Rearrangements and Reactive Intermediates 34
Rearrangements and Reactive Intermediates1A Organic Chemistry
Handout 2 - Carbenes and Nitrenes
http://burton.chem.ox.ac.uk/teaching.html
nO toσ*C-C σC-C toσ*C-N
O
NN
O
NN
Rearrangements and Reactive Intermediates 35
Carbenes
◼ neutraldivalentcarbonspecies– 6electronsaroundcentralcarbonatom– highlyreactive,generallyelectrophilic
R
R singletR
R ••
◼ typicalbondanglerangeforsingletcarbenesare100° - 110°
R
R
◼ structure– singletcarbenes
◼ singletcarbenesarebentwiththebondpairsandlonepairsinsp2 hybridisedorbitals,alongwithavacantp-orbital
◼ singletcarbeneshavethreeelectronpairsandanemptyorbitaltoplacearoundthecentralatom- asimilarcasetocarbocations (carbeniumions)
◼ structure– tripletcarbenes
tripletR
R ••
R
R
◼ tripletcarbenesarebentwithatypicalbondanglerangeof130° - 150°
◼ carbenestructuresfromspectroscopy,inlowpressuregas,andinlowtemperaturematrix(<77K)
- electronicspectrawithrotationalstructure
- infraredanalysis
- electronspinresonance(fortriplets)
Rearrangements and Reactive Intermediates 36
R
Rtriplet
R
R ••
◼ imaginealineargeometryforthetripletcarbene- therewillbeacentralsp hybridisedcarbonatomwiththetwobondingpairsofelectronsareinsp-hybridorbitals
(50%s-character)- theunpairedelectronsareinthetwoorthogonal2porbitals
◼ thislineararrangementmeansthattheunpairedelectronshavenos-character– themores-characterthemorestabletheelectron
◼ bendingthelinearstateleadstooneoftheunpairedelectronsgainingsomes-characterandbeingloweredinenergy– hereoneofthep-orbitalsbecomesanspn hybridorbital(aσ-orbtial)
◼ duetoelectronelectronrepulsionthereisanenergycostinpairingelectrons(Hund’s rule)
◼ themorebentthecarbeneisthegreaterthedifferenceinenergybetweenthepandσ-orbitals
◼ ifthereisasmallenergygapbetweenσ andp-orbitalstheelectronswillremainunpairedi.e.triplet
◼ Whyaretripletcarbenesbent?
R R
Rearrangements and Reactive Intermediates 37
H HH HH H
◼WalshdiagramforCH2 givesamoresophisticatedanalysisandaccountsforelectronicstructureofCH2
– seeProfMcGrady “BondinginMolecules”course2nd year
linearCH2 bentCH2
◼ simplifiedWalshdiagramforCH2
◼ beginningwithlinearCH2,MOdiagrampredictsatripletgroundstate
◼ slightbendingshouldbestabilisingasoneoftheelectronsisnowinabondingMO
◼ with furtherbending,thelowerenergyofthebondingMOovercomeselectron-electronrepulsionandthesingletcarbenebecomesmorestable
◼ takehomemessage – tripletcarbenesandsingletcarbenesarebent– wewillconsiderthembothtobesp2 hybridised◼ tripletcarbeneshavealargerbondanglethansingletcarbenes◼ theaboverepresentationsareadequateforourpurposes◼ neitherWalshdiagramnorhybridisationallowsustopredictthegroundstateforanyparticularcarbene
R
Rsinglet
R
R ••R
R
tripletR
R ••
R
R
σ
p
Rearrangements and Reactive Intermediates 38
N
NR
R
Cl Cl
••
N
N
N
N
R
RR
R
••
••
N
NR
R
N
NR
R
◼ firstX-raystructureofacarbene(J.Am.Chem.Soc.,1991,113,361).
◼methylene(CH2)hasatripletgroundstate– thesingletstateisca.38kJmol-1 higherinenergy
H
H
H
H134° 102°
◼ dialkylcarbenes,arylalkylcarbenes andsomediarylcarbenes havetripletgroundstates
◼ heteroatomsubstitutedcarbeneshavesingletgroundstatesduetodelocalisation
Cl
Cl••
• •
singlet
increasingcarbenestability
tripletgroundstate
singletgroundstate
N N
• •
◼ carbeneorylid?c.f.
