Rearrangements and Reactive Intermediates [email protected] 1 Rearrangements and Reactive Intermediates Hilary Term 2018

1A Organic Chemistry

Handout 1

Me Me 1 7 2 7 2 3 H 3 1 Me HO 6 5 4 Me 4 6 5 Me 8 8 isoborneol camphene http://burton.chem.ox.ac.uk/teaching.html ◼ Polar Rearrangements, Oxford Chemistry Primer no. 5; L. M. Harwood ◼ Organic Chemistry J. Clayden, N. Greeves, S. Warren – Chapters 36-41 ◼ Reactive Intermediates, Oxford Chemistry Primer no. 8; C. J. Moody, G. H. Whitham

◼ Mechanism and Theory in Organic Chemistry, T. H. Lowry, K. S. Richardson ◼ Advanced Organic Chemistry, F. A. Carey, R. A. Sundberg ◼ Modern Physical Organic Chemistry; E. Anslyn, D. Docherty Rearrangements and Reactive Intermediates 2

Synopsis ◼ and NMR spectroscopy and X-ray structures of carbocations; aggregation and pyramidal inversion of carbanions. Reactivity, including SE1, redox, hydride elimination and rearrangements: Wagner–Meerwein, pinacol, semi-pinacol.

◼ Rearrangement of anions and carbocations Orbital theory; Is 3c-2e structure TS or HEI? Stepwise versus concerted rearrangements; non-classical carbocations (carbonium ), transannular hydride shifts. Carbanions: Favorskii, Ramberg-Bäcklund, Stevens and Wittig rearrangements.

◼ Structural features that influence stability. Methods of making them; carbenes versus . General classification of the types of reaction that these species undergo. Rearrangements: Wolff, cyclopropanation, C-H insertion.

◼ Rearrangements to electron-deficient nitrogen and oxygen Structure of nitrenes; structural features that influence stability. Methods of making them. Types of reaction: aziridination, C–H insertion. Nitrene versus non-nitrene mechanisms. Rearrangements to electron-deficient nitrogen (Beckmann, Neber, Hoffmann, 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 1–4.

◼ 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 7. Rearrangements and Reactive Intermediates 3

Types of High Energy Intermediates ◼ Electron Rich Anions reactive towards (8 electrons) a) ◼ Electron Deficient Cations reactive towards b) acids Two classes of carbocations a) nucleophiles c) oxidising agents b) bases R R • Carbenium (6 electrons) c) reducing agents R R • R R R R R R R R ◼ Electron Rich Anions Radical Anion (8 electrons) H H H H H H e.g. CH5 •

Radical cation H H H H H H H H H H H H • ◼ Neutral species • + Radical (7 electrons) H H H H reactive towards H H R a) electrophiles or nucleophiles • b) other high energy agents ◼ Neutral species R R c) oxidising or reducing agents Carbenes (6 electrons)

R • R ◼ Neutral species ◼ Neutral species R R • R • • ketenes arynes R R R R R R singlet triplet • O R Rearrangements and Reactive Intermediates 4

Stuctures of Carbocations ◼ Crystal structure of an adamantyl 110° 1.44 Å 118° 99° 1.53 Å

° δC 38 ppm 1.62 Å 111 δ 29 ppm Me Me C

1.52 Å F5SbFSbF5 adamantane Me ◼ C-C σ to empty p

Me Me Me Me Me Me

Me Me Me δ 294 ppm F C C-C sp3-sp3 1.54 Å δC 71 ppm

3 2 C-C sp -sp 1.50 Å 2SbF5 δC 90 ppm

2 2 C-C sp -sp 1.46 Å Me Me SO2 Me Me δC 30 ppm C=C 1.34 Å Me Me δC 49 ppm ◼ Bond lengths and bond angles provide evidence of (T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349). Rearrangements and Reactive Intermediates 5

◼ Crystal structure of a t-butyl carbocation H H H C-C sp3-sp3 1.54 Å 1.44 Å C-C sp3-sp2 1.50 Å H H C-C sp2-sp2 1.46 Å C=C 1.34 Å H H H H

