Pericyclic Reactions PDF

lOMoARcPSD|6077384 Pericyclic reactions Advanced Organic Chemistry and Laboratory (The University of Warwick) Studocu is not sponsored or endorsed by any college or university Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 Week 1 – pericyclic reactions       What is...

lOMoARcPSD|6077384 Pericyclic reactions Advanced Organic Chemistry and Laboratory (The University of Warwick) Studocu is not sponsored or endorsed by any college or university Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 Week 1 – pericyclic reactions       What is a pericyclic reaction, and can you give the 4 types with definitions? Can you use FMO theory to predict the outcome and stereochemistry for the electrocyclization reaction of an alkene? o What is the stereochemistry of the starting material? o Out of phase ends (antarafacial) leads to a conrotory rotation (same direction), R groups on opposite ends o Is it with heat or irradiation/hv?  P.21: Hv results in the excitation of an electron from orbital 2 to orbital 3, causing 3 to be new homo. Suprafacial (in phase) causing a disrotary process (different directions bond rotation) and then R groups on the same side. Can you use FMO theory to predict the outcome, stereochemistry and regiochemistry of [2+2]-cycloaddition and [4+2]-cycloaddition with heat and with hv? – cycloaddition is between 2 polyenes or 2 alkenes. Things to note: o Woodward-Hoffman rules: p-electrons have to = 4n+2 o Is it diene s-cis or s-trans (wont react) – orbitals have to be close together o Dienophile stereospecific, the stereochemistry will maintain in the product o Is it endo or exo product?  draw both  Endo is the kinetically favoured product (major), even though there is a steric clash, due to secondary orbital interaction (interaction between 2 or more p orbitals not directly involved in bonding)  Exo is the thermodynamically/sterically favoured product (minor) – with a better LG this is major  is it then an intramolecular? (this ignores the endo rule) o Suprafacial or antarafacial? o Is it thermally forbidden?  2+2, 4+4 – yes under thermal conditions  Can become favourable under photochemical conditions due to promotion of an electron from HOMO to LUMO making the LUMO the new HOMO!  Another orbital adding another bonding interaction could make it possible too i.e. p or d o Effect of an EWG or EDG?  Dienophiles favour EWG – leads to lowering of LUMO  Dienes favour EDG – leads to raising of HOMO  Both cases lead to better overlap and increase in stabilisation energy  Regioselecctivity – big orbital with big orbital  Can use the eV of orbitals to calculate energy differences and see which is more favourable o Impact of catalyst?  Addition of a catalyst say Lewis acid binding to carbonyl will make the group more electron withdrawing = lower lumo = faster ROR = increase in polarisation+difference between coefficients of p-orbitals increasing selectivity What is the reaction of thermal [2+2] cycloaddition of dichloroketene? o Ketenes and allenes have linear sp-hybridisation with db orthogonal to each other o 2+2 can occur if an extra bonding interaction can occur aFnd HOMO of alkene will bond with HOMO of the allene o Dichloroketene is a good 2+2 partner as Cl lowers LUMO of alkene What is the reaction of 1,3-dipolar cycloadditions? o 6 pi electron pericyclic reactions, the 4 pi component is 1,3-dipole. See page 52 What is the outcome and stereochemistry of [1,5] and [3,3]-sigmatropic rearrangement with hv and with heat? Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 o o o o o o o o o o Unimolecular isomerisation and involved a concerted migration of atoms or of groups of atoms – e.g. migration of a sigma bond – internal Anti is favoured product – shown via chair conformer Suprafacial, 6e process HOMO/LUMO defines stereochemistry (S,E) forms (R,E) and (Z,S) – some level of stereocontrol Only suprafacial occurs in standard 4n+2 (photochemically and thermally) Antarafacial occurs in 4 pi systems, but only photochemically due to sterics Antarafacial can occur thermally in extended 4n pi systems i.e. [1,5] or [1,7] as there is a flexible chain/conjugation See suprafacial examples [1,5] on page.60. [1,7] wouldn’t work as it would have to cross the plane of the ring [3,3] sigmatropic rearrangements: migration of c-c sigma bond  Note, starting alkene fixes the subsituent axial or equatorial – no rotation. With sp3 centres there is the ability to rotate. – stereochemistry ‘locked in’  Claisen cope (heteroatoms) – not reversible, Z,E to syn product- retention of stereochemistry  Cope – reversible, E,E to anti product – retention of stereochemistry  Substituents favour eqt due to 1,2 diaxial interactions  Wedge/dash alternate each bond Week 2 – Reactive intermediates      Can you recognise, rationalise and describe the