R N C R N C R N C ••
isonitrile
Cl Cl
••
Cl Cl
nCl toemptyp
N-heterocycliccarbenes
C O C O C O••
triplet singlet
••CH2 Ph2C••
Rearrangements and Reactive Intermediates 39
◼ Grubbs-Hoveyda 2nd generationmetathesiscatalyst(J.Am.Chem.Soc.,2000,122,8168)–morenextyear
N
N
NH2
Me
N
S
Me
OP O
P OOO
OO
deprotonation
◼ themajorityofcarbenesareelectrophilic– therearesixelectronsaroundthecentralcarbonandhencetheyareelectrondeficient
◼ N-heterocycliccarbenes(andrelatedcarbenes)arenucleophilic- theyarewidelyusedasligandsfortransitionmetals
D2O
nucleophilic carbene
◼ Naturewasherebeforeuswithnucleophilic carbenes–thiaminepyrophosphate(vitaminB1)– morenextyear
N N
Ru
OMe
Me
Cl
Cl
Me
Me Me
Me
MeMe
N N
• •
Me
MeMe
Me
MeMe
N
N
NH2
Me
N
S
Me
H
N
N
NH2
Me
N
S
Me
D
D2O
pH 7PPO PPO
N N N N••
Rearrangements and Reactive Intermediates 40
R N
R
NR N
RNH2
oxidiseR
R
OH2N NH2
R
ORH2N NHTs
R
NRNHTs
aprotic solventalkoxide base
HClClCl
base ClClCl
Cl Cl
•• • • + Cl
◼ somemethodsforcarbeneformation
R N
R
NR N
R
N
R
R••
+ N2
• •
• OR
RR R + CO
MeO OMe
MeO OMe
• •
+
• •
R R
NN
R R+ N2
heatorlight
heatorlight
◼ directirradiationnormallyproducesacarbeneinthesingletexcitedstate
◼ irradiationorheatingdiazo ordiazirinecompoundsformssingletcarbenes
◼ relaxationofthesingletstatetothetripletstate(ifitislowerinenergy)canoccurbutrequirescollisionwithothermolecules
◼ directformationofthetripletstatecanoccurbyirradiationinthepresenceofatripletsensitiser
diazirene
retroDiels-Alder
Rearrangements and Reactive Intermediates 41
Me Me
Me N N
Me Me
Me N N
Me Me
MeTs
Me Me
Me NN
◼ reactionsofcarbenes
◼ insertionintoC-Hbonds– generallyunselective,occurswithveryreactioncarbenes,notCl2C:◼ forsingletcarbenesreactionoccurswithretentionofconfiguration– withtripletcarbenesstereochemistryislost
◼ example– theBamfordStevensreactions– solventdependentproductformation
Me Me
Me N NHTs
NaOMe
Me Me
Meaprotic solvent
alkoxide baseMe
Meprotic solvent
Me Me
Me N NS O
O Ar
base
Me Me
Me NN
Me Me
Me ••H
H
Me Me
Me NNRO H
Me Me
Me H
N2
carbeneformation
C-Hinsertion
- N2carbocation
rearrangement
camphene
◼ rememberontreatmentwith2equivalentsofanalkyllithium,tosylhydrazonesundergotheShapiroreactionMe Me
Me
Me Me
Me N NHTs
2 equivalents MeLivia
Rearrangements and Reactive Intermediates 42
R
R
C
R
R
POMe
◼ insertionreactionsintoadjacentC-Hbondsaretheequivalentofa1,2-shift
Me
N2
hν•• H
HH H
HH
1,2-migration
R
R
H
R
◼ carbene1,2-shift◼ cation 1,2-shiftR Hhigh temperature H
R ••
alkylidene carbene
◼ insertionreactions
Me MeClPO
Hn-BuLi, t-BuOK
Me MeClPO
Li
MePO
H HH
••
Schlosser’sbase-averystrongbase carbenoid
◼ insertionintoXHbondsiscommonusingtransitionmetalcatalysis
O O
OMeN2Ar
Me Rh2(OAc)4
O O
OMeRhLn
- N2
HAr
Me
O
OMe
O
ArMe
C-Hinsertion ◼ rhodiumcarbenoid is
equivalenttoacarbene
MeO
O
OMe
O
N2
HO+Rh2(OAc)4
- N2 O
CO2Me
MeO2C