120° F5SbFSbF5

δC = 335 ppm O F CH3 2SbF5 2SbF5 δC = 94 ppm H3C F H C CH3 3 SO2 H3C CH3 SO2 H3C CH3 δ = 28 ppm CH3 δC = 171 ppm C δ = 47 ppm C δH = 4.35 ppm (adamantyl acid fluoride)

δC = 320 ppm F H δ = 13.5 ppm SbF5 H

H3C CH3 SO2 H3C CH3

δH = 5 ppm δC = 51.5 ppm ◼ Bond lengths provide evidence of hyperconjugation (T. Laube, J. Am. Chem. Soc. 1993, 115, 7240). Rearrangements and Reactive Intermediates 6

◼ Hyperconjugation donation of C-H σ-bond (or C-C σ- bond) electrons into empty p orbital empty p-orbital

H filled σ C-H orbital CH3 H CH H 3 energy of the bonding electrons reduced system stabilised ◼ greater number of C-H (or C-C) σ-bonds the greater the extent of hyperconjugation and the greater stabilisation tertiary secondary primary ◼ carbenium ion stability therefore goes in the order: R R R R R > > R ◼ conjugation with , 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

◼ Ph3C BF4 is a commercially available crystalline solid

HSO4 Ph H2SO4 Ph OH

Ph CH2Cl2

δC = 212 ppm B(CN)4 Rearrangements and Reactive Intermediates 7

Structures of Carbanions

◼ generally aggregated in the solid state and in solution

◼ methyllithium is a tetramer (MeLi)4 with CH3 groups sitting above each face of a Li4 tetrahedron — overall a distorted cube

◼ tert-butyllitium is also tetrameric in the solid state (X-ray crystal structures below)

Li C C Li C Li Li C

t-butyllithium methyllithium idealised arrangement of

(t-BuLi)4 (MeLi)4 lithium and carbon (H-atoms removed for clarity)

◼ in coordinating solvents e.g. THF, Et2O most organolithiums become less aggregated and hence more reactive Rearrangements and Reactive Intermediates 8

◼ stability of carbanions is related to the pKa of their conjugate acids

H H H H H H

increasing pKa of conjugate acid, 16 24 41 43 44 increasing reactivity, decreasing stability H H H H H H

aromatic sp-hybridised conjugated sp2-hybridised sp2-hybridised

CH3 CH3CH2 (CH3)2CH (CH3)3C H increasing pKa of conjugate acid, 46 48 50 51 53 increasing reactivity, decreasing stability

H H H H Me H Me Me H H Me Me Me sp3-hybridised sp3-hybridised sp3-hybridised sp2-hybridised sp3-hybridised electron donating electron donating electron donating group alkyl groups alkyl groups Rearrangements and Reactive Intermediates 9

3 ◼ pyramidal inversion is generally fast for sp hybridised carbanions (they are isoelectronic with NH3) and hence chiral carbanions generally undergo rapid racemisation.

‡ fast R'' R'' R R R'' R R' R' R'

◼ 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 Br Ph Ph R Br Li Ph R

Br tBuLi R Br Li R Ph Ph Ph

2 Br Li CO2H ◼ sp hybridisation at transition state for Me BuLi Me CO2 Me pyramidal inversion ◼ ideal 120 ° angles only ca. 60° for Ph Ph Ph Ph Ph Ph ◼ transition state highly strained (S) ‡ retention therefore slow rate of inversion R Rearrangements and Reactive Intermediates 10

Reactions of Carbocations and Carbanions

◼ Generic reaction map of carbocations and carbanions

hydride loss reaction with nucleophile reduction E carbocation deprotonation Nu rearrangement X R R H H R R R + 2e - H Nu - H electrophilic ionisation SET substitution + e X - X + e - X X R R R R R • SN1 or E1 - e - e SE1 single electron - H transfer (SET) E - H R E R R R reaction with R electrophile carbanion deprotonation hydride loss reaction addition Rearrangements and Reactive Intermediates 11

⊕ ◼ most common reaction of carbanions is reaction with electrophiles (e.g. RLi or RMgBr plus E ) which is amply covered elsewhere

◼ some other reactions are shown below

SE1 – Subsitution Electrophilic Unimolecular - formally related to a carbanion as SN1 is to a carbocation

