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Rearrangements and Reactive Intermediates
70
Rearrangements and Reactive Intermediates
1A Organic Chemistry
Handout 4 - Elucidating the Mechanisms of Rearrangements
h"p://burton.chem.ox.ac.uk/teaching.html
Favorskiirearrangement
O
RR'
X
OR'
R
R''OR''O
Rearrangements and Reactive Intermediates 71
MeO
MeOH ROMe
O
O
MeOMe
overallintheFavorskiirearrangementanalkylgroup(R)movesfromonesideofthecarbonylgrouptotheother
CaseStudies:Elucida0ngtheMechanismsofRearrangements
chemistsgatherevidencetobothsupportandrefuteaproposedmechanism
Favorskiirearrangement–previouslydiscussedmechanism
OClHMeO +
OCl
O O
MeO
O OMeO
MeO
HMeO
HMeO
OMeO
MeOH
symmetricalintermediateestablishedbyLo@ieldwithdoublylabelledsubstrate(=14Clabel)
OCl
O
NaOMe
O O OMeMeO
OMeO
MeOH 1:1mixture
butdoestheLo@ieldexperimentreallydemonstrateasymmetricalintermediate?
O
RR'
X
OR'
R
R''OR''O
Lo@ieldexperimentruledoutanumberofpreviouslyproposedmechanismssuchas:
R
OCl
MeOR
OCl
R
O
•• R •O
reasonablemechanismruledoutbydoublelabelingexperiment
Rearrangements and Reactive Intermediates
72
ClMeO O
OCl K2CO3, H2O
OOH
MeOO
OMeO
MeOH
symmetricalintermediateestablishedbyLo@ieldwithdoublylabelledsubstrate=14Clabel
OCl
O
NaOMe
O O OMeMeO
OMeO
MeOH 1:1mixture
iftheα-chloroketoneundergoesisomerisaIonunderbasiccondiIonsthenthesameisotopedistribuIoncouldbeobservedbyaquasi-Favorskiimechanism
OCl
OMeO, MeOH ClOMe
O
ClOMeO
ClOMeO
Lo@ielddemonstratedthattheisomerisaIonproposedabovedoesnotoccurunderthereacIoncondiIonsbyhalIngthereacIonpriortocompleIonandreisolaIngthestarIngmaterialwhichhadthelabelledcarbonsattheiroriginalposiIons
KMnO4CO2HCO2H HN3, H2SO4
NH2
NH2O
O+
chlorideisomerisaIondoesnotoccurunderreacIoncondiIons
SchmidtreacIon
Rearrangements and Reactive Intermediates
73
PhMe
O
MeOMeOH
Cl
BrO
Me
MeO O
Et3N, EtOHMeO
O OEt
MeOO
O
+
MeOH
furtherevidenceforacyclopropanoneintermediate–isomericsubstratesgivethesameproduct
Ph ClO
MeOMeOH Ph OMe
O
O
Ph
MeO
Ph
O OMePh OMe
O
evidenceforanoxyallylintermediate
Et3N
Ar
Br
OAr
O Ar
O
EtOH
ArO
O
cycloaddiIonFavorskiiproduct
intheFavorskiireacIondeuteriumexchangeoccursdemonstraIngthatenolatesareformedreversibly
PhO
Cl
Ph OMe
O
D D
D D
MeOMeOD
Rearrangements and Reactive Intermediates
74
subsItuenteffects:aHamme"plotshowingtheeffectofsubsItuentsontherateofreacIonisgivenbelow
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
-0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
X=p-OMe
X=p-Me
X=m-Me
X=HX=m-OMe
X=m-Cl
X=m-NO2
logkrel
σ
ρ=–2.93(R2=0.907)
deuteriumexchangeindicatesarapidequilibriumpriortorearrangement
Hamme"equaIon-refresher
OClX
MeONa
MeOHX
O
OMe
X
O
OH X
O
O + HKa
σx=log10Kax– log10KaH
∴ σx=pKa(C6H5CO2H)–pKa(XC6H4CO2H)
i.e.σxisposiIveforEWGandnegaIveforEDG
Hamme"equaIonlog10(kx/kH)=ρσ
aposiIve ρ meanselectronsflowintotransiIonstatei.e.electronrichtransiIonstate
anegaIveρmeanselectronsflowoutoftransiIonstatei.e.electronpoortransiIonstate
negaIve ρ valueforFavorskiirearrangementneedstobeinterpretedcarefullyduetoequilibriumpriortorearrangement
theabovealsoappliestoequilibria-aposiIveρmeansthattheproductsideoftheequilibriumisfavouredbyEWGsandviceversa
Rearrangements and Reactive Intermediates
75
OX
OX
Hamme"ρvalueisacombinedvalueforallthestepsuptoandincludingtheratedeterminingstep
ρ valueforenolisaIonofarylmethylphenylketones=+1.73
enolisaIoninbaseshouldbefavouredbyEWGonaromaIcring∴ ρ =+1.73makessense
forFavorskiireacIonρreac0on=–2.93whichismadeupoftheenolisaIonstepandthesubsequentlossofchloride
ρ=–2.93O
ClX MeO+O
ClXr.d.s
- Cl
ρreaction = ρenolistion + ρchloride loss
∴ ρchlorideloss=–2.93–1.73=–4.66i.e.moderate-to-largeandnegaIve-electronsflowoutoftransiIonstate
magnitudeofnegaIveρ impliesposiIvechargeneartheringandisconsistentwithlossofchloridetogiveanoxyallylcaIon
OClX MeO+
OClX
r.d.s
- Cl
O
PhX base+
O
PhX ρ=+1.73
ρ=+1.73 ρ=-4.66
Rearrangements and Reactive Intermediates
76
OClMeO
O O
ArAr
Ar
H+MeOH
OCl
MeOO
ClAr ArMeOH
O
••
H
ArO O
ArAr
products
carbeneC—HinserIon
deprotonaIonfollowedbylossofchlorideshouldberelaIvelyinsensiIvetosubsItuentsonthearylgroupasthereisnoconjugaIon–theinducIveeffectofthearylgroupwillbesmall∴ρ=–2.93inconsistentwithcarbenemechanism
concertedmechanism
products
X
H
EtOEtOHCl
X
forE2eliminaIon(1,2-eliminaIon)fromarylethylchloridesρ=+2.61i.e.reacIonisacceleratedbyEWG
theconcerted1,3-eliminaIonshouldhaveasimliarρvaluebutasρ=–2.93fortheFavorskiirearrangementthisallowstheconcertedmechanismtobediscountedinthissystem
proposedmechanismswhichdonotfitthedata
carbenemechanisms
ρ=+2.61
Rearrangements and Reactive Intermediates
77
Me
ClO
useofanon-hydroxylicsolventrestoresthestereospecificity
MeOMeOH MeO
MeOH
stereochemistryoftheFavorskiirearrangement
Me
ClO
H BnO Na
Et2OMe
CO2BnMe
Me
Cl BnO Na
Et2OMe
MeCO2Bn
O Me
innon-hydroxylicsolvents,stereospecificreacIonscanbeobserved–hereSN1lossofchloridetoformanoxyallylcaIonisdisfavouredduetonon-hydroxylicsolvent
Me
O
BnO
Me
O OBn
Me
CO2BnBnOH
Me
CO2BnMe
inmorepolar,alcoholicsolvent,reacIonisno-longerstereospecific
Me
ClO
HMeO Na
MeOH Me
CO2MeMe
+Me
MeCO2Me
Me
ClO
Me
O
Me
O
Me
+ O
Me
ClO
Me
MeO Na
Me
CO2MeMe
+Me
MeCO2Me
MeOOMe
40% 50%
95% trace
inversion
Rearrangements and Reactive Intermediates
78
OCl
Me Me
Me
MeOMeOH
furtherevidence–cyclopropanonescanbeisolatedandtheygivethesamedistribuIonofproductsastheFavorskiirearrangementofα-haloketonesunderthesamereacIoncondiIons
•O
Me
Me
NMe
N O
Me
Me N2CH2Cl2
O
MeMeMe
νmax=1850cm-1
1HNMR:δH=1.91(q,J=7.5Hz,1H),1.31(s,3H),1.08(d,J=7.5Hz,3H),1.06(s,3H)
O
MeMeMe
OMe MeMeO
O MeO
MeOH
Me OMe
O
Me Me
Me OMe
OMe
Met-BuO
Me O
O
Me MeMe
MeMe t-BuO
80%
20%
100%cyclopropanonescanalsobeisolatedunderFavorskiirearrangementcondiIons
t-Bu t-BuO
Br
O
t-Bu t-Bu
OMe
MeAr K
Rearrangements and Reactive Intermediates
79
R R
OO
R
O
OR
R
O
OR
R R
O
O OH
OR' +RR
HO OO
O
R'
R R
O
O OH
OR'+
R R
OHO
HO
OR
R O R
OR
R
O
OR
O
PhPh
O
Ph OOH +
O
OPhPh
Baeyer-VilligeroxidaIon-thegroupwhichbestsupportsaposiIvechargemigrates
someotherreasonablemechanismswereoriginallyproposed
acceptedmechanism(Criegeemechanism)
R R
O
O OH
OR'+
RR
HO OO
O
R'
R
O
OR
dioxiranemechanism
dioxirane
peroxidemechanism
peroxide
isotopelabelingstudiesareonlyconsistentwiththeCriegeemechanism(=18O)
R R
OO
R
O
OR
labelincarbonyloxygen
labeldistributedbetweenbothoxygenatoms
labelinnon-carbonyloxygen
Rearrangements and Reactive Intermediates
80
O OH
MeX
O
O
F3C
O
O
CF3HO
Baeyer-VilligeroxidaIon– natureoftheratedeterminingstep
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
-0.3 -0.1 0.1 0.3 0.5 0.7 0.9
logkrel
ρ=–1.45(R2=0.983)
X=p-Me
X=H
X=p-BrX=p-Cl
X=m-NO2
X=p-NO2
σ
XMe
OCF3CO3H
MeCNX
O Me
O
H
OH
MeX
step1
step2
step3
Hamme"plotfortheaboverearrangementhasρ=–1.45
typicalHamme"valuesforacidcatalysedaddiIonofheteroatomstocarbonylgroups(steps1and2)haveposiIveρvalues-e.g.acidcatalysedhydrolysisofethylbenzoates(ArCO2Et)hasρ=+0.144
foraboveBaeyer-VilligerreacIonρ=–1.45∴likelystep3isratedetermining
rememberposiIveρelectronsflowintotransiIonstate,negaIveρelectronsflowoutoftransiIonstate
negaIveρforstep3makessense–reacIonisacceleratedbyelectrondonaIngarylgroups
Rearrangements and Reactive Intermediates
81
Baeyer-VilligeroxidaIon– natureoftheratedeterminingstep(=14C)
Me
O
CHCl3
O Me
O
Cl CO3H
X X
X k12/k14
CN 1.085
Cl 1.052
H 1.048
CH3 1.003
CH3O 0.998
kineIcisotopeeffectdemonstratesthatratedeterminingstepisstep3forallthesubsItuentsexceptX=OCH3i.e.thereissignificantalteraIoninthebondingtothelabelledcarbonintheratedeterminingstepgivingrisetotheobservedkineIcisotopeeffect
H
OH O OHMe Me
O
O
Ar
m-CPBA
X X
step1
step2
step3
lackofkineIcisotopeeffectforX=OCH3indicatesformaIonofthetetrahedralintermediateisratedeterminingforX=OCH3
withX=OCH3step3becomesfast(EDGincreaserateofBaeyer-VilligerreacIon)andstep2becomesratedetermining–i.e.a"ackofm-CPBAonacIvatedcarbonylgroupisslowerthanrearrangement
ingeneral,rearrangementistheratedeterminingstep