LECTURE 4 Neighbouring Group Participation (NGP), Rearrangements & Fragmentations

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1 1 CEM50002: rbitals in rganic Chemistry - Stereoelectronics LECTURE 4 Neighbouring Group Participation (NGP), Rearrangements & Fragmentations Alan C. Spivey a.c.spivey@imperial.ac.uk Feb-Mar 2018

2 2 Format & scope of lecture 5 Neighbouring Group Participation (NGP) Non-classical carbocations Ionic 1,2-rearrangements, part 1 Wagner-erwein methyl and hydride shifts Ionic 1,2-rearrangements, part 2 Pinacol & semi-pinacol Baeyer-Villiger reaction Beckmann rearrangement Ionic fragmentations Grob Eschenmoser ring expansion Reflection on Importance of Reaction Stereoelectronics

3 Neighboring group participation (NGP) 3 Groups remote from a reaction centre can participate in substitution reactions Neighboring Group Participation (NGP) (or anchimeric assistance): lone pairs of electrons, typically on N,, S or al atoms interact with electron deficient/cationic centres NGP is characterised by: rate acceleration Cl 2 Ph S Cl 2 Ph S Cl Ph S RELATIVE RATE 1 : 600 retention of stereochemistry (via double inversion): Rearrangements occur when the participating group ends up bonded to a different atom...

4 NGP with rearrangement 4 Payne rearrangements: aza-payne rearrangements: Et 2 N Cl Na, 2 inversion Et 2 N NEt 2 Bromonium ion rearrangements:

5 5 NGP with rearrangement involvement of p & s bonds NGP by aryl groups (& alkenes) results in related rearrangements via phenonium/arenium ions: NGP by alkyl groups can also proceed via non-classical cations: Crystal structure of this carbocation finally obtained in 2013! See: Scholz Science, 2013, 341, 62 [DI] The rearranged products of the above NGP processes can also be regarded as having undergone [1,2]-sigmatropic rearrangements...

6 [1,2]-Sigmatropic rearrangements 6 [1,2]-Sigmatropic rearrangements take place when an electron deficient/cationic centre is formed adjacent to a group capable of migration using a lone or bonding pair of electrons Participation of bonding electrons of aryl, alkyl and hydride groups are of particular importance: 1,2-Aryl-, alkyl- & hydride shifts towards carbenium ions/electron deficient carbon: /R/Ar /R/Ar = /R/Ar /R/Ar + LG LG a range of mechanistic cases from true carbenium ion-mediated to fully concerted rearrangements 1,2-Aryl-, alkyl- & hydride shifts towards electron deficient oxygen: /R/Ar oxenium ion too high in energy to exist /R/Ar /R/Ar = LG group exhibiting oxenium ion character /R/Ar + LG 1,2-Aryl-, alkyl- & hydride shifts towards electron deficient nitrogen: /R/Ar N /R/Ar N /R/Ar = N LG /R/Ar N + LG nitrenium ion too high in energy to exist group exhibiting nitrenium ion character

7 chanistic variations The mechanism of 1,2-migrations vary from stepwise to concerted (cf. S N 1 S N 2): 7 The migrating centre however always retains* its configuration as it retains an octet of electrons: Consider the case of a 1,2-alkyl shift: s # s p vac transition state p vac *Inversion of configuration at the migrating centre is possible for 1,3 and higher sigmatropic rearrangements (see Pericyclic reactions lectures), but loss of stereochemical integrity at this centre is never observed

8 Migratory Aptitudes 8 The ease with which carbon-based groups migrate vary according to the particular reaction & the conditions owever, an approximate ranking is possible: Data has been accrued from relative rate data and from competition experiments on various rearrangements In general, the group best able to stabilise positive charge (in the transition state/intermediate) migrates: EDG EWG > R R R > > > R R > R > benzyl/allyl tert-alkyl electron rich aryl electron deficient aryl sec-alkyl primary alkyl methyl The position of YDRIDE in this series is highly unpredictable often migrates very readily! Care is required in interpreting results as other factors may dominate: e.g. a pinacol rearrangement where cation stability is the determining factor: owever, CRRECT RBITAL VERLAP IS CRUCIAL in the transition state and so (by ammond s postulate) the orbital alignment in the substrate must be appropriate for migration...

9 9 1,2-Shifts to C + - Wagner-erwein rearrangements [1,2]-Sigmatropic shifts of hydride & alkyl groups towards carbenium ions are referred to as Wagner-erwein shifts (a group 1,2-shift is specifically known as a Nametkin rearrangement) e.g. rearrangement during substitution at a neopentyl centre: e.g. rearrangement during Friedel-Crafts alkylation: Cl AlCl 3 cat. = # + s C- -> p vac (pp) 1,2-hydride shift ~1:1 mix as both cations precursors are secondary

10 Wagner-erwein rearrangements - isomerisations 10 Synthetically useful Wagner-erwein rearrangements e.g. isomerisation of alkyl halides: A remarkable synthesis of adamantane (C ): Schleyer J. Am. Chem. Soc. 1960, 82, 4645 [DI] Whitlock J. Am. Chem. Soc. 1968, 90, 4929 (2897 possible pathways!) [DI]

11 Wagner-erwein rearrangements - biosynthesis Wagner-erwein rearrangements are prevalent in the biosyntheis of terpenoids such as lanosterol (precursor to cholesterol & the human sex hormones) lanosterol is formed by the polycyclisation of 2,3-oxidosqualene by the enzyme xidosqualene Cyclase (SC) the conformation enforced by the enzyme is ~ chair-boat-chair, the process is NT concerted, discrete cationic intermediates are involved & stereoelectronics dictate the regio- & stereoselectivity 11 EnzB- 2,3-oxidosqualene 1) epoxide opening 2) 2x Markovnikov ring-closures (6-memb rings) Markovnikov ring-closure (5-memb ring) s C-C -> p vac (pp) suprafacial ring expansion (5 -> 6) 1,2-alkyl shift 1) 1,2- shift 2) 1,2- shift E 1 elimination = 3) 1,2-hydride shift 4) 1,2-hydride shift :BEnz all s C-/C -> p vac (pp) lanosterol protosterol cation all suprafacial The enzyme s role is most likely to shield intermediate carbocations thereby allowing the hydride and methyl group migrations to proceed down a thermodynamically favorable and kinetically facile cascade Wendt Angew. Chem. Int. Ed. 2000, 39, 2812 [DI]

12 Wagner-erwein rearrangements - monoterpenes Wagner-erwein rearrangements occur widely during the biosynthesis of terpenes (isoprenoids) and are also synthetically useful for the functionalisation of these metabolites: e.g. synthesis of camphor sulfonic acid from camphor: 12 NB. 2 S 4 /Ac 2 is a weak sulfonylating mixture (cf. oleum) for S E Ar:

13 [1,2]-Sigmatropic rearrangements 13 [1,2]-Sigmatropic rearrangements take place when an electron deficient/cationic centre is formed adjacent to a group capable of migration using a lone or bonding pair of electrons Participation of bonding electrons of aryl, alkyl and hydride groups are of particular importance: 1,2-Aryl-, alkyl- & hydride shifts towards carbenium ions/electron deficient carbon: /R/Ar /R/Ar = /R/Ar /R/Ar + LG LG a range of mechanistic cases from true carbenium ion-mediated to fully concerted rearrangements 1,2-Aryl-, alkyl- & hydride shifts towards electron deficient oxygen: /R/Ar oxenium ion too high in energy to exist /R/Ar /R/Ar = LG group exhibiting oxenium ion character /R/Ar + LG 1,2-Aryl-, alkyl- & hydride shifts towards electron deficient nitrogen: /R/Ar N /R/Ar N /R/Ar = N LG /R/Ar N + LG nitrenium ion too high in energy to exist group exhibiting nitrenium ion character

14 1,2-Shifts to C + pinacol rearrangements 14 Treatment of the 1,2-diol pinacol with acid results in a 1,2-rearrangement to give a ketone pinacolone : Review: Song et al. Chem. Rev. 2011, 111, 7523 [DI] pinacol protonation 'push' 'pull' the push of the lone pair and the pull of the carbenium ion provide a low energy kinetic pathway the exothermicity of C= bond formation provides a thermodynamic driving force The reaction is a useful method of preparing spirocyclic compounds: 1,2- shift 1) n -> s* C-C (app) 2) s C-C -> p vac (pp) deprotonation pinacolone More generally, any functionality giving rise to a carbenium ion adjacent to an oxygenated carbon can undergo a semi-pinacol rearrangement...

15 1,2-Shifts to C + semi-pinacol rearrangements 15 Treatment of epoxides with Lewis acids results in semi-pinacol rearrangements: Diazotisation of b-amino alcohols results in semi-pinacol rearrangements (Tiffaneau-Demyanov): 1) N 2 /NaEt 2) 2 /Raney-Ni N 2 NaN 2, Cl (= N 2 ) N N N 2 diazotisation 1,2-alkyl shift deprotonation cyclohexanone 1) n -> s* C-C (app) 2) s C-C -> p vac (pp) cycloheptanone 1) C 2 N 2 ; 2) Et/ 2

16 Semi-pinacol rearrangement - stereochemistry 16 The importance of correct orbital alignment for 1,2-shifts is illustrated by subjecting all four isomers of the following bromohydrin to identical conditions:

17 1,2-Shifts to + Baeyer-Villiger reaction 17 Treatment of ketones & aldehydes with peracids induces a Baeyer-Villiger reaction: use of basic hydrogen peroxide on an electron rich aryl ketone/aldehyde is called the Dakin reaction the driving force is the exothermicity of cleavage of a weak - bond and formation of a C= bond order of migration generally follows migratory aptitude series presented earlier: n Bu n ex oxidation occurs at indicated position i.e. blue group migrates

18 1,2-Shifts to N + Beckmann rearrangement ydride, alkyl & aryl groups also migrate towards electron deficient nitrogen centres NB. nitrenium ions themselves are too high in energy to exist (cf. carbenium ions) 18 ximes undergo useful 1,2-rearrangements in acidic media the Beckmann rearrangement: the group app to the N- bond migrates irrespective of migratory aptitude BUT beware oxime E/Z isomerisation

19 Ionic fragmentations characteristics Ionic fragmentation reactions are reactions in which C-C bonds are broken in a heterolytic fashion They are relatively rare NT because C-C bonds are particularly strong: cf. Bond Dissociation Energies: C-C 339kJmol -1 C- 351 kjmol -1 C- 418 kjmol -1 weakest kjmol -1 strongest 19 BUT because C-C bonds are not generally highly polarised/polarisable It follows that fragmentations occur for polarised/polarisable C-C bonds the most common scenario involves an electron source at one end and an electron sink at the other: X electron source 4 Y electron sink Grob fragmentation 1 1 C-C bond fission X C-C bond broken Y cf. X R 3 Y semi-pinacol rearrangement R migrates X R Y 1) n X -> s* C-C (app) 2) s C-C -> s* C-Y (app) NB. the molecule breaks into three fragmments 1) n X -> s* C-C (app) 2) s C-C -> s* C-Y (app) This type of fragmentation is sometimes referred to as a Grob fragmentation (=homologous pinacol) As with 1,2-rearrangements CRRECT RBITAL VERLAP IS CRUCIAL...

20 Grob-type fragmentations There are numerous variants of the Grob fragmentation in all cases correct conformation & stereoelectronics are crucial for success Contrast the behaviour of two isomeric tosylates: 20 2 N cis-isomer Ts = N Ts both groups eqatorial Ts Et 3 N Et, 2 fragmentation 2 N 2 N 2 alkenyl aldehyde [64%, exclusive prod] 1) n N -> s* C-C (app) 2) s C-C -> s* C- (app) 2 N 2x severe 1,3-diaxial interactions Ts = 2 N MINR Ts Ts fragmentation (MINR path) Et 3 N Et, 2 2 N 2 N 2 alkenyl aldehyde [11%, minor prod] trans-isomer 2x less severe 1,3-diaxial interactions MAJR 2 N Ts Ts E 2 elimination (MAJR path) 2 N 2 N + = 2 N cyclohexenes [49%, mix of regioisomers] s C- -> s* C- (app)

21 The Eschenmoser fragmentation A particularly spectacular type of fragmentation for ring-expansion was developed in the late 1960s by the Swiss chemist Albert Eschenmoser the Eschenmoser fragmantation 21 the driving force for the fragmentation is enthalpic (formation of toluene sulfinate) & entropic [formation of N 2 (g)] Na 2 2 TsNN 2 Ts N N N 2 + Ts 2 /Pd-C 12,5-fused bicycle epoxidation hydrazination NaC 3 Eschenmoser fragmentation hydrogenation muscone 15-membered ring fragrance ketone

22 Stereoelectronics - A panacea for rationalisation of conformation & reactivity? 22 N! stereoelectronic analysis is constrained by the limitations of: APPRXIMATINS INVLVED IN CNSIDERING NLY LCALISED MLECULAR RBITALS (e.g. NBs) PERTURBATIN TERY (i.e. the Klopman-Salem expression) FRNTIER RBITAL TERY Moreover, stereoelectronic analysis must, as we have seen, be augmented by consideration of many additional factors which influence chemical reactivity: STRAIN: Compressive/tensile: Bayer (=angle)/pitzer (=torsional)/prelog (=transannular). All van der Waals in origin STERIC EFFECTS: van der Waals in origin (e.g. hydrocarbon conformations; Lennard-Jones potential) ENTRPY EFFECTS: Statistics! [e.g. possibly of significance in the Thorpe-Ingold effect ] SLVENT EFFECTS: electrostatic and dipole interactions with the reaction medium ELECTRSTATIC/DIPLE EFFECTS: [e.g. a factor in the anomeric effect, significant factor in carbonyl addition reactions cf. Felkin-Anh]