◼ herethe(rhodium)carbeneisattackedbythenucleophilicalcoholfollowedbyprotontransfer
Rearrangements and Reactive Intermediates 43
◼Wolffrearrangement
R
ONN
R
ONN O
• RNuH O
NuR
hν orheatormetalcatalyst
◼ concertedorstepwisemechanism– dependsonsubstrateandreactionconditions
R
ONN O
• R R
ONN
R
O
••
O• R
◼ theacylcarbenesarealsoinequilibriumwithanoxirene insomecases(=13C)
concerted stepwiseviacarbene
Me
O
Me
N2 hν, waterMe
O
Me
••
Me Me
O
Me
O
Me
••
O
Me
Me
Me
MeO
OH•O
Me
Me
Me
MeO
OHH2O H2O
mixture
◼ Arndt-Eistert homologation
R
O
OH
SOCl2
R
O
Cl
CH2N2
R
ON2
Ag(I) cat.R •
O H2OR
OH
O
◼ asaruleofthumb,thethermalreactionsareconcertedandthephotochemicalreactionsproceedvia carbenes
oxirene
Rearrangements and Reactive Intermediates 44
ON
NO
NN • O
hν, MeOH
O
OMe99%
◼Wolffrearrangement– alookattheorbitals
◼ withcyclicketonesthereactionislikelytobeconcertedundermostconditions
antiperiplanar bonds ◼mechanisminmoredetailcorrectorbitaloverlaprequiredformigration
nO toσ*C-C σC-C toσ*C-N
O
NN
O
NN
RCHBr3, NaOH
R
BrBr BuLi
R
LiBr
R
••
R
•
◼ Doering-LaFlamme allenesynthesis
◼ Skattebol rearrangement
Br
BrBuLi ••
••
H
◼ someotherrearrangements
◼migrationwithretentionofconfiguration
C-Hinsertion
cyclopropanationviacarbene
Rearrangements and Reactive Intermediates 45
◼ orbitalpicture
◼ carbeneadditionreactions
◼ additiontoC=Cbonds:i)stereospecificforsingletcarbenes;ii)non-stereospecificfortripletcarbenes;iii)distinguishesbetweentripletandsingletcarbenes
◼ singletcarbene– concertedreaction
Me Me
Cl Cl••
Me Me
Cl Cl Cl
Cl ••
Cl
Cl
HOMOπ
LUMOp
HOMOsp2
LUMOπ*
◼ tripletcarbene– non-concertedradicalreaction– spininversion(requiresmolecularcollision)maybeslowerthanbondrotationleadingtostereochemicalscrambling
Me Me
R R
Me Me
R R
Me Me
R R
Me Me
R R
Me
R R
Meand
H H H
spininversion
triplet triplet singletbondrotation
Rearrangements and Reactive Intermediates 46
HOH
O
Cl
Cl
OH
H
O
◼ veryelectrophiliccarbeneswilladdtobenzene
N2 CO2Etheat in benzene
- N2
O
OEt•• CO2Et CO2Et
6πelectrocyclicringopening
◼ dichlorocarbene addstopyrrolefollowedbyrearrangement
HN CHCl3, NaOH N
Cl
Cl
HHO
N
Cl
OHCHCl3, NaOH
OH
H
O
OH
H
O+
O
Cl Cl••
CHCl3, NaOH
O
Cl
ClH
HO
O
ClOH
O
Cl
OH
OH
O
H
O
◼ Reimer– Tiemann reaction
major minor
O
Cl
Cl
Rearrangements and Reactive Intermediates 47
O
t-BuO O
O TsN3, K2CO3
O
t-BuO O
O
N
CuIO
O
t-BuO
O
N
N2O
Cu
O
◼ SimmonsSmithcyclopropanation
I I ZnMeMe
I ZnI
MeMe
zinccarbenoid
OHCH2I2, Zn
OH
zinccarbenoid coordinatedbyOHgroup
◼metalcatalysedadditionreactionsofdiazocompounds - commoncatalystsinclude:Cu,CuI,Rh2(OAc)4,Cu(OAc)2
O
t-BuO O
O
K2CO3
NNNSO2Ar
O
t-BuO O
O
NNN
H
ArO2S
O
t-BuO O
O
NNNH
ArO2S
- TsNH
◼ cyclopropanationmostlikelyproceedsbyCu(I)carbeneintermediate
O
t-BuO O
O
CuI
Rearrangements and Reactive Intermediates 48
N
NR
R
OH
Ph
◼ carbenesreadilyreactwithnucleophiles
◼ nucleophilic carbenesareusefulcatalysts
NN RR
XPh H
O cat.
