Pericyclic Reactions 6 Lectures, Year 3, Michaelmas 2016

Transcription

1 Pericyclic eactions Pericyclic eactions 6 Lectures, Year 3, Michaelmas 26 jonathan.burton@chem.ox.ac.uk M diene π 4 s odd π 2 s LUM dienophile construczve overlap 6 electrons no nodes ückel h)p://burton.chem.ox.ac.uk/teaching.html Pericyclic eac+ons, xford Chemistry Primer no. 67; Ian Fleming rganic Chemistry Jonathan ayden, ick Greeves, Stuart Warren, Peter Wothers Advanced rganic Chemistry: eac+ons, chanisms and Structures; Jerry March Fron+er rbitals and rganic Chemical eac+ons; Ian Fleming Molecular rbitals & rganic Chemical eac+ons; Ian Fleming Modern ysical rganic Chemistry; Eric Anslyn and Dennis Docherty

2 Pericyclic eactions 2 Synopsis The nature of pericyclic reaczons Examples of pericyclic reaczons Drawing molecular orbitals CorrelaZon diagrams The Woodward-offmann rule FronZer Molecular rbitals Möbius-ückel thod CycloaddiZons Electrocyclic reaczons Sigmatropic rearrangements Group transfer reaczons

3 Pericyclic eactions 3 The nature of pericyclic reac>ons Ionic reaczons may or may not have an intermediate S reaczons are stepwise and have a defined intermediate u + X Et I u ($) ($) u I Et u u Et + I X (") (") u I Et u S 2 reaczons are concerted and have no intermediate In ionic reaczons the curly arrows idenzfy where the electrons have come from and where they are going and which bonds have been made and which broken. adical reaczons involve the correlated movement of single electrons Et I u Et C C frequently shortened to C C

4 Pericyclic eactions 4 Pericyclic eac>ons Third disznct class of reaczons Pericyclic reaczons eaczons in which all first-order changes in bonding relazonships take place in concert on a closed curve.. B. Woodward and. offmann 969. i.e. the reaczons have cyclic transizon states in which all bond-forming and bondbreaking take place in a concerted manner without the formazon of an intermediate. Pericyclic reaczons involve a transizon state with a cyclic array of interaczng orbitals; a reorganisazon of σ and π-bonds occurs within this cyclic array. riginally termed no mechanism reaczons they could not be explained by standard nucleophile/electrophile mechanisms. o absolute sense in which the electrons flow from one component to another; however, somezmes it is more sensible to push the arrows in only one direczon. ere curly arrows are used to show which bonds are being made/broken rather than the direczon of flow of electrons.

5 Pericyclic eactions 5 Pericyclic eaczons four classes. CycloaddiZons - Two components come together to form two new σ-bonds at the ends of both components and joining them together to form a ring. Cheletropic reaczons are a sub-class of cycloaddizon reaczons in which the two σ bonds are made or broken to the same atom. + C Electrocyclic eaczons Unimolecular reaczons characterised by the forma>on of a ring from an open chain conjugated system with a σ-bond forming across the ends of the conjugated system.

6 Pericyclic eactions 6 Sigmatropic rearrangements Unimolecular isomerisa>ons which formally involve the overall movement of a σ-bond from one posizon to another [3,3] [3,3] 3 2 Cope rearrangement 3 2 aisen rearrangement 5 [,5] [,5]-hydride shik [3,4] Group transfer appear to be a mix of a sigmatropic rearrangement and a cycloaddizon. They are bimolecular and so are not sigmatropic rearrangements, and no ring is formed so they are not cycloaddizons. Alder-ene - reac>ons Se Se diimide reduc>on

7 Pericyclic eactions 7 equire a theory/theories to explain these results heat X heat heat [,5] [,5] heat [,7] X [,5] heat [,7]

8 Pericyclic eactions 8 ückel Molecular rbital Theory for Linear π-systems. Applicable to conjugated planar cyclic and acyclic systems. nly the π-system is included; the σ-framework is ignored (in reality σ-framework affects π-system). Used to calculate the wave funczons (ψ k ) and hence rela+ve energies by the LCA method. M = ψ k, A = ϕ i and ψ = Σ c ki ϕ i n i = i.e. ψ k = c ϕ + c 2 ϕ 2 + c 3 ϕ 3 + c 4 ϕ 4 + c 5 ϕ 5.. k = M number ( n); i = atom posizon in π system ( n); n = number of p-orbitals For n contribuzng p-orbitals there will be n molecular orbitals c ki = (2/(n + )) /2 sin(πki/(n + )) ϕ ϕ 2 ϕ 3 ϕ 4 For each M ψ k Σ c 2 i = (normalisazon) i.e. the sum of the squares of the coefficients for any M must be..5 $ $ For each A ϕ i Σ c k 2 = i.e. the sum of the squares of the coefficients for any A over all Ms must be. Each M must be symmetric or anzsymmetric with respect to any symmetry operazon of the molecule. Molecular rbital Energies = E k = α + m j β m j = 2cos[jπ/(n+)] j =, 2 n

9 Pericyclic eactions 9 To draw a molecular orbital diagram: i) count the number of p-orbitals n ii) count the number of electrons π-bond = 2, unpaired electron =, carbanion = 2, carbocazon = iii) iv) draw n horizontal lines stacked on top of one another to represent the Ms draw the molecular orbitals as the combinazon of p-orbitals with an increasing number of nodes from for ψ to n- for ψ n such that each M is symmetric or ansymmetric with respect to any symmetry operaon of the molecule. v) if the number of nodes is even then the terminal orbital coefficients will be the same phase vi) if the number of nodes is odd then the terminal coefficients will be of opposite phase increasing number of nodes ψ 6 5 ψ 2 ψ 3 ψ 4 ψ 3 ψ 5 ψ 5 ψ 4 ψ non#bonding ψ 2 ψ 3 ψ ψ 2 ψ 2 ψ 3 2 ψ ψ ψ ψ 2 ψ ethene allyl butadiene pentadienyl hexatriene