structure of carbon-centred radicals? Can you evaluate the relative stability of radicals based on kinetics and thermodynamics? Can you identify routes to radical formation and draw mechanisms for radical chain reactions? Can you apply radical chain mechanism to rationalise the outcome of intermolecular and intramolecular reactions involving radical intermediates? Can you understand and apply the factors that govern outcomes of radical reactions? Structure of radicals   Types: o Planar o Pyramidal o Linear o Non-linear/bent Orbital effects: Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384  o Want to promote mixing of SOMO and LUMO of planar structure to get the pyramidal structure o This can be done by raising SOMO with pi donors and lowering LUMO energy with sigma acceptors Promotion of radical stability: o Must have t1/2> 10-3 s o Steric hindrance o Thermodynamically stable due to:  Resonance  Hyperconjugation  Hybridisation  Conjugation Radical formation     Homolytic cleavage – either weak bonds break i.e. O-O and/or strong products form i.e. N(triple bond)N Abstraction – inter/intramolecular Chemoselectivity of alkyl halide reaction using Bu3SnH – chain transfer/polymerisation o Weaker bond cleaved off i.e. Br would cleave off instead of Cl Figure 1: Radical formation through addition Radical formation through addition o Bond strengths – only works with R-Br or R-I o Conc of Bu2SnH low to prevent reaction of polymerisation or radical+tin hydride o Reactivity of alkyl radical – frontier orbital effects + EWG for stabilisation  Electron rich alkene HOMO reacts with a simple radical/nucleophilic, high energy SOMO  Electron rich radical, low energy SOMO reacts with a electron poor alkene LUMO  Looking at the diagram this visually makes sense as they are closer in energy and therefore have more favourable interactions. o Intramolecular radical addition: radical cyclisation  5-Exo-trig, syn, product favoured – even though it is primary to primary and exo is primary to secondary  Must consider the regioselectivity: cyclisation follows a chair-like TS  Optimum angle is 109 degrees  Radical attacks the LUMO pi star  With substituents, there is a shift to the endo 6mem product due to more congestion, meaning the radical cant move around as much  Stereochemistry – syn favoured o Radical rearrangement/translocation  6-exo, 7endo, reduction and translocation potential products  Chair like TS, puesdo eqt abstraction of H ---- close to the radical in proximity, favourable position  When high conc. of Bu3SnH used, radical will just react again with the H on SnBu3H and reaction stops there  no alkene rearraganement Carbenes and nitrenes as reactive intermediates     When can carbenes/nitrenes have the potential to be formed in situ and take part in reactions? Can you draw mechanisms for their formation? Can you identify and reproduce the possible structures of carbenes and nitrenes whilst understanding hybrdisation and electron configuration of available spin-states? Can you rationalise how neighbouring substituents and the method of formation dictate the structures adopted? Can you understand how the structure of carbenes and nitrenes can affect reactivity and stereochemistry in organic synthesis? Can you predict the outcome and draw mechanisms for the reaction of carbenes and nitrenes with alkenes and alkanes? Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 Carbene structure   SP2 singlet or SP2 triplet most favoured Triplet state is the ground state when R=H Carbene formation      Alpha elimination o Heterolysis of CX bond and X must be a good leaving group e.g. halide, phosphine, suplhide o CH bond breaks and group that leaves takes the electrons with it i.e. Br- or PPh3 From carbonyl compounds o Ketone forms an unstable, very reactive diazoalkanes using tosylhydrazones (TsNHNH 2 tosylhydrazine) – give off N2 as a LG o Ketones under light/thermal conditions give off CO as a LG Diazocarbonyls o More stable than diazoalkanes (stabilised by resonance into EWG) – very electrophilic o Decomposition via thermal/photolytic vibes + in the prescence of TM o Forms a carbenoid with Rh2(OAc)4, which reacts like a singlet carbene o Carbenes readily undergo cycloproponation. – using benzene o N2 to carbenoid – singlet carbene behaviour Halogen-metal exchange of gem-dihaloalkanes o Similar to alpha elimation however it is progressed with the zinc/copper mixture o Iodide can leave with a pair of electrons Reactivity of carbenes – cycloproponation o Forms a transition state that means everything occurs on the same face, and helped via the chelating zinc o 2 electrons come from the centre of the zinc carbenoid o Concerted, stereospecific, can be stereoselective, cheletropic Reactions of Carbenes Cycloproponation   Singlet: o Concerted and stereospecific. i.e. cis