Rearrangements and Reactive Intermediates Hilary Term 2018

Transcription

1 earrangements and eactive Intermediates earrangements and eactive Intermediates ilary Term 0 A rganic Chemistry andout isoborneol camphene Polar earrangements, xford Chemistry Primer no. 5; L. M. arwood rganic Chemistry J. Clayden, N. Greeves, S. Warren Chapters 6-4 eactive Intermediates, xford Chemistry Primer no. ; C. J. Moody, G.. Whitham chanism and Theory in rganic Chemistry, T.. Lowry, K. S. ichardson Advanced rganic Chemistry, F. A. Carey,. A. Sundberg Modern ysical rganic Chemistry; E. Anslyn, D. Docherty

2 earrangements and eactive Intermediates Synopsis Carbocations and carbanions NM spectroscopy and X-ray structures of carbocations; aggregation and pyramidal inversion of carbanions. eactivity, including S E, redox, hydride elimination and rearrangements: Wagner erwein, pinacol, semi-pinacol. earrangement of anions and carbocations rbital theory; Is c-e structure TS or EI? Stepwise versus concerted rearrangements; non-classical carbocations (carbonium ions), transannular hydride shifts. Carbanions: Favorskii, amberg-bäcklund, Stevens and Wittig rearrangements. Carbenes Structural features that influence stability. thods of making them; carbenes versus carbenoids. General classification of the types of reaction that these species undergo. earrangements: Wolff, cyclopropanation, C- insertion. earrangements to electron-deficient nitrogen and oxygen Structure of nitrenes; structural features that influence stability. thods of making them. Types of reaction: aziridination, C insertion. Nitrene versus non-nitrene mechanisms. earrangements to electron-deficient nitrogen (Beckmann, Neber, offmann, Curtius, Schmidt, Lossen). Baeyer Villiger rearrangement. Introduction to radicals Structure; stability. General types of reaction involving radicals: homolysis, recombination, redox, addition, β-scission, substitution, disproportionation. Problem class relating to lectures 4. Case studies Elucidating mechanisms of rearrangements. Evidence for currently accepted mechanisms for the Baeyer Villiger, Beckmann and Favorskii rearrangements. Problem class relating to lectures 5 and.

3 earrangements and eactive Intermediates Types of igh Energy Intermediates Electron Deficient Cations Two classes of carbocations Carbenium ion (6 electrons) Carbonium ion ( electrons) adical cation + e.g. C 5 Neutral species Carbenes (6 electrons) reactive towards a) nucleophiles b) bases c) reducing agents Electron ich Anions Carbanion ( electrons) Neutral species adical ( electrons) Electron ich Anions adical Anion reactive towards a) electrophiles b) acids c) oxidising agents reactive towards a) electrophiles or nucleophiles b) other high energy agents c) oxidising or reducing agents singlet triplet Neutral species ketenes Neutral species arynes

4 earrangements and eactive Intermediates 4 Stuctures of Carbocations Crystal structure of an adamantyl carbocation.44 Å 99.5 Å 0.6 Å δ C ppm δ C 9 ppm.5 Å F 5 SbFSbF 5 adamantane C-C σ to empty p C-C sp -sp.54 Å C-C sp -sp.50 Å C-C sp -sp.46 Å C=C.4 Å F SbF 5 S δ C 94 ppm Bond lengths and bond angles provide evidence of hyperconjugation (T. Laube, Angew. Chem. Int. Ed. 96, 5, 49). δ C ppm δ C 90 ppm δ C 0 ppm δ C 49 ppm

5 earrangements and eactive Intermediates 5 Crystal structure of a t-butyl carbocation C-C sp -sp.54 Å.44 Å C-C sp -sp.50 Å C-C sp -sp.46 Å C=C.4 Å δ C = 94 ppm δ C = ppm F C C C SbF 5 C S C C δ C = 4 ppm δ C = 5 ppm 0 SbF 5 C S C δ = 4.5 ppm C F F 5 SbFSbF 5 δ C = ppm (adamantyl acid fluoride) δ C = 0 ppm F SbF 5 δ =.5 ppm C C S C C δ = 5 ppm δ C = 5.5 ppm Bond lengths provide evidence of hyperconjugation (T. Laube, J. Am. Chem. Soc. 99, 5, 40).

6 earrangements and eactive Intermediates 6 yperconjugation donation of C- σ-bond (or C-C σ- bond) electrons into empty p orbital empty p-orbital C C filled σ C- orbital energy of the bonding electrons reduced system stabilised greater number of C- (or C-C) σ-bonds the greater the extent of hyperconjugation and the greater stabilisation carbenium ion stability therefore goes in the order: tertiary secondary primary > > conjugation with alkenes, arenes and lone pairs, also stabilises carbenium ions most carbocations are fleeting reaction intermediates the triphenylmethyl (trityl) cation persists - crystal structure of trityl cation demonstrates all the phenyl groups are twisted out of plane C BF 4 is a commercially available crystalline solid S 4 C Cl S 4 δ C = ppm B(CN) 4

7 earrangements and eactive Intermediates Structures of Carbanions generally aggregated in the solid state and in solution methyllithium is a tetramer (Li) 4 with C groups sitting above each face of a Li 4 tetrahedron overall a distorted cube tert-butyllitium is also tetrameric in the solid state (X-ray crystal structures below) Li C Li Li C C C Li t-butyllithium (t-buli) 4 methyllithium (Li) 4 (-atoms removed for clarity) idealised arrangement of lithium and carbon atoms in coordinating solvents e.g. TF, Et most organolithiums become less aggregated and hence more reactive

8 earrangements and eactive Intermediates stability of carbanions is related to the pka of their conjugate acids increasing pk a of conjugate acid, increasing reactivity, decreasing stability aromatic sp-hybridised conjugated sp -hybridised sp -hybridised increasing pk a of conjugate acid, increasing reactivity, decreasing stability C C C (C ) C (C ) C sp -hybridised sp -hybridised sp -hybridised electron donating alkyl group sp -hybridised electron donating alkyl groups sp -hybridised electron donating alkyl groups

9 earrangements and eactive Intermediates 9 pyramidal inversion is generally fast for sp hybridised carbanions (they are isoelectronic with N ) and hence chiral carbanions generally undergo rapid racemisation. '' ' fast '' ' '' ' vinyl anions and cyclopropyl anions are the exceptions and are generally considered configurationally stable lithium halogen exchange with alkenyl iodides and bromides is a stereospecific process tbu Li Li tbuli Li (S) BuLi Li C C retention sp hybridisation at transition state for pyramidal inversion ideal 0 angles only ca. 60 for cyclopropane transition state highly strained therefore slow rate of inversion

10 earrangements and eactive Intermediates 0 eactions of Carbocations and Carbanions Generic reaction map of carbocations and carbanions hydride loss E reaction with nucleophile Nu carbocation rearrangement reduction X deprotonation ionisation - Nu SET + e - electrophilic substitution X electrophile reaction - X S N or E - deprotonation + e - e single electron transfer (SET) reaction with electrophile + e - e E E - hydride loss - X S E carbanion addition X

11 earrangements and eactive Intermediates most common reaction of carbanions is reaction with electrophiles (e.g. Li or Mg plus E ) which is amply covered elsewhere some other reactions are shown below S E Subsitution Electrophilic Unimolecular - formally related to a carbanion as S N is to a carbocation generic mechanism X - X S E E E examples N N - N P, heat P P + P +

12 earrangements and eactive Intermediates β-hydride elimination from carbanions common for transition metals reverse reaction is hydrometallation well known from hydroboration chemistry PdX + PdX B B not a common reaction for Grignard reagents or organolithiums; however, β-hydride elimination is a decomposition pathway for organolithiums and tert-butyllithium can act as a source of hydride Li redox reactions Single Electron Transfer - SET + Li Mg + Cl Cl + SET dimerisation of Cl + Cl Cl SET Cl

13 earrangements and eactive Intermediates rearrangement of carbocations the neopentyl system I AgN, water + not Ag then - -,- shift the, shift is a Wagner- erwein rearrangement as an aside, remember that neopentyl systems, although primary, are unreactive under S N conditions as the nucleophile is severely hindered from attacking the necessary carbon atom Nu LG (-) (-) Nu LG Nu ' '' LG staggered conformation requires nucleophile to approach passed one of the methyl groups

14 earrangements and eactive Intermediates 4 Wagner-erwein rearrangements exemplified isoborneol camphene rotate overall red bond is broken and blue bond is formed in general alkyl shifts occur to yield a more stable carbocation secondary carbocation tertiary carbocation rotate best orbital overlap is also important in determining which group migrates orbital overlap σ C-C into empty p-orbital 4 migration would lead to 4-membered ring poor orbital overlap for migration best orbital overlap for migration (ca. co-planar)

15 earrangements and eactive Intermediates 5 Wagner-erwein rearrangements exemplified Nature was here before us biosynthesis of camphene linalyl pyrophosphate P P pyrophosphate, or diphosphate PP. PP is a good leaving group c.f. Ts - PP form cation form cation Wagner-erwein rearrangements exemplified Nature was here before us biosynthesis of lanosterol (precursor of cholesterol) chair boat chair conformation camphene form cation relief of ring strain squalene oxide two,-hydride shifts lanosterol two,-methyl shifts conformation of squalene oxide controlled by enzyme (lanosterol synthase) reaction occurs via discrete carbocation intermediates and is not concerted 4 4

16 earrangements and eactive Intermediates 6 Pinacol and semi-pinacol rearrangements pinacol pinacolone - mechanism in more detail correct orbital overlap required for migration C C σ C-C to empty p C C n to σ* C-C useful method for the preparation of spirocyclic ketones. - the starting diols can be readily prepared by the pinacol reaction Mg SET Mg Mg Mg epoxides and halohydrins can be substrates for the pinacol rearrangement

17 earrangements and eactive Intermediates semi-pinacol rearrangements the Tiffeneau-Demayanov reaction i) CN ii) LiAl 4 or N N N - i) C N. Et ii) LiAl 4 semi-pinacol rearrangements - stereochemistry N n to σ* C-C tbu N C-C migration tbu tbu tbu N N tbu n to σ* C-C N σ C-C to σ* C-N C-C migration tbu tbu tbu N σ C-C to σ* C-N tbu N tbu N N N n to σ* C- tbu tbu N N C,-hydride shift σ C- to σ* C-N epoxide formation n to σ* C-N tbu tbu tbu tbu anti-periplanar bonds means best overlap of σ and σ* orbitals

18 earrangements and eactive Intermediates the dienone-phenol rearrangement formally the reverse of the pinacol rearrangement the dienone-phenol rearrangement can be mechanistically complex but can also just involve a simple,-shift of an alkyl group the pinacol rearrangement is driven by formation of a strong C= bond the dienone-phenol rearrangement involves loss of a C= bond and gain of an aromatic ring the dienone-phenol rearrangement provides a method for ring annulation tbu Cl Cl

19 earrangements and eactive Intermediates 9 Theory of,-shifts curly arrow mechanism orbital description ''' ' '' retention ''' ' '' retention ''' ' '' C C C -centre--electron system at the transition state in the transition state we have three orbitals and two electrons to distribute c.f. the allyl cation ψ ψ ψ ψ ψ ψ allyl cation ψ ψ,-shift transition state (carbocation) ψ,-shift transition state (carbanion)

20 earrangements and eactive Intermediates 0,-cation and,-anion shifts overall for carbocation,-shift, transition state has net bonding ψ ψ ψ,-shift transition state carbocation the transition state has electrons cyclically conjugated in a ring and is therefore aromatic more of this next year,-shifts occur with retention of configuration in the migrating group the -centre--electron structure may be a transition state or a high energy intermediate as we have seen, concerted migration with loss of the leaving group is another mechanistic possibility take home message,-shifts easy for carbocations, difficult for carbanions and radicals ψ ψ ψ,-shift transition state carbanion both y and y are antibonding therefore,-shifts of carbanions and radicals would be expected to be far less favourable (y is occupied) transition state for,-shift of carbanions has 4 electrons cyclically conjugated (y y ) in a ring and is anti-aromatic one can also view the difficulty of,-carbanion shifts arising from the geometrical impossibility of the carbanion performing an intramolecular S N reaction with inversion of configuration ''' ' X ''

21 earrangements and eactive Intermediates as we have seen, for efficient rearrangement orbital alignment is critical all three indicated hydrogen atoms are in the same plane - rearrangement to the more stable carbocation does not occur retention of configuration at the migrating centre is observed N N N migration with 9% retention of configuration at the migrating terminus inversion or racemisation can occur racemisation will occur if the mechanism is S N -like i.e. via a full carbocation Et enantiopure Et Et Et racemic inversion at the migrating terminus will occur if the mechanism is concerted

22 earrangements and eactive Intermediates Concerted earrangements Neighbouring group participation (NGP) Definition (IUPAC): the direct interaction of the reaction centre (usually, but not necessarily, an incipient carbenium centre) with electrons contained within the parent molecule but not conjugated with the reaction centre could be lone pair, π-bond, or σ-bond A rate increase due to neighbouring group participation is known as 'anchimeric assistance neighbouring group participation and anchimeric assistance are often used interchangeably diastereomeric single enantiomer bromohydrins inversion meso C symmetric inversion enantiomers same relative configuration as starting material racemic product inversion inversion same structure meso - achiral outcome of above reactions is excellent evidence for symmetrical intermediates and hence neighbouring group participation

23 earrangements and eactive Intermediates why do these single enantiomer tosylates undergo solvolysis at significantly different rates to give the same racemic product? non-classical carbocations, A.K.A. carbonium ions endo-ts Ts rds no NGP Ac k rel = Ac Ac + Ac Ts racemic Ac k rel = 50 Ac exo-ts Ac Ac rds NGP rotate 6 5 non-classical carbocation - carbonium ion 4 alternative perspective of NGP. Å Ts -centre--electron bond exo-ts reacts faster due to NGP of antiperiplanar C-C sigma bond endo-ts ionises slower to give classical carbocation followed by non-classical carbocation formation non-classical cation has plane of symmetry leading to racemic products

24 earrangements and eactive Intermediates 4 evidence for non-classical carbocation (carbonium ion) over equilibrating carbenium ions for the -norbornyl cation i.e. is the non-classical cation an intermediate or TS? low temperature C NM (5 K) shows a symmetrical ion X-ray crystal structure (Science, 0, 4, 6) provided definitive evidence of bridged structure. Å δ C 5 ppm AlAl Note: non-classical carbocations are only formed if they are more stable than their classical counterparts The,-dimethylnorbornyl cation is a rapidly equilibrating species with partial σ-delocalisation. X-ray structure of the analogous tetramethylnorbornyl cation also demonstrates partial σ-delocalisation.. Å. Å F 5 SbFSbF 5

25 earrangements and eactive Intermediates 5 π-bonds are better donors than σ-bonds J Ts Ac k rel = 0 Ts Ts Ac k rel = Ac classical carbocation (carbenium ion) Ac same structure Ac SbF 6 SbF 6 J. Am. Chem. Soc., 99,, 94 Ac k rel = 0 non-classical carbocation (carbonium ion) complete retention of configuration (double inversion) Ts Ac Ac k rel = 0 4 allyl cation Ac

26 earrangements and eactive Intermediates 6 More neighbouring group participation with π-bonds phenonium ions meso phenonium ion (σ-plane) Ts diastereomeric single enantiomer substrates Ac inversion C -symmetric phenonium ion inversion Ac Ac enantiomers racemic product δ C = 60 ppm ppm 55 ppm ppm 69 ppm Ts Ac inversion inversion Ac same single enantiomer product Ac

27 earrangements and eactive Intermediates multiple,-shifts - - formation of adamantane Diels-Alder, Pd Al heat all C 0 6 hydrocarbons rearrange to adamantane on treatment with Lewis acid C 0 6 adamantane C 0 6 adamantane is the thermodynamically most stable C 0 6 isomer it possess repeating units of the diamond lattice

28 earrangements and eactive Intermediates transannularhydride shifts D - - D D δ cyclodecyl cation -centre--electron bond c.f. diborane = +4.0 ppm SbF 5, FS F -40 C δ = -.9 ppm δ C = 4 ppm B B δ = -0.5 ppm δ = -6.5 ppm 6 5 Cl δ C = 5 ppm or or SbF 5, FS F -40 C δ = +6.0 ppm,6-cation slightly higher in energy than,5-cation

29 earrangements and eactive Intermediates 9 Carbanion rearrangements carbanions are much less prone to rearrangement than carbocations,-aryl shifts Cl Li, -60 C -LiCl Li C C 0 C C C delocalised therefore more stable carbanion X-ray structure evidence for spirocyclic intermediate C Li, -5 C then C Cl Cs-K-Na alloy -5 C C C carbanion delocalised, dearomatised carbanion more stable than carbanion

30 earrangements and eactive Intermediates 0 Favorskii rearrangement Cl Na S E overall in the Favorskii rearrangement an alkyl group () moves from one side of the carbonyl group to the other Na Cl -electron electrocyclic ring closure - more of this next year X ' '' '' ' oxyallyl cation symmetrical intermediate established by Loftfield with doubly labelled substrate = 4 C label Cl Na : mixture

31 earrangements and eactive Intermediates quasi-favorskii rearrangement Favorskii rearrangement on substrates with no enolisable hydrogen atoms N Cl N Cl N the mechanism is a base catalysed semi-pinacol rearrangement and is closely related to the mechanism of the benzilbenzillic acid rearrangement amberg-bäcklund reaction S S Cl Na S Cl S cheletropic extrusion of S more next year concerted,-shifts of carbanions are geometrically impossible - as the carbanion cannot reach to perform an intramolecular S N reaction with inversion of configuration ''' ' ''

32 earrangements and eactive Intermediates Concerted,-shifts of carbanions are geometrically impossible - as the carbanion cannot reach to perform an intramolecular S N reaction with inversion of configuration ''' 'X '',-Shifts of carbanions occur by a radical mechanism,-wittig,,-stevens and related rearrangements,-wittig rearrangement BuLi solvent cage Stevens rearrangement N N N N N solvent cage

33 earrangements and eactive Intermediates the,-wittig rearrangement occurs predominantly with retention of configuration in the migrating group BuLi solvent cage * * predominant retention of configuration at the migrating centre *