10 Pericyclic eactions,3,5-exatriene six 2p atomic orbitals give 6π molecular orbitals; n = 6, j =, 2, 3, 4, 5, 6 m j = 2cos(π/7) =.8 2cos(2π/7) =.25 2cos(3π/7) = and the corresponding negazve values energy E = α +.8β α +.25β α +.45β α.45β..etc M no. nodes energy MT M (calculated) ψ 6 5 α -.8β.232 %.48 % %.232 ψ 5 4 α -.25β & &.52 ψ 4 3 α -.45β & &.52 α.52 & ψ 3 2 α +.45β.232 ' ' ψ 2 α +.25β.52 (.232 ( (.52 ψ α +.8β stabilisazon energy = E stab = 2(3α + 3.5β) = 6α + 7β remember E stab (ethene) = 2α + 2β

11 Pericyclic eactions The M of (neutral) polyenes can be readily constructed by puxng nodes on the single bonds; hence the M appears to be alternazng isolated π-bonding pairs. The LUM of (neutral) polyenes can be constructed by beginning with an isolated p-orbital and then alternazng isolated π-bonding pairs and ending with an isolated p-orbital. The M and LUM are termed the FronZer rbitals. M LUM CorrelaZon Diagrams During a pericyclic reaczon the orbitals of the starzng material are smoothly converted into the orbitals of the product. This means that the symmetry of the orbitals with respect to any symmetry operazons of the molecule must be conserved in moving from the starzng material(s) to product this is the ConservaZon of rbital Symmetry, which is readily depicted in an orbital correlazon diagram

12 Pericyclic eactions 2 Draw bare bones of reaczon. IdenZfy orbitals undergoing change. Draw sensible approach of substrates. IdenZfy symmetry elements maintained during reaczon. ank orbitals approximately by energy. assify each orbital with respect to the symmetry element(s) conserved during reaczon. ψ 4 π* σ A A A S A σ σ 4 σ 3 π* Construct orbital correlazon diagram conneczng orbitals of starzng materials with those closest in energy and of the same symmetry in the product. ψ 3 S In the Diels-Alder reaczon a plane of symmetry, perpendicular to the molecular planes of both the diene and dienophile and passing through the double bond of the dienophile and the central single bond of the diene. In the orbital correlazon diagram of the Diels- Alder reaczon all interaczng bonding orbitals in the diene/ dienophile are correlated with new bonding orbitals in the product. The reaczon is thermally. ψ 2 π ψ A S S S A S π σ 2 σ

13 Pericyclic eactions 3 CorrelaZon diagram for [2+2] cycloaddizon of alkenes IdenZfy orbitals undergoing change (curly arrows tell us which orbitals these are) π. σ 2 σ 2 Draw sensible approach of substrates in this case face on approach of the two alkenes for maximum orbital overlap. IdenZfy symmetry elements maintained during reaczon in this case two planes of symmetry, σ and σ 2. ank orbitals approximately by energy. assify each orbital with respect to symmetry element(s) conserved during reaczon. π 4 π 3 σ σ σ 2 AA AS σ σ 2 AA SA σ σ 4 σ 3 Construct orbital correlazon diagram conneczng orbitals of starzng materials with those closest in energy and of the same symmetry in the product. π 2 SA ere the ground state π 2 π 2 2 does not correlate with the ground sate of the product (σ 2 σ 22 ) but with a doubly excited state σ 2 σ 3 2 the thermal [2+2] cycloaddizon of alkenes is thermally dis. π SS AS SS σ 2 σ For more on correla+on diagrams see:. B. Woodward,. offmann, Angew. Chem. Int. Ed. 969, 8,

14 Pericyclic eactions 4 CorrelaZon diagram for electrocyclic reaczons Z,E : E,E 2,: Longuet-iggins & Abrahamson, J. Am. Chem. Soc., 965, 87, 245. There are two modes of opening conrotatory or disrotatory Conrotatory rota+on around the axes of the σ-bonds (do]ed lines ) occurs in the same direc+on - throughout this process the molecule retains a C 2 -axis which passes through the plane of the molecule and the breaking σ bond. Disrotatory rota+on around the axes of the σ-bonds (do]ed lines) occurs in opposite direc+ons throughout this process the molecule retains a plane of symmetry which is perpendicular to the plane of the molecule and passes through the breaking σ-bond C 2 plan view σ plan view

15 Pericyclic eactions 5 CorrelaZon diagram for electrocyclic reaczons. IdenZfy orbitals undergoing change (curly arrows) σ and π. The orbitals undergoing change are either symmetric or anzsymmetric with respect to the symmetry elements preserved during the reaczon. ank orbitals approximately by energy. Label orbitals as S or A. Construct orbital correlazon diagram conneczng orbitals of starzng materials with those closest in energy and of the same symmetry in the product. molecular) plane C 2 σ conrotatory under C 2 disrotatory under σ ψ 4 σ* ψ 4 ψ 3 π* ψ 3 ψ 2 π ψ 2 ψ σ ψ

16 Pericyclic eactions 6 conrotatory under C 2 disrotatory under σ molecular) plane ψ 4 S A σ* A A ψ 4 C 2 σ ψ 3 A S π* A S ψ 3 ψ 2 S A π S A ψ 2 ψ A S σ S S ψ In the conrotatory mode, all ground state bonding orbitals in cyclobutene (σ 2 π 2 ) correlate with ground state bonding orbitals in butadiene (ψ 2 ψ 22 ) the conrotatory opening of butadiene is thermally (favoured). In the disrotatory mode, the ground state bonding orbitals in cyclobutene (σ 2 π 2 ) correlate with a doubly excited state of butadiene (ψ 2 ψ 32 ) the disrotatory opening of butadiene is thermally forbidden (disfavoured). The photochemical ring closure of butadiene to give cyclobutene is disrotatory. The st excited sate of butadiene is ψ 2 ψ 2 ψ 3 which correlates smoothly with the st excited sate of cyclobutene (σ 2 π π* ); under conrotatory ring closure ψ 2 ψ 2 ψ 3 correlates with a much high energy state in cyclobutene (σ π 2 σ* ). hν

17 Pericyclic eactions 7 CorrelaZon diagrams can be diszlled into a simple rule for prediczng which pericyclic reaczons are. The Woodward-offmann ules: A ground state pericyclic reaczon is symmetry when the total number of (4q + 2) s and (4r) a components is odd (q and r must be integers). A pericyclic change in the first electronically excited state (i.e. a photochemical reaczon) is symmetry when the total number of (4q + 2) s and (4r) a components is even. We will use the Diels-Alder reaczon to exemplify the applicazon of the Woodward-offmann rules. Draw a curly arrow mechanism to idenzfy the components. For the Diels-Alder reaczon these are 4π (diene) and 2π (dienophile). Draw a convincing 3-D orbital diagram to show the overlap of the components. Label the components as supra or antarafacial. Sum the components according to the Woodward-offmann rule.

18 Pericyclic eactions 8 Draw a curly arrow mechanism this generally allows idenzficazon of the components. For the Diels-Alder reaczon these are 4π (diene) and 2π (dienophile), Draw a convincing 3-D orbital diagram to show the overlap of the components. Label the components as supra or antarafacial. ere the diene is being used in a suprafacial manner the two new bonds are being formed on the same face of the diene. The alkene is also being used in a suprafacial manner being used in a suprafacial manner Sum the components according to the Woodward-offmann rule π 4 s π 2 s odd π 2 s π 2 s 3 3 odd π2 a π2 a odd π2 s π2 a X π2 s 2 2 even forbidden π 2 s Generally simplest to maximise suprafacial components and not subdivide conjugated systems. π 2 s

19 Pericyclic eactions 9 [2 + 2] cycloaddizons Draw a curly arrow mechanism to idenzfy the components 2π, 2π Draw a convincing 3-D orbital diagram to show the overlap of the components Label the components as supra or antarafacial. Sum the components according to the Woodward-offmann rule heat X π 2 s π2 s 2 even forbidden (thermally) even photochemically π2 a π 2 s π2 s π 2 a (thermally) but geometrically unreasonable, therefore does not occur Woodward-offmann rule gives you the symmetry orbital overlap but you have to decide whether the overlap you have drawn is geometrically reasonable. odd

20 Pericyclic eactions 2 omenclature for suprafacial and antarafacial components. Suprafacial and antarafacial refer to modes of bond formazon that are respeczvely on the same face or on opposite faces of a molecular component. C π-suprafacial π-antarafacial σ-suprafacial σ-antarafacial σ-suprafacial σ-antarafacial ω-suprafacial ω-antarafacial

21 Pericyclic eactions 2 Woodward-offmann approach for thermal electrocyclic reaczons Draw a curly arrow mechanism to idenzfy the components these are 2π (alkene) and 2σ (single bond) Draw a convincing 3-D orbital diagram to show the overlap of the components Label the components as supra or antarafacial. Sum the components according to the Woodward-offmann rule. π 2 a σ2 s odd (conrotatory) π 2 s σ2 a odd (conrotatory) π2 s σ2 s 2 2 even forbidden disrotatory X Thermal ring opening of cyclobutene is conrotatory. Thermal disrotatory opening is symmetry forbidden.

22 Pericyclic eactions 22 Woodward-offmann approach for sigmatropic rearrangements Draw a curly arrow mechanism to idenzfy the components 2π, 2σ, 2π Draw a convincing 3-D orbital diagram to show the overlap of the components Label the components as supra or antarafacial. Sum the components according to the Woodward-offmann rule. σ 2 s π 2 s π 2 s σ 2 s σ 2 s π 2 s π2 s 3 3 odd π2 s π2 s 3 3 odd aisen rearrangement via chair TS is. aisen rearrangement via boat TS is. Woodward-offmann rule does not tell us that the chair TS is lower in energy than the boat TS. You need to use your chemical knowledge/intuizon to decide that a chair is generally lower in energy than the corresponding boat and that it is generally more favourable to have equatorial subsztuents than axial subsztuents on a chair.

23 Pericyclic eactions 23 Woodward-offmann approach for sigmatropic rearrangements and group transfer Draw a curly arrow mechanism to idenzfy the components Draw a convincing 3-D orbital diagram to show the overlap of the components Label the components as supra or antarafacial. Sum the components according to the Woodward-offmann rule. S S S σ2 s S ω 2 s π2 s 3 3 odd σ2 s π 2 s π2 s 3 3 odd [2,3]-sigmatropic rearrangement via envelope TS. ene-reaczon (group transfer) via envelope TS. For thermal cycloaddizons and group transfers: If the total number of electrons is (4n + 2) both components can be used in a suprafacial manner. If the total number of electrons is (4n) one of the components is suprafacial and the other antarafacial. For electrocyclic reaczons: Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4n and disrotatory if the total number of electrons is (4n +2).

24 Pericyclic eactions 24 FronZer Molecular rbital approach revision As two molecules approach each other, three major forces operate: (i) The occupied orbitals of one repel the occupied orbitals of the other. (ii) Any posizve charge on one a racts any negazve charge on the other (and repels any posizve) (iii) The occupied orbitals (especially the Ms) of each interact with the unoccupied orbitals (especially the LUMs) of the other, causing an a raczon between the molecules. (from Fleming, Molecular rbitals and rganic Chemical eaczons) FronZer Molecular rbital considers the interaczon of the ighest ccupied Molecular rbital (M) and the Lowest Unoccupied Molecular rbital (LUM) to be of overriding importance. LUM a empty M a empty M b thermal reaczon M b filled M a filled M b For photochemical reaczons one molecule is in the excited state ψ 4 ψ 3 SM hν ψ 4 ψ 3 LUM excited state a ground state b ψ 2 ψ LSM ψ 2 ψ M SM a LSM a unoccupied M ψ 3 occupied M ψ 2 a ψ 2 ψ 2 2 a* ψ 2 ψ 2 ψ 3 b

25 Pericyclic eactions 25 The FM approach To apply the FM method one has to assign a single M and a single LUM to the reaczon components and see how they interact. The FM approach is simple to apply to reaczons with two components (e.g. cycloaddizons, electrocyclic ring opening) but its applicazon to sigmatropic rearrangements and group transfer reaczons is somewhat contrived. Draw a curly arrow mechanism to idenzfy the components Assign a single M and a single LUM to the reaczon Draw a convincing 3-D orbital diagram to show the overlap of the components Check to see if there is construczve overlap between the orbitals M diene LUM diene π4 s π2 s odd LUM dienophile construczve overlap M dienophile construczve overlap

26 Pericyclic eactions 26 The FM approach Draw a curly arrow mechanism to idenzfy the components Assign a single M and a single LUM to the reaczon Draw a convincing 3-D orbital diagram to show the overlap of the components heat Check to see if there is construczve overlap between the orbitals LUM alkene LUM alkene M sigma construczve overlap M sigma construczve overlap M alkene LUM sigma construczve overlap π2 s σ2 a 3 odd (conrotatory) The preference of one conrotatory (or disrotatory) mode is termed torqueoselec+vity (more later).

27 Pericyclic eactions 27 The FM approach Draw a curly arrow mechanism to idenzfy the components hν Assign a single SM and a single LUM to the reaczon, (or a single LSM and M) note a SM has the same phases as the LUM and a LSM has the same phases as the M) Draw a convincing 3-D orbital diagram to show the overlap of the components Check to see if there is construczve overlap between the orbitals M alkene LSM alkene hν construczve overlap (disrotatory) π4 s even photochemically (disrotatory)

28 Pericyclic eactions 28 The FM approach Draw a curly arrow mechanism to idenzfy the components Assign a single M and a single LUM to the reaczon Draw a convincing 3-D orbital diagram to show the overlap of the components Check to see if there is construczve overlap between the orbitals M π + σ LUM π + σ π 2 s σ 2 s LUM alkene construczve overlap M alkene construczve overlap 3 odd π2 s ψ 2 ψ 3 M butadiene LUM butadiene

29 Pericyclic eactions 29 The FM approach Draw a curly arrow mechanism to idenzfy the components Assign a single M and a single LUM to the reaczon S S Draw a convincing 3-D orbital diagram to show the overlap of the components Check to see if there is construczve overlap between the orbitals S S M ω LUM, σ + ω S M alkene LUM, alkene + σ construczve overlap construczve overlap ψ 3 ψ 3 LUM butadiene LUM 4e - allyl ω2 s σ 2 s S π 2 s 3 3 odd

30 Pericyclic eactions 3 The Möbius-ückel thod Draw a curly arrow mechanism to assign components Draw a convincing 3-D orbital diagram to show the overlap of the components (easiest to draw ψ for all components and minimise number of nodes). Count the number of phase inversions in the closed loop of interaczng orbitals as always, phase inversions within an (atomic) orbital are not counted. Even number of phase inversions: ückel topology dd number of phase inversions: Möbius topology A thermal pericyclic reaczon involving a ückel topology is when the total number of electrons is (4n +2). A thermal pericyclic reaczon involving a Möbius topology is when the total number of electrons is 4n. (For photochemical reaczons the rules are reversed.) from. S. zepa J. Chem. Ed., 27, 84, 535 Diels-Alder reaczon [2 + 2] cycloaddizon S Sigmatropic rearrangement no phase inversions, ückel system 6 electrons no phase inversions, ückel system 4 electrons forbidden (thermally) no phase inversion ückel system 6 electrons

31 Pericyclic eactions 3 The Möbius-ückel thod A thermal pericyclic reaczon involving a ückel topology is when the total number of electrons is (4n +2). A thermal pericyclic reaczon involving a Möbius topology is when the total number of electrons is 4n. (For photochemical reaczons the rules are reversed.) electrocyclic reaczons one phase inversion Möbus system 4 electrons (conrotatory) no phase inversions, ückel system 4 electrons forbidden (thermally) (disrotatory)