◼ generic mechanism

X - X E E R R R SE1 ◼ examples

O O O O OH Br Br H Br Ph Ph Ph Ph

R R R - N2 ROH N H R N R R

O O HO O O P OH, H O Ph P P P H Ph 2 HO Ph + Ph Ph Ph O Ph + heat Ph Rearrangements and Reactive Intermediates 12

◼ β-hydride elimination from carbanions common for transition metals ◼ reverse reaction is hydrometallation – well known from chemistry

H H H PdX + HPdX BR2 BR2

◼ 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 Me Me H + LiH Me Me ◼ redox reactions – Single Electron Transfer - SET

MgBr Cl H + Cl + H • H H dimerisation SET of Ph•

Cl Cl • Cl SET + • Cl • Rearrangements and Reactive Intermediates 13

◼ rearrangement of carbocations ◼ the neopentyl system Me Me Me Me Me Me AgNO3, water Me HO + not Me Me I Me Me Me OH Ag H2O then - H - H

Me 1,2- shift Me Me ◼ the 1,2 shift is a Wagner- Me Meerwein rearrangement Me Me

◼ as an aside, remember that neopentyl systems, although primary, are unreactive under SN2 conditions as the nucleophile is severely hindered from attacking the necessary carbon

Me Me ‡ Me Me Me Me Me Me (-) (-) Me Nu Nu H LG Nu LG R'' LG H R' H H

◼ staggered conformation requires nucleophile to approach passed one of the methyl groups Rearrangements and Reactive Intermediates 14

◼ Wagner-Meerwein rearrangements exemplified

Me 1 Me 7 7 2 7 2 1 - H 2 3 H 3 Me 3 1 Me HO 6 5 ◼ overall red bond is broken and 4 4 6 Me Me 5 4 6 5 Me 8 blue bond is formed isoborneol camphene 8 Me 8 H ◼ in general alkyl shifts occur to rotate yield a more stable carbocation

Me 1 Me Me Me Me 1 Me Me 1 1 Me 2 2 Me 7 2 7 8 7 2 5 3 3 5 3 6 6 6 best orbital overlap is also H2O 6 ◼ 5 4 5 4 4 rotate 7 Me Me 8 Me 3 important in determining which 8 4 8 group migrates ◼ secondary ◼ tertiary carbocation carbocation

Me poor orbital overlap 1 Me Me 1 Me Me 1 Me migration Me Me for migration 2 2 2 7 7 3 3 3 would lead to 1 6 6 7 5 4 5 4 6 4-membered 5 Me Me Me 5 2 8 8 4 ring 8 best orbital overlap H Me 8 for migration (ca. 3 4 co-planar) ◼ orbital overlap σC-C 7 6 into empty p-orbital H Rearrangements and Reactive Intermediates 15

◼ Wagner-Meerwein rearrangements exemplified – Nature was here before us – biosynthesis of camphene

Me Me Me Me Me 1 Me Me Me 1 Me 1 linalyl 2 Me 2 7 3 2 3 7 pyrophosphate - OPP 5 3 6 4 6 6 4 Me 5 4 5 7 8 Me O O 8 P P O Me Me Me 8 O O ◼ form 2° cation O O ◼ form 3° cation ◼ form 3° cation relief of ◼ pyrophosphate, or camphene diphosphate – PPO. 7 7 Me 1 Me Me 1 Me PPO is a good leaving 2 2 3 1 3 1 Me 2 2 Me 7 7 group c.f. TsO - H 3 3 6 5 6 4 6 4 6 Me 5 Me 5 4 5 4 Me 8 Me Me 8 8 8 ◼ Wagner-Meerwein rearrangements exemplified – Nature was here before us – biosynthesis of lanosterol (precursor of cholesterol) Me Me Me Me chair – boat – chair Me conformation Me Me H Me Me H Me Me H Me Me H Me Me Me Me Me O HO HO H H H Me Me Me Me H Me H Me H H squalene oxide two 1,2-hydride shifts lanosterol two 1,2-methyl shifts ◼ conformation of squalene oxide controlled by enzyme (lanosterol synthase) – reaction occurs via discrete carbocation intermediates and is not concerted Rearrangements and Reactive Intermediates 16

◼ Pinacol and semi-pinacol rearrangements ◼ mechanism in more detail pinacol pinacolone correct orbital overlap required for migration O HO OH H H Me Me CH Me Me HO Me O 3 Me Me Me Me Me H CH3 Me Me Me nO to σ*C-C H - H H CH O 3 OH CH σC-C to empty p HO OH2 HO Me H 3 Me Me Me Me Me Me Me Me Me Me Me Me

◼ useful method for the preparation of spirocyclic .

HO H2O H -H

OH OH OH OH O

◼ the starting diols can be readily prepared by the pinacol reaction

Mg Mg O O 2 O O O O HO OH Mg Mg H2O • • • SET

◼ and halohydrins can be substrates for the pinacol rearrangement Rearrangements and Reactive Intermediates 17

◼ semi-pinacol rearrangements – the Tiffeneau-Demayanov reaction

i) CN NH2 N2 O O OH ii) LiAlH4 HO HO or HNO2 - H

i) CH3NO2. EtO ii) LiAlH4 ◼ semi-pinacol rearrangements - stereochemistry H C-C H OH nO to σ*C-C H HNO migration 2 O tBu tBu O tBu N2 O tBu NH 2 σ to σ* H H H C-C C-N H H H O C-C OH nO to σ*C-C H HNO migration 2 H tBu tBu N2 tBu O O tBu NH2 σC-C to σ*C-N H H H H H H nO to σ*C-H 1,2-hydride OH HNO C O O 2 O shift tBu H tBu H tBu NH2 σ to σ* H C-H C-N H tBu N2 H OH O OH HNO2 formation H O H tBu tBu H H tBu tBu NH2 n to σ* H H O C-N N2 ◼ anti-periplanar bonds means best overlap of σ and σ* orbitals Rearrangements and Reactive Intermediates 18

◼ 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 1,2-shift of an alkyl group O OH OH OH OH

H Me Me H Me Me Me Me Me Me Me Me

◼ the pinacol rearrangement is driven by formation of a strong C=O bond

◼ the dienone-phenol rearrangement involves loss of a C=O bond and gain of an aromatic ring

◼ the dienone-phenol rearrangement provides a method for ring annulation

OH O O OH tBuO H Cl Cl Rearrangements and Reactive Intermediates 19

Theory of 1,2-shifts retention retention R' ◼ curly arrow mechanism R'' R' R''' R'' R' R''' R''' R'' R R R R R R R R R R ◼ orbital description R R

C C C 3-centre-2-electron system R R R R ◼ at the transition state R R R R R R R R

◼ in the transition state we have three orbitals and two electrons to distribute c.f. the allyl cation

ψ R R 3 R R ψ3 R R ψ3 R R

R R • ψ2 R ψ R R R 2 ψ R R 2

ψ 1 R R ψ1 R R ψ1 R R R R allyl cation 1,2-shift transition state 1,2-shift transition state (carbocation) (carbanion) Rearrangements and Reactive Intermediates 20

◼ 1,2-cation and 1,2-anion shifts ◼ overall for carbocation 1,2-shift, transition state has net bonding R R ◼ the transition state has 2 electrons cyclically conjugated in a ring and is therefore ψ3 R R aromatic – more of this next year ◼ 1,2-shifts occur with retention of configuration in the migrating group R R ψ R R 2 ◼ the 3-centre-2-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 R R ψ 1 mechanistic possibility R R 1,2-shift transition state carbocation ◼ take home message – 1,2-shifts easy for carbocations, difficult for carbanions and radicals

R R ψ3 ◼ both y2 and y3 are antibonding R R ◼ therefore 1,2-shifts of carbanions and radicals would be R R expected to be far less favourable (y2 is occupied) ψ R R 2 ◼ transition state for 1,2-shift of carbanions has 4 electrons R'X 2 2 R'' cyclically conjugated (y1 y2 ) in a ring and is anti-aromatic R''' R R ψ 1 ◼ one can also view the difficulty of 1,2-carbanion shifts arising R R R from the geometrical impossibility of the carbanion performing 1,2-shift transition state R an intramolecular S 2 reaction with inversion of configuration R carbanion N R Rearrangements and Reactive Intermediates 21

◼ as we have seen, for efficient rearrangement orbital alignment is critical H H ◼ all three indicated hydrogen atoms are in the same plane - H rearrangement to the more stable 3° carbocation does not occur H H

◼ retention of configuration at the migrating centre is observed

Me Me Me Me Me Me H O HO NH2 HNO2 N2 2 Me Me Me Me Me Me Me Me ◼ migration with 98% Me Me retention of configuration

◼ at the migrating terminus inversion or racemisation can occur

◼ racemisation will occur if the mechanism is SN1-like i.e. via a full carbocation

HO OH H H2O OH Et OH Et O Et Et H Me Me Me H Me H enantiopure racemic

◼ inversion at the migrating terminus will occur if the mechanism is concerted Rearrangements and Reactive Intermediates 22

Concerted Rearrangements ◼ 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

meso Br HMe H ◼ enantiomers H Me Br Br HMe HBr Br Me Br same relative H H H H inversion configuration as Me OH inversion Me Me Me OH 2 Me H Br starting material H racemic product Br Me diastereomeric Br single enantiomer bromohydrins C symmetric 2 Br Me H H Me Me Br H HBr Br H Br Me Br ◼ same structure H H H Me inversion H Br meso - achiral Me OH Me OH2 inversion Me H Me Me Br Br H

◼ outcome of above reactions is excellent evidence for symmetrical intermediates and hence neighbouring group participation Rearrangements and Reactive Intermediates 23

◼ 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 rds AcOH AcOH NGP H OAc + AcO OTs krel = 1 krel = 350 endo-Ts OTs H H H racemic exo-Ts rds

no NGP 3 5 6 4 rotate 5 4 7 H 3 2 OAc 7 6 1 1 2 H AcO ◼ non-classical O O carbocation - H carbonium ion Me OH AcO Me OH H AcO

◼ alternative perspective of NGP ◼ exo-Ts reacts faster due to NGP of antiperiplanar C-C 1.8 Å sigma bond H ◼ endo-Ts ionises slower to give classical carbocation followed by non-classical carbocation formation non-classical cation has plane of symmetry leading to TsO ◼ 3-centre-2-electron bond ◼ racemic products Rearrangements and Reactive Intermediates 24

◼ evidence for non-classical carbocation (carbonium ion) over equilibrating carbenium ions for the 2-norbornyl cation i.e. is the non-classical cation an intermediate or TS?

◼ low temperature 13C NMR (5 K) shows a symmetrical ion

◼ X-ray crystal structure (Science, 2013, 341, 62) provided definitive evidence of bridged structure

1.8 Å

δC 125 ppm

Br3AlBrAlBr3 ◼ Note: non-classical carbocations are only formed if they are more stable than their classical counterparts ◼ The 1,2-dimethylnorbornyl cation is a rapidly equilibrating species with partial σ-delocalisation. ◼ X-ray structure of the analogous tetramethylnorbornyl cation also demonstrates partial σ-delocalisation. 2.1 Å Me 1.7 Å Me Me Me Me Me Me Me F5SbFSbF5 Rearrangements and Reactive Intermediates 25

◼ π-bonds are better donors than σ-bonds J Ph

OTs Me AcOH 7 Me krel = 10

Me O HO H TsO AcO OAc AcOH SbF6 SbF6

krel = 1 classical carbocation ◼ same structure J. Am. Chem. Soc., 1989, 111, 9224 (carbenium ion) Me O TsO HO AcO

AcOH

k = 1011 rel non-classical carbocation ◼ complete retention of configuration (carbonium ion) (double inversion)

OTs H H H H AcOH AcOH

k = 104 rel allyl cation H H OAc Rearrangements and Reactive Intermediates 26

◼ More neighbouring group participation with π-bonds – phenonium ions

◼ meso phenonium ion (σ-plane)

Me H Me Me H H OAc ◼ enantiomers AcOH racemic product Me Me Me inversion H OTs inversion H H H Me O 133 ppm Me 155 ppm AcO Me OH H diastereomeric 172 ppm single enantiomer 69 ppm substrates ◼ C2-symmetric phenonium ion δC = 60 ppm

HMe Me H Me AcOH H OAc ◼ same single Me Me H inversion enantiomer product H OTs inversion H Me H Me O H Me OH AcO Me Rearrangements and Reactive Intermediates 27

◼ multiple 1,2-shifts

Me OH Me Me Me HO H H2O

- H

H - H2O

Me Me Me Me

formation of adamantane ◼ Me Me

Me Me H AlBr3 Diels-Alder H2, Pd Br heat

C10H16 adamantane C10H16

◼ all C10H16 hydrocarbons rearrange to adamantane on treatment with Lewis acid

◼ adamantane is the thermodynamically most stable C10H16 isomer – it possess repeating units of the diamond lattice Rearrangements and Reactive Intermediates 28

◼ transannular hydride shifts

HO Me Me Me D H - H

- H2O HO D HO D O δ = +4.0 ppm ◼ cyclodecyl cation – 3-centre-2-electron bond c.f. diborane H 1

H Me H H Me H B B SbF5, FSO3F H H H H -140 °C 3 HO Me Me δH = -3.9 ppm δ = 142 ppm δH = -0.51 ppm C 6 5

δH = -6.85 ppm Cl δ = 153 ppm H C

SbF5, FSO3F or or H -140 °C H δH = +6.80 ppm H ◼ 1,6-cation slightly H higher in energy than H H H H 1,5-cation H H H

H H H Rearrangements and Reactive Intermediates 29

◼ Carbanion rearrangements – carbanions are much less prone to rearrangement than carbocations ◼ 1,2-aryl shifts

2Li, -60 °C CO2 Ph Ph Ph -LiCl Ph Cl Ph Li Ph CO2H

0 °C

Ph CO2 Ph

HO2C Ph Ph Ph Ph ◼ delocalised therefore more stable carbanion ◼ X-ray structure

◼ evidence for spirocyclic intermediate Me Me Me Me Me Me Me Me Me Me Me Me CO2H Me Cl Me Me Li, -75 °C Me Me Cs-K-Na alloy CO2 Me Me Me

then CO2 -75 °C

Ph Ph Ph Ph CO H Ph 2

◼ 3° carbanion ◼ delocalised, dearomatised carbanion more stable than 3° carbanion Rearrangements and Reactive Intermediates 30

◼ Favorskii rearrangement O O OMe O OMe O OMe ◼ overall in the Favorskii Cl NaOMe MeOH SE1 rearrangement an alkyl group (R) moves from one side of the to the other

NaOMe ◼ 2-electron electrocyclic ring O O closure - more of this next year R' R''O R' R R''O O O O O OMe X R Cl

O

oxyallyl cation

◼ symmetrical intermediate established by Loftfield with doubly labelled substrate = 14C label

O OMe O O O O OMe O OMe Cl NaOMe MeO MeOH ◼ 1:1 mixture

MeOH Rearrangements and Reactive Intermediates 31

◼ quasi-Favorskii rearrangement – Favorskii rearrangement on substrates with no enolisable hydrogen atoms

O O O Cl Cl OH HO Ph Ph OH Ph MeN MeN MeN

◼ the mechanism is a base catalysed semi-pinacol rearrangement and is closely related to the mechanism of the benzil- benzillic acid rearrangement

◼ Ramberg-Bäcklund reaction

O O S O O O O O O S S Cl S Cl NaOMe ◼ cheletropic extrusion of SO2 – more next year

◼ concerted 1,2-shifts of carbanions are geometrically impossible - as the carbanion cannot R' R'' reach to perform an intramolecular SN2 reaction with inversion of configuration R''' R R R R Rearrangements and Reactive Intermediates 32 X ◼ Concerted 1,2-shifts of carbanions are geometrically impossible - as the carbanion cannot R' R'' reach to perform an intramolecular S 2 reaction with inversion of configuration N R''' ◼ 1,2-Shifts of carbanions occur by a radical mechanism – 1,2-Wittig, 1,2-Stevens and R R related rearrangements R R ◼ 1,2-Wittig rearrangement Me

O

solvent cage • Me Me Me • Me Me • O BuLi O O O OH •

◼ Stevens rearrangement

Me Me O Me Me O Me Me O O O Me N HO N N N N Ph Ph •• Ph Ph • Me • Me Ph Me • • solvent cage Rearrangements and Reactive Intermediates 33

◼ the 1,2-Wittig rearrangement occurs predominantly with retention of configuration in the migrating group

O BuLi O O• O • H Me H Me H • • Me Me H H solvent cage

OH O H Me * Me * H H

◼ predominant retention of configuration at the migrating centre *