Ph
O
OH
Phbase
H
NN RRNN RR••
N
NR
R
OH
HPh
O
H Ph
N
NR
R
OPh
PhO
H
- catalyst
B
••
◼ N-heterocycliccarbenecatalysesthebenzoinreaction
◼ actslikecyanide:- goodnucleophile- stabilisesadjacentnegativecharge- goodleavinggroup
OMe
cat. Rh2(OAc)4O
MeO
Me
••
OMe
ON2
ORhII
O
H
OO
O
Me
H
Rearrangements and Reactive Intermediates 49
Nitrenes
◼ neutralmonovalentnitrogenspecies– 6electronsaroundnitrogenatom,isoelectronicwithcarbenes
singletsp2
◼ aswithcarbenes,goodπdonorsubstituentscangivesingletgroundsates
◼ similarchemistrytocarbenes,somedifferencesandnitrenes aregenerallymorereactive
◼ nitrenes arebydefinitionlinear,aswithcarbenestheyhavesingletandtripletstates
tripletsp
R N ••
• •R N ••R N ••
••
R N•••• R N
••••
◼ nitrenes havealargerenergyseparationbetweenthetripletandsingletstates– tripletisusualgroundstate
◼mostcommonmethodforgenerationisthermolysis orphotolysisofazides
RN
NN
hν or heatR N
••
••
+ N2
◼ anumberofmethodsfornitrene generation,analogoustothemethodsforcarbenegeneration,areknown
N N••
•• N N••
••
Me
Me
Me
Me
Me
Me
Me
Me
◼ freenitrenes arenotalwaysformedundertheseconditions
R NH
OTs
Et3N R NOTs
- OTs R N
••
••
α-elimination
Rearrangements and Reactive Intermediates 50
- R3PO
◼ plausiblemechanism
NO2PPh3heat
N3HN
heat
ArNO
OPR3
◼ generationbyreductionofnitrocompounds
ArNO
OPR3
ArN••
••
PR3Ar
NOPR3Ar
NO
◼ carbazole synthesis
α-elimination
◼ generationfromisocyanates
ArN
CO
hνAr
N- CO
••••
N N•••• H
HN
1,5-hydrideshift
electrocyclicreaction
- R3PO
Rearrangements and Reactive Intermediates 51
◼ competingreaction– 1,3-dipolarcycloaddition
MeMe
Me
O
EtO N••
••
N
i-Pr Me
O OEt
N
i-Pr Me
O OEt
◼ additiontoC=Cbonds◼ aswithcarbenes,additionofnitrenes toalkenesisstereospecificwithsingletnitrenes,andnon-stereospecificwithtripletnitrenes
NH
OEtO
O Et3N
SO O
NO2
NO
EtO
O
SO O
NO2 O
EtO N••
••
- ArSO3singletnitrene
Me
MeMe
N N
i-Pr Me i-Pr Me
O OEt O OEtO
EtO N••
••
majorwithexcessolefin
majorwithexcessolefin
mixtureofcis andtransaziridineswith1equivalentolefin
◼ withhighconcentrationofolefinsingletnitrene reactsstereospecifically togiveaziridine products– trans-olefingivestrans-aziridine;cis-olefingivescis-aziridine◼ withlowconcentraion ofolefinsingletnitreneundergoesintersystemcrossingtogroundstatetripletandreactsnon-stereospecificallywitheachalkene(diradicalmechanism)togivemixturesofaziridineproducts◼ photochemicalgenerationofnitrene givesanalogousresults
N N NR
NN
NRhν or heat N
R
triazoline
Rearrangements and Reactive Intermediates 52
R' N•••• H
R
RR+ N
H RRR
R'R'
HN R
RR
◼ insertionreactions
singlet concerted
retention
R' N••
•• HR
RR+ R'
HN R
RR
R' N•
••
H
R
RR•
triplet radicalreaction
racemisation
N3H
EtMe
heat
NH
EtMe
••
•• NH
EtMe
- N2
singletnitrene
retentionfast
OO
H2N
OO
NPhI(OAc)2
IPh
cat. Rh2(OAc)4O
ON
RhII
O
HN O
RhII
C-Hinsertionrhodiumnitrenoid
86%
◼ nitrenoids frequentlygivebetteryieldsofC-Hinsertionreactionsundermilderconditions
◼ inasimilarmannertransitionmetalnitrenoids reactwithalkenestogivegoodyieldsofaziridines
iodonium ylid
Rearrangements and Reactive Intermediates 53
R
O
NNN
R
O
NO•NR••••
R
O
NNN O
•NR
◼ rearrangementofnitrenes
◼ photolysisofalkylazidesyieldsimines– nitrenes aremostlikelynotintermediatesinsuchreactions
R N
R' R'NN
hνN
R'
R' Rconcerted1,2shift
◼ Curtius rearrangementoracylazides
◼ therearetwoplausiblemechanisms
concerted stepwisevianitrene
O
NRN
NO
ClRNaN3 hν or heat N
R •O
ROH or waterNH
RO
ORor RNH2
◼ thethermalreactionisconcerted;thephotochemicalreactionmayproceedvia anitrene,butmaybeconcerted
◼ theCurtius rearrangementproceedswithretentionofconfigurationinthemigratinggