3]-shift [1,5]-shift1 2 3 4 5 A sigmatropic rearrangement is the migration of a sigma bond from one position in a conjugated system to another position in the system, accompanied by reorganization of the connecting pi bonds. The number of pi and sigma bonds remains constant. The rearrangement is an [m,n] shift when the sigma bond migrates across m atoms of one system and n atoms of the second system. Examples: [3,3]-shift3 21 3'1' 2' 3 21 3'1' 2' X=CR2, Cope rearrangement X=O, Claisen rearrangement (5) GROUP TRANSFER REACTIONS: In a group transfer reaction one or more groups get transferred to a second reaction partner. Hydrogen Transfer: Ene Reaction: + + + + + hν Examples: B AA B A B B A B AA B A B A B A B A B A B A B Me Me Me H H Me MeMe HMe H Me Me Me Me Me ? ? Me Me Me Me H MeH Me Me H Me H Me Me hν hν Me Me Chem 206D. A. Evans, B. Breit, T. B. Dunn Electrocyclic Reactions Conrotatory Closure: The termini rotate in the same direction The Stereochemical issues: ELECTROCYCLIC RING CLOSURE/RING OPENING: Ring closure can occur in two distinct ways. This has consequences with regard to: a73 The orbital lobes that interacta73 The disposition of substituents on the termini Disrotatory Closure: The termini rotate in opposite directions Empirical Observations: conrotation conrotation disrotation disrotation Butadiene to cyclobutene: A 4-electron (4q) system Hextriene to cyclohexadiene: A 6-electron (4q+2) system It was also noted that changing the "reagent" from heat to light reversed this reactivity pattern. Under photochemical conditions 4 electron systems undergo disrotatory motion, while 6 electron systems undergo conrotatory motion. controtationdisrotation heat heat 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.) C Ψ1 Ψ1 Ψ2 Ψ3 Ψ4 Ψ2 Ψ3 pi pi? Chem 206D. A. Evans, T. B. Dunn Conjugated pi systems 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.bonding 2 p-orbitals 3 p-orbitals 4 p-orbitals 5 p-orbitals 6 p-orbitalsantibonding nonbonding nonbonding Ψ4 Ψ3 Me H H Me hν Me H H Me H MeH Me H Me Me H MeHHMe Me H H Me Me HH Me Ψ1 Ψ2 Me H H Me MeHHMe Me H H Me Me HH Me Ψ2 (HOMO) Me H H Me Ψ3 (HOMO) H MeH Me H Me Me H Ψ1 Ψ4 Ψ3 Ψ2 Chem 206D. A. Evans, B. Breit, T. B. Dunn a73 FMO Treatment of Electrocyclic reactions. a73 Examine the interactions that occur in the HOMO as the reaction proceeds. a73 If the overlap is constructive (i.e. of the same phase) then the reaction is "allowed." a73 If the overlap is destructive (i.e. of different phases) then the reaction is "forbidden." Destructiveoverlap Constructiveoverlap Ψ2 (diene HOMO) Ψ2 (diene HOMO) Conrotatory Closure: (Allowed and observed) Disrotatory Closure: (Forbidden and not observed) Thermal Activation: A similar analysis for the hexatriene system proves that under thermal conditions, disrotation is allowed and conrotation is forbidden. Photochemical Activation: When light is used to initiate an electrocyclic reaction, an electron is excited from Ψ2 to Ψ3. Treating Ψ3 as the HOMO now shows that disrotatory closure is allowed and conrotatory closure is forbidden. Photon absorption Destructiveoverlap ConstructiveoverlapΨ3 (new HOMO) Conrotatory Closure: (Forbidden and not observed) Disrotatory Closure: (Allowed and observed) Ψ3 (new HOMO) We have so far proven which ring closures are allowed and which are forbidden. Do we now have to go back and examine all the ring openings? NO! The principle of microscopic reversiblity says that if the reaction is allowed in one direction, it must be allowed in the other direction. Electrocyclic Reactions: FMO Analysis Chem 206D. A. Evans, B. Breit, T. B. Dunn Electrocyclic Reactions: Dewar-Zimmerman ConnectOrbitals DisrotatoryClosure ConrotatoryClosure Zero Phase Inversions ∴Hückel Topology 4 electrons in system ∴ Antiaromatic and Forbidden One Phase Inversion ∴M?bius Topology 4 electrons in system ∴ Aromatic and Allowed Note that I can change the phase of an abitrary orbital and the analysis is still valid! ConnectOrbitals DisrotatoryClosure ConrotatoryClosure Two Phase Inversions ∴Hückel Topology 4 electrons in system ∴ Antiaromatic and Forbidden Three Phase Inversions ∴M?bius Topology 4 electrons in system ∴ Aromatic and Allowed The Dewar-Zimmerman analysis is based on identifying transition states as aromatic or antiaromatic. We will not go into the theory behind why this treatment works, but it will give the same predictions as FMO or Orbital Symmetry treatments, and is fundamentally equivalent to them. Using the Dewar-Zimmerman model: a73 Choose a basis set of 2p atomic orbitals for all atoms involved (1s for hydrogen atoms). a73 Assign phases to the orbitals. Any phases will suffice. It is not important to identify this basis set with any molecular orbital. a73 Connect the orbitals that interact in the starting material, before the reaction begins. a73 Allow the reaction to proceed according to the geometry postulated. Connect those lobes that begin to interact that were not interacting in the starting materials. a73 Count the number of phase inversions that occur as the electrons flow around the circuit. Note that a phase inversion within an orbital is not counted. a73 Based on the phase inversions, identify the topology of the system. Odd number of phase inversions: M?bius topology Even number of phase inversions: Hückel topology a73 Assign the transition state as aromatic or antiaromatic, based on the number of electrons present. System Aromatic AntiaromaticHückel 4q + 2 4q M?bius 4q 4q + 2 a73 If the transition state is aromatic, then the reaction will be allowed thermally. If the transition state is antiaromatic, then the reaction will be allowed photochemically. Chem 206D. A. Evans, B. Breit, T. B. Dunn [1,3]-Sigmatropic Rearrangements: FMO Analysis The Stereochemical issues: The migrating group can migrate across the conjugated pi 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 pi system to the other, it is said to migrate antarafacially with respect to that system. A B A B BA BAA B A B Suprafacial migration: The group moves across the same face. A B A B A B A B BA BA Antarafacial migration: The group moves from one face to the other. a73 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. a73 Imagine the two pieces fragmenting into a cation/anion pair, (or a pair of radicals) and examine the HOMO/LUMO interaction. a73 If the migrating atom is carbon, then we can also entertain the possiblity of the alkyl group migrating with inversion of configuration (antarafacial on the single atom). a73 The suprafacial migration is forbidden and the bridging distance too great for the antarafacial migration. Hence, [1,3] hydrogen migrations are not observed under thermal conditions. Antarafacial GeometrySuprafacial Geometry bonding Ψ2 (allyl anion HOMO) antibondingbonding bonding a73 Construct TS by considering an allyl anion and the proton (or radical pair): a73 [1,3] Sigmatropic Rearrangements (H migration) Y X YX a73 Under photochemical conditions, the [1,3] rearrangement is allowed suprafacially. How would you predict this using FMO? H a73 The analysis works if you consider the other ionic reaction, or consider a radical reaction. In each case it is the same pair of orbitals interacting. Proton 1S (LUMO) XX HH Y YX Y?? a73 If the migrating atom is hydrogen, then it cannot migrate with inversion. H XX HH Y YX Y a73 Sigmatropic Rearrangements: FMO Analysis H H Chem 206D. A. Evans, B. Breit, T. B. Dunn [1,3]-Sigmatropic Rearrangements Ψ2 (allyl anion HOMO) a73 Construct TS by considering an allyl anion and the methyl cation: a73 Under photochemical conditions, the [1,3] rearrangement is allowed suprafacially with retention of stereochemistry. a73 The stereochemical constraints on the migration of carbonwith inversion of configuration is highly disfavored on the basis of strain. Such rearrangements are rare and usually only occur in highly strained systems. bonding bonding Inversion at carbon Suprafacial on allyl fragment Retention at carbon bonding antibonding Suprafacial on allyl fragment C H HX H C HH YHXY H H H H2p on Carbon a73 The analysis works if you consider the other ionic reaction, or consider a radical reaction. In each case it is the same pair of orbitals interacting. Using a similar analysis, one can prove that [1,5] hydrogen and alkyl shifts should be allowed when suprafacial on the pi component and proceeding with retention. Please refer to Fleming for more applications of FMO theory to [1,n] sigmatropic shifts. a73 Sigmatropic Rearrangements: Dewar-Zimmerman The [1,5] shift of a hydrogen atom across a diene. H H Orbital interactions in the parent system The basis set of s and p orbitals with arbitrary phase: Completing the circuit across the bottom face Zero Phase InversionsHückel Topology Six ElectronsAllowed thermally Dewar-Zimmerman also predicts the [1,3] suprafacial migration to be forbidden. Orbital interactions in the parent system Completing the circuit across the bottom face Two Phase InversionsHückel Topology Four ElectronsForbidden thermally CH3 XX CH3CH3 Y YX Y?? a73 [1,3] Sigmatropic Rearrangements (C migration) H H X Z X Z Z X Chem 206D. A. Evans, B. Breit, T. B. Dunn [3,3] Rearrangements: A thermally allowed reaction in either of two geometries, the "chair" or the "boat" geometry. Depicted below is the "chair" geometry. You should be able to work out the details of the "boat" geometry yourself. Two Phase InversionsHückel Topology Six ElectronsAllowed Thermally ? X & Z = C, O, N etc The FMO Analysis: Bring two Allyl radicals together to access for a possible bonding interaction between termini. ? ? ? bonding bondingThe nonbonding allyl MO The Dewar-Zimmerman Analysis: a73 The Toggle Algorithm: The toggle algorithm is a simple way to take one reaction of each class that you remember is allowed (or forbidden) and derive if the reaction is allowed or forbidden under new conditions. a73 How does it work? All of the various parameters of the pericyclic reaction are the input variables, the "switches." The output is either "allowed" or "forbidden."Write out all the relevant parameters of a reaction together with the known result.Each time you change a parameter by one incremental value ("toggle a switch"), the output will switch.This is the prediction of the reaction under the new parameters. a73 So it's nothing really new, is it? No, its just a convenient way to rederive predictions without memorizing a table of selection rules. An Example: Rearrangement [1,3] [1,3] [1,3] [1,5] Conditions Heat Heat Light Heat Component 1 Suprafacial Antarafacial Antarafacial Suprafacial Component 2 Suprafacial Suprafacial Suprafacial Suprafacial Output Forbidden Allowed Forbidden ? Take the [1,3] sigmatropic rearrangement of an alkyl group. We know this is forbidden under thermal conditions in a supra-supra manner, and so we make it the first entry in the table. Each incremental change in the "input" registers changes the "output" register by one. Multiple changes simply toggle the output back and forth. What is the prediction in the last line? [3,3]-Sigmatropic Rearrangements HOMO HOMO Chem 206D. A. Evans, B. Breit, T. B. Dunn The [2+2] Cycloaddition: FMO Analysis Cycloaddition Reactions The Stereochemical issues: In a cycloaddition, a pi system may be attacked in one of two distinct ways. If the pi system is attacked from the same face, then the reaction is suprafacial on that component. If the system is attacked from opposite faces, then the reaction is antarafacial on that component. Suprafacial attack Antarafacial attack For the [2+2] cycloaddition two different geometries have to be considered. Suprafacial/Suprafacial Antarafacial/Suprafacial bonding antibondingbonding bondingLUMO LUMO Forbidden Allowed The simplest approach (Supra/Supra) is forbidden under thermal activation. The less obvious approach (Antara/Supra) is allowed thermally but geometrically rather congested. It is believed to occur in some very specific cases (e.g. ketenes) where the steric congestion is reduced. The [4+2] Cycloaddition: Dewar-Zimmerman The most well known cycloaddition is the Diels-Alder reaction between a four pi component (the diene) and a two pi component (the dienophile). An exhaustive examination of this reaction is forthcoming, so we will limit ourselves to a simple examination. Summary: a73 There are three fundamentally equivalent methods of analyzing pericyclic reactions: Two are much simpler than the third. a73 Fukui Frontier Molecular Orbital Theory a73 Dewar-Zimmerman Hückel-M?bius Aromatic Transition States a73 Woodward-Hoffmann Correlation Diagrams a73 Some methods are easier to use than others, but all are equally correct and no one is superior to another. Conclusions drawn from the correct application of one theory will not be contradicted by another theory. a73 The principle of microscopic reversibility allows us to look at a reaction from either the forward direction or the reverse direction. a73 There is a general trend that reactions will behave fundamentally different under thermal conditions and photochemical conditions. Zero Phase InversionsHückel Topology Six ElectronsAllowed thermally