to syn and trans to anti o MO approach:  Symmetry dictates orientation of attack o 1,2-chelotropic reaction Triplet o Stepwise mechanism and not stereospecific – gives a mixture of diastereomers – krot and kflip consideration o Cis to syn or anti o Electrons unpaired and behave like radicals aka singularly o There is an eqm formed whereby the molecule can undergo bond rotation or flip o This eqm is formed by the rate constants krot and k flip o krot> kflip  forms anti product from a trans SM (not stereospecific) o kflip>krot  forms syn product from a trans SM (retention of stereochemistry) CH bond insertion  Rh(OAc)4 using a diazocarbonyl. Uses a singlet carbene like mechanism Nitrenes – carbenoid (acts like a carbene but isn’t a carbene) Structure Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384      1X normal LP 2x non bonding electrons Sp triplet and sp2 singlet Triplet stabilised by resonance Singlet stabilised by electron rich pi donors Formation   Extrusion of a thermodynamically stable molecule i.e. N2, CO, SO  similar to carbenes Alkyl/aryl azide, azidocarbonyl, isocyanate, sulfinyl amine Reaction of nitrenes    Cycloaddition CH insertion Both behave stereo specifically – hence is a singlet carbene mechanism vibe Lecture 8: Carbocation rearrangements     Predict the fate of a carbocation in the absence of inter/intramolecular nucleophiles i.e. Wagner-Meerwein shift (1,2-hydride/alkyl group migrations). Understand and provide mechanisms for the reaction of a 1,2-diol with acid i.e. Pinacol rearrangement. Understand the selectivity of the Pinacol rearrangement and how this can be manipulated i.e. semi-Pinacol rearrangement. Identify and provide mechanisms for where a rearrangement can result in ring expansion i.e. TiffeneauDemyanov reaction Carbocation reactions   These are all the relevant carbocation reactions. In the absence of these conditions, we can see carbocation rearrangements – an intramolecular type reaction This is what we will be covering next Carbocation rearrangements    1,2- hydride/alkyl shifts o Carbocations are electron deficient = electrophiles o Adjacent CH, CC sigma bonds can act as a source of electron density = nucleophiles o Formation of more stable carbocations provides the driving force o Final products depends on how the reaction is quenched o Note: o X must be a good LG o Migratory origin = where the migrating groups (R/H) comes from o Migratory terminus = where the migrating groups (H/R) ends up o Stepwise rearrangement occurs via a planar intermediate i.e.SN1 o Concerted rearrangement requires anti-periplanar alignment of LG and migrating group – resulting in an inversion of migratory terminus MO insight o So we can follow a reaction pathway, with reactants SbF 5, SO2ClF at -70 degrees Celsius, whereby we see a 2o  1o  3o. This is a thermodynamically controlled reaction, as although we see a primary carbocation formed, which is less stable than secondary that it started as, to form a tertiary carbocation. 1,2-alkyl shifts in terpenes (Wagner-Meerwein shifts): o Complex skeletal transformations from a single alkyl group migration. o Migrating group decided by:  Migratory aptitude (discussed further along)  Stereochemical requirement imposed by lack of rotation in multi (cyclic) systems Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384 o o Ring strains and degrading secondary/tertiary positions are very unfavourable and reactions will not occur Examples of unfavoure 1,2-alkyl shifts: Pinacol rearrangement (push and pull): 1,2 rearrangements often involving 1,2-diols – more electron rich will migrate Driving force is formation of C=O OH lone pair provides the ‘push’ Suitable LG provides the ‘pull’ – degree of electron deficiency – promotes migration Symmetrical diols: must consider the migratory aptitude for which group migrates. Most electron rich group will migrate. o Unsymmetrical diols: must proceed via the most stable carbocation intermediate, the migratory group still follows the same rules as in symmetrical diols aka the most electron rich will migrate. Semi-Pinacol rearrangements: TsCl, o Controlling regioselectivity via the LG i.e. OTs is a good LG o Tosylation occurs at least hindered OH with OTs giving the pull o OH provides the push, like in pinacol rearrangements, and catalysed via basic conditions. o Alternative LG includes the halides with Ag, N2, Cl, Br, I, Oms, OTf o Beta amino alcohol substrates readily convert into diazonium salts (N2 LG) – Tiffeneau Demyanov reaction o Commonly employed for ring expansion o o o o o  Carbanion Rearrangements      Recognise the potential for intramolecular carbanion rearrangement in the presence of a suitable leaving group. Provide, with details of regiochemistry, the mechanism of the Favorskii rearrangement of α-haloketones and α,α’-dihaloketones. Predict the products and draw the mechanism of the reaction of α-halosulfones with base (i.e. Ramberg Bäcklundn rearrangement) and comment on the stereochemistry observed. Appreciate the utility of carbanion rearrangements as a route to ring contraction. Favorskii rearrangement, 1-3 bond migration              Use NaOR as a reagent Substrates require acidic alpha protons and an alpha’ leaving group – must be good i.e. X=Cl,Br,I Migration via a reactive cyclopropenone intermediate Strain of cyclopropenone drives reaction (60 degrees, rather than 120 degrees typically seen in sp2) Planar, enolate forms Evidence o Can see the migration of a C14 Regiochemistry: 1) best LG drives regiochemistry 2) The reaction will follow the most stable carbanion intermediate, whereby the negative charge is stablised via resonance – driving force of the reaction Benzyl>Me>Et>iPr>tBu We want to move the negative charge away from carbon Stereochemistry o Planar enolate leads to loss of stereochemistry at origin, inversion seen at terminus o SN2 substitution results in inversion of the stereochemistry, and a backside attack Used for ring contraction. Break bond at least substituted carbon Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384   Alpha-alpha’ dihaloketones yield alpha,beta unsaturated products Rearrangement can occur in the absence of alpha-protons Ramberg-Backlund rearrangement              Alpha-halo-sulfone substrates Formation of thiirane/episulfone intermediates Nature of the LG determines the rate We need an acidic hydrogen kI>kBr>kCl Non-linear chelotropic extrusion – removal of SO 2 Stereochemisrty: With a stronger base+heat, a-halo-sulfone substrates will form the E constituent, rather than Z which occurs under weaker basic conditions If we can use a stabilising R group– i.e. Phenyl – then we can see an equibiliation occur and therefore the anti-cyclic molecule is formed, forming the E product. Note here that this is because the anti version is thermodynamically more stable than the syn, which Is obtained via kinetic pathway, and so this is favoured. Rearragement: Can be used for ring contraction like seen in previous questions H and X must be co-planar i.e. in the same plane – see notes for this as it is not necceasirly clear rn Questions Lecture 10: Rearrangements to electron deficient C,N,O termini L.O.     Recognise and draw mechanisms for the formation of carbenes, which can rearrange i.e. Wolff Rearrangement Distinguish between and provide mechanisms that take place to electron deficient nitrogen i.e. Curtius, Lossen, Schmidt, Hofmann, Beckmann rearrangements Mechanism for Baeyer-Villiger rearrangements + understand stereochemistry Usefulness of formation of ring contracted/expanded carbo and heterocycles (lactone/lactam) Wolf Rearrangement - Migration to electron deficient carbon     Diazocarbonyl substrates are thermally and photolytically unstable Akyl migration occurs from carbonyl to carbene carbon Stepwise and concerted mechanisms possible – under debate o Stepwise: Forms carbene intermediate and forms a ketene product o Concerted: Forms a ketene intermediate and forms a carboxylic acid product Mechanistic consideration: the C14 label can be on either the keto or alpha- c. This gives 50% product of each, suggesting 2 different mechanistic routes Ring contraction    Similar to Favorskii rearrangement Growth of carbon chain OH-R, acid, light Arndt-Eistert Homologation/chain extension   Concerted H2O, light, SOCl2, CH2-N2 Rearrangement to electron deficient Nitrogen Downloaded by Anushaya Jeyabalan ([email protected]) lOMoARcPSD|6077384         Concerted (unlike carbenes that have stepwise too) and reactions share a common intermediate that is an isocyanate Curtius rearrangement – nitrene analogue of Wolff Schmidt rearrangement We also can see alternative substrates (NH) undergo rearrangement: i.e. Lossen rearrangement X=CO2R o Good LG X concerted rearrangement occurs o General scheme: 1) deprotonation, 2) concerted migration 3) isocyanate quenched i.e. Hoffman rearrangement X=Br Isocyanate follows 3 reactions with hydrolysis, alcohol and amine reactants = how isocyanate is quenched Beckmann rearrangement o ketoxime substrates, ring expansion o Reactants: NH2OH and acid workup o Oxime formation (ketoxime) generate LG o Stereospecific – trans alkyl group migrates preferentially and under eqm condition electronic effects dictate movement Rearrangement to electron deficient oxygen Baeyer-villiger rearrangement       Ketone and peracid reagents Ester products i.e. oxidation Peroxy reagants contain nucleophilic group, weak O-O and good LG Mechanism – tetrahedral intermediate, concerted, stereochemistry retained Cycli ketones yield lactones via ring expansion Electron rich groups favour migration Downloaded by Anushaya Jeyabalan ([email protected])