32 Pericyclic eactions 32 CycloaddiZons The Diels-Alder reaczon is greatly accelerated by having an EDG on the diene and an EWG on the dienophile. 65 C, 7 h 9 atm 5 C,.5 h C, 2 h 2 C, 6 h ortho and para products predominate. Lewis acids catalyse the reaczon. endo products predominate. Al 3, -78 C endo C 2 + without catalysis 9% % with Al 3 98% 2%

33 Pericyclic eactions 33 CycloaddiZons Increase rate of reaczon with EWG on dienophile. An EWG ( Z subsztuent) on the dienophile lowers the energy of the LUM (and of all orbitals). (M ethene is α + β, LUM is α β). The best energy match is therefore the M of the diene with the LUM of the dienophile (full double-headed arrow) rather than the M of the dienophile with with the LUM of the diene (dashed double-headed arrow). Catalysis by Lewis acids arises from further lowering of the LUM of the dienophile. LUM M ψ 4 ψ 3 ψ 2 ψ ).43 ).58 ).23 ) ) ) α -.53β α -.35β α α +.β α +.88β ψ 3 ψ 4 ψ 2 ψ 2 LUM ψ 3 LUM α Al ₃ Al₃ ψ M ψ ψ ψ 2 M Al₃

34 Pericyclic eactions 34 CycloaddiZons In a similar manner placing an EDG on the diene raises the energy of the M making it a be er energy match for the LUM of the dienophile..37 &.6.6 &.37 ψ 4 α.62β aving an EDG on the dienophile (higher energy M) and an EWG on the diene (lower energy LUM) is generally less effeczve at increasing the late of the Diels-Alder reaczon. (Inverse electron demand) ψ 4 ψ 5.6 &.37 &.37.6 ψ 3 ψ 2 α -.62β α α +.62β ψ 2 ψ 3 LUM ψ &.37 &.6 ψ α +.62β ψ 3 α ψ ψ 2 ψ 2 M ψ ψ In general: EWG (Z-subsZtuents) lower M & LUM energies EDG (X-subsZtuents) raise M & LUM energies carbon conjugazng systems e.g. C=C, raise M & lower LUM These groups distort orbital coefficients.

35 Pericyclic eactions 35 CycloaddiZons Diels-Alder reaczon regioseleczvity ψ 4 ) ).58 α -.53β $ $.6.6 $.37 large.44 $ small LUM LUM M ψ 3 ψ ).23 ).43 ) ).58 α -.35β α α +.β.77 $.77.6 $.37 $ $.9 $.54 ψ α +.88β.77 M ψ $.37 $ $.7.5 $.77.5 &.6.6 & ψ 3 &.37 & $.77 ψ 2 Al ₃ Coefficients for acrolein just taken as average of allyl cazon and butadiene coefficients see Fleming..37 &.37 &.6 Al₃ In the presence of a Lewis acid (e.g. Al 3 ) acrolein will have more allyl cazon character and hence the C-terminus coefficient of the LUM will be larger ψ Al₃

36 Pericyclic eactions 36 CycloaddiZons ψ 5 Diels-Alder reaczon regioseleczvity.37 &.6.6 & $.5.58 $.5.29 ψ 4.37 &.6.6 & &.5.58 &.5.29 LUM.33 & &.44.6 &.37 & $.5.5 $.5 ψ 3.6 &.37 & &.5.5 &.5 large.55 &.44 & &.37 &.6.58 $ &.37 &.6.58 & M.59.9 &.48 & $.5 $.5 ψ 2 ψ &.5 & &

37 Pericyclic eactions 37 CycloaddiZons Diels-Alder reaczon regioseleczvity (Z = EWG e.g. C 2 ; X = EDG e.g.. M diene / LUM dienophile is the predominant interaczon Large-large and small-small overlap is best. LUM Z X C As noted previously, in the presence of a Lewis acid (e.g. Al 3 ) C-terminus coefficient of the LUM of a Z- subsztuted alkene will be larger leading to increased regioselecizvity in the Diels-Alder reaczon. M Z X C Z X C Z X C LUM LUM Z X C M M Z X C

38 Pericyclic eactions 38 CycloaddiZons Diels-Alder reaczon regioseleczvity (Z = EWG e.g. C 2 ; X = EDG e.g.. X Z ortho product M LUM Z para product X M LUM C C C C Z Z ortho product M LUM

39 Pericyclic eactions 39 CycloaddiZons Diels-Alder reaczon the endo rule endo-product is generally the major product with dienophiles containing π- conjugazng subsztuents. C 2 not C 2 Secondary orbital overlap is a simple explanazon for the kinezc preference for the endo-adduct M LUM endo exo In cases where the reaczon readily reverses (e.g. Diels Alder reaczons with furan) the thermodynamically preferred exo-adducts are usually obtained. endo-kinezc exo-thermodynamic

40 Pericyclic eactions 4 CycloaddiZons ElectrostaZc arguments have also been proposed as a reasonable explanazon for endo -seleczvity (+) (+) (+) (+) endo C 2 (+) (+) C endo (favoured) (+) exo (disfavoured) (+) endo (+) (+) endo (favoured) exo (disfavoured) Steric effects can favour the exo product. exo endo (disfavoured) exo (favoured)

41 Pericyclic eactions 4 CycloaddiZons Drawing stereochemistry for the Diels-Alder Ac endo Ac Ac 2 3 Ac Ac 2 3 Ac C Ac BF 3 Et 2,*5* C Ac? C Ac Ac

42 Pericyclic eactions 42 CycloaddiZons Ketenes undergo (thermal) [2+2]-cycloaddiZons with alkenes providing an excellent method for cyclobutane synthesis. The simplest explanazon for this reaczon is that the orbitals of the ketene are used as an antarafacial component. π2 s π 2 a π 2 s odd π2 a TreaZng the ketene as a vinyl cazon allows a geometrically more reasonable overlap to orthogonal orbitals π2 s ω s odd π 2 a

43 Pericyclic eactions 43 CycloaddiZons Ketene FronZer rbitals M alkene C C LUM + (C=C π*) LUM + ketene construczve overlap C C LUM (C= π*) M alkene LUM alkene C C M (C=C π) LUM ketene M ketene With ketenes it is probable that the low lying C= π* orbital is involved in the reaczon. ther cumulated π systems which contain a central sp-hybridised carbon atom (e.g. allenes, vinyl cazons) also readily undergo [2+2] cycloaddizon.

44 Pericyclic eactions 44 CycloaddiZons Ketenes readily react with cyclopentadiene to give cyclobutanes. π 2 a LUM + ketene π2 s M diene construczve overlap odd With an unsymmetrical ketene, the larger ketene subsztuent will point away from the plane of the alkene. egioseleczvity can be predicted from simple arrow-pushing arguments (the C= carbon of ketenes is very electrophilic), or from looking at FM coefficients. In reaczons of unsymmetrical alkenes the less sterically demanding C= part of the ketene will be oriented above the larger alkene subsztuents.

45 Pericyclic eactions 45 CycloaddiZons Another possible mechanism is a hetero Diels-Alder reaczon followed by a aisen rearrangement. π 4 s LUM ketene σ 2 s π2 s π2 s odd M diene construczve overlap π2 s Certain ketenes appear to react with cyclopentadiene via both a [2+2] cycloaddizon, and a [4+2] cycloaddizon followed by a aisen rearrangement mechanism.

46 Pericyclic eactions 46 xyallyl-diene LUM ω M sigma construczve overlap disrotatory ω s σ 2 s odd disrotatory M diene π4 s odd LUM allyl cazon construczve overlap π 2 s

47 Pericyclic eactions 47 Allyl cazon-diene AgBF 4 π 4 s π 2 s Br Allyl anion-alkene and reverse process LDA,%45% C LUM alkene π2 s odd M allyl anion construczve overlap π4 s

48 Pericyclic eactions 48 Allyl anion-alkene (reverse process) BuLi + C 2 ψ 3 LUM butadiene M ω LUM σ +σ construczve overlap σ 2 s σ 2 s 3 3 odd ω 2 s It can be easier to analyse the reverse reaczon. M carboxylate LUM alkene construczve overlap

49 Pericyclic eactions 49,3-Dipolar cycloaddizons. sp-hybridized central atom X Y Z π 4 s π 2 s X Y Z X Y Z X Y Z,3-dipole nitrile ylids nitrile oxides B B nitrile imines diazoalkanes 2 oxidazon ArS alkyl azides X nitrous oxide

50 Pericyclic eactions 5,3-Dipolar cycloaddizons. sp 2 -hybridized central atom X Y Z π 4 s π 2 s X Y Z X Y Z X Y Z,3-dipole azomethine ylids azomethine imines carbonyl oxides carbonyl ylids ozone nitrones

51 Pericyclic eactions 5 zonolysis M alkene construczve overlap ψ 3 π 2 s odd LUM ozone LUM allyl anion π 4 s ω 2 s σ 2 s σ 2 s M carbonyl LUM carbonyl construczve overlap ψ 2 LUM carbonyl ylid M allyl anion C construczve overlap M carbonyl ylid

52 Pericyclic eactions 52 Azomethine ylids. M ω ω 2 a Et 2 C C 2 Et Et 2 C C 2 Et Et 2 C C 2 Et LUM σ σ 2 s C 2 Et C 2 Et construczve overlap conrotatory C 2 Et C 2 Et ψ 3 ψ 2 odd conrotatory [ π 2 s π 4 s ] ψ Et 2 C C 2 Et

53 Pericyclic eactions 53 itrone cycloaddizons. itrones are readily formed between aldehydes and subsztuted hydroxylamines. The nitrone cycloaddizon can predominantly M nitrone LUM dipolarophile, or LUM nitrone M dipolarophile depending on the subsztuents on the dipolarophile. + ' ' ' Stockman synthesis of histrionicotoxin; J. Am. Chem. Soc., 26, 28, ' C C 2 C C C C C heat 8 C C C C C C

54 Pericyclic eactions 54 Gin s ominine synthesis J. Am. Chem. Soc., 26, 28, C X C C C C C C 3.6 C

55 Pericyclic eactions 55 Gin s ominine synthesis J. Am. Chem. Soc., 26, 28, C i)#ab 4 C ii)#s 2 i)#bu 3 Sn,# AIB C i)#dibal ii)# 3 P=C 2 +,$ 2 a,$ 3, $ipr,"

56 Pericyclic eactions 56 Cheletropic eaczons c.f. ketenes as vinyl cazons A sub-class of cycloaddizon/cycloreversion reaczons in which the two σ bonds are made or broken to the same atom. + C More important are the reaczons of singlet carbenes with alkenes which are stereospecific. Side on approach of the carbene is required for conservazon of orbital symmetry. odd π 2 s ω s π2 a 2 3 odd ω a ω2 s π2 s M carbene LUM alkene LUM carbene M alkene construczve overlap construczve overlap

57 Pericyclic eactions 57 Cheletropic eaczons The other important cheletropic reaczons involve the reversible addizon of sulfur dioxide to polyenes. S S 2 S 2 S 2 S 2 heat and pressure S heat and pressure M lone pair ω 2 s S π 4 s odd LUM S M S 2 S LUM S 2 LUM diene construczve overlap M diene construczve overlap

58 Pericyclic eactions 58 Cheletropic eaczons With trienes the extrusion process dominates but considering the reverse process the reaczon must be antarafacial with respect to the triene component. S 2 heat %&S 2 M lone pair S 2 heat %&S 2 LUM triene π 6 a M triene S ω 2 s odd LUM LUM hexatriene S M S 2 S LUM S 2 S construczve overlap construczve overlap X too strained; ca. 4 Zmes less reaczve than S 2

59 Pericyclic eactions 59 Cheletropic eaczons in Synthesis Steroid synthesis S 2 exo Colombiasin endo S 2

60 Pericyclic eactions 6 Electrocyclic reaczons Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4n and disrotatory if the total number of electrons is (4n +2) this is reversed for photochemical reaczons. All electrocyclic reaczons are (provided they are are not constrained by the geometry of the product). 4 C, 5 h 4 C, 5 h π 6 s odd disrotatory π 6 s odd disrotatory X odd conrotatory π2 a σ2 s but geometrically constrained therefore does not occur.

61 Pericyclic eactions 6 Electrocyclic reaczons hν SM diene LUM σ π 4 s σ 2 a even conrotatory Cyclopropyl cazon / allyl cazon interconversion construczve overlap conrotatory ψ 3 Lewis acid low temperature ψ 2 ψ The ionisazon of cyclopropyl halides and tosylates is a concerted process to give allyl cazons (i.e. discrete cyclopropyl cazons are not formed). The reaczon can be viewed as an internal subsztuzon in which the electrons in a σ-bond (M) feed into the C-X σ* (LUM). The reaczon is disrotatory and the sense of rotazon (torquoseleczvity) is specified this dictates the geometry of the allyl cazon and can have a large influence on reaczon rate.

62 Pericyclic eactions 62 Electrocyclic reaczons X σ 2 s ω s odd disrotatory M σ LUM σ construczve overlap disrotatory construczve overlap disrotatory construczve overlap disrotatory Influence on rates solvolysis in acezc acid Ts Ts Ts Ts Ts Ts

63 Pericyclic eactions 63 Electrocyclic reaczons - pentadienyl systems. CaZonic - azarov reaczon. 3 Si Fe 3 3 Si Fe 3 3 Si Fe 3 π 4 a odd conrotatory 6π electrocyclic ring closure M allyl cazon LUM alkene construczve overlap conrotatory Thermal azarov cyclisazon is conrotatory; photochemical azarov reaczon is disrotatory. Anionic. Li 4π electrocyclic ring closure relazve configurazon set by pericyclic reaczon π6 s odd disrotatory

64 Pericyclic eactions 64 Electrocyclic reaczons exemplified the endiandric acids. endiandric acid A methyl ester C 2 endiandric acid B methyl ester C 2 endiandric acid C methyl ester C 2 C 2 endiandric acid D methyl ester Diels Alder Diels Alder Diels Alder 6π electrocyclic endiandric acid E methyl ester C 2 endiandric acid F methyl ester C 2 endiandric acid G methyl ester C 2 8π electrocyclic C 2 6π electrocyclic 6π electrocyclic C 2 8π electrocyclic C 2 C 2 C 2 Biosynthesis proposed by Black J. Chem. Soc., Chem. Commun., 98, 92. BiomimeZc synthesis by K. C. icolaou, J. Am. Chem. Soc., 982, 4, 5558.

65 Pericyclic eactions 65 Electrocyclic reaczons exemplified the endiandric acids. 2 Lindlar C 2 π 8 a C 2 C 2 π 6 s 8π electrocyclic ring closure - conrotatory heat, C C 2 exo-diels Alder reaczon C 2 C 2 endiandric acid E methyl ester ' 6π electrocyclic ring closure - disrotatory 6π electrocyclic ring closure - disrotatory C 2 π 6 s ' endiandric acid A methyl ester endiandric acid D methyl ester C 2 C 2

66 Pericyclic eactions 66 Electrocyclic reaczons exemplified the endiandric acids. heat, C endiandric acid B methyl ester exo-diels Alder reaczon C 2 C 2 C 2 endiandric acid C methyl ester 2 Lindlar C 2 endiandric acid F methyl ester C ₂ endo-diels Alder reaczon C 2 ' 6π electrocyclic ring closure - disrotatory π 6 s C 2 6π electrocyclic ring closure - disrotatory π 8 a C 2 C 2 8π electrocyclic ring closure - conrotatory ' endiandric acid G methyl ester π6 s C ₂

67 Pericyclic eactions 67 Sigmatropic rearrangements. SyntheZcally the most important sigmatropic rearrangements are the Cope and aisen rearrangements and variants thereof. The aisen/cope rearrangements can proceed via chair-like or boat-like transizon states the chair-like transizon state is strongly favoured unless there are steric constraints that force a boat-like transizon state. Where possible, subsztuents generally adopt equatorial sites in the chair-like transizon state. assical aisen rearrangement. [3,3]-sigmatropic rearrangement =, tautomerism ' ' [3,3]-sigmatropic rearrangement tautomerism ' '

68 Pericyclic eactions 68 aisen and Cope heat + major equatorial minor π 2 s σ 2 s heat π 2 s 3 3 odd chair trans, trans - major axial cis, cis - minor chair boat cis, trans - trace cis, trans

69 Pericyclic eactions 69 aisen rearrangement - variants. Johnson-aisen rearrangement - synthesis of γ,δ-unsaturated esters. Et Et Et Et Et ± + Et Et cat.%%%%%%%heat Et Et Et equatorial Et Eschenmoser-aisen rearrangement - synthesis of γ,δ-unsaturated amides. Et via 2 heat Carroll rearrangement - synthesis of γ,δ-unsaturated methyl ketones. then%heat Ireland aisen rearrangement. LDA$then 3 Si Si Si 3

70 Pericyclic eactions 7 xy-cope rearrangement. Generally the Cope rearrangement requires very high temperatures > 2 C. heat The anionic oxy-cope can be conducted at low temperature ( C). k oxy-cope K k 2 /k 7 k 2 anionic oxy-cope Useful method for the synthesis of cis-decalins

71 Pericyclic eactions 7 Bulvalene - valence isomers interconvert by degenerate Cope rearrangements. c d c c b,n-ydride shi s. a b b a a a a a b b c b c c d A suprafacial,n-hydride shi involves the hydrogen moving from one end of the conjugated system to the other across one face of the conjugated system. An antarafacial,n-hydride shi involves the hydrogen moving from one end of the conjugated system to the other and moving from one face of the conjugated system to the opposite face [, 5] suprafacial shi of antarafacial shi of 6 [, 7] π4 s π4 a 2 σ2 s σ2 a π6 a odd odd σ 2 s odd

72 Pericyclic eactions 72,5-ydride shi s occur readily when the two ends of the diene are held close. T C D tbu In acyclic systems,5-hydride shi s can be much slower. T D tbu allylic strain disfavoured conformazon T tbu tbu D T D T D tbu T D 2 C [,5]-hydride shi chiral acezc acid T D tbu

73 Pericyclic eactions 73,2-Shi s of alkyl groups can also be pericyclic. CarbocaZons readily undergo,2-shi s. σ 2 s ω s odd Allowed, concerted,2-shi s of carbanions are geometrically impossible. X σ 2 s ω 2 s 2 2 even forbidden,2-shi s of carbanions occur by a radical mechanism,2-wixg,,2-stevens and related rearrangements.,2-wixg rearrangement. BuLi X

74 Pericyclic eactions 74 3 Thermal [,3]-alkyl shi s occur with inversion of configurazon in the migrazng group. 2 Ac D,3-alkyl shi D Ac Ac D odd π 2 s Ac D σ 2 a Thermal,3-shi of hydrogen is only geometrically reasonable in a suprafacial sense which is thermally dis. σ 2 s π2 s even forbidden In the following [,4]-shi, migrazon occurs with inversion of configurazon with D always on the concave face of the bicyclic structure. (4q + 2) D s = D π2 s 3 4 odd M σ construczve overlap Ac antarafacial shi but geometrically unreasonable LUM π D σ2 a D D

75 Pericyclic eactions 75,5-Alkyl shi with retenzon of configurazon in the migrazng group. heat [,5] [,5] odd π 4 s σ 2 s A number of [2,3]-sigmatropic shi s are useful synthezcally. [2,3]-Wixg rearrangement most likely proceeds via an envelope transizon state; large groups at the allylic posizon will tend to occupy a pseudo-equatorial posizon. Ar BuLi Ar [2,3] Ar σ 2 s Ar ω 2 s π 2 s 3 3 odd Sommelet-auser rearrangement. [2,3] 2 2 tautomerism

76 Pericyclic eactions 76 isenheimer earrangement. [2,3] 2 earrangement of allyl sulfoxides, sulfinimines and sulfonium ylids. [2,3] X S X S X =, Ts, C 2 A [9,9]-sigmatropic shi [9,9] 2 2 odd π8 s 2 σ2 s 2 π 8 s

77 Pericyclic eactions 77 Group transfer reaczons. Group transfer appear to be a mix of a sigmatropic rearrangement and a cycloaddizon. They are bimolecular and so are not sigmatropic rearrangements, and no ring is formed so they are not cycloaddizons. Alder ene reaczon 23 C σ 2 s π 2 s π 2 s 3 3 odd LUM π Al 3 25 C construczve overlap Conia-ene reaczon. M σ + π 35$ C ene C 3 tautomerise

78 Pericyclic eactions 78 Carbonyl-ene reaczon - frequently catalysed by Lewis acids. C 2 C 2 C 2 C 2 2 C C2 8 C, 48 h Sn 4, C C 2 C 2 C 2 C 2 Thermal carbonyl ene reaczon, sterics are important. Sn 4 C 2 C 2 2 C C2 In the Lewis acid-catalysed reaczon significant posizve charge develops in the eneophile. etro-ene and retro group transfer reaczons are common. S S heat + S S X heat + X retro-ene retro group transfer: X = S, Se, or (Cope eliminazon)

79 Pericyclic eactions 79 Pericyclic reaczon summary: Four classes: CycloaddiZons (chelotropic reaczons); Electrocyclic reaczons; Sigmatropic rearrangements; Group transfer. Woodward-offmann rules: A ground state pericyclic reaczon is symmetry when the total number of (4q + 2) s and (4r) a components is odd (q and r must be integers). A pericyclic change in the first electronically excited state (i.e. a photochemical reaczon) is symmetry when the total number of (4q + 2) s and (4r) a components is even. For thermal cycloaddizons and group transfers: If the total number of electrons is (4n + 2) both components can be used in a suprafacial manner. If the total number of electrons is (4n) one of the components is suprafacial and the other antarafacial. For electrocyclic reaczons: Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4n and disrotatory if the total number of electrons is (4n +2). And just because you can draw a pericyclic curly arrow mechanism does not necessarily mean the reaczon is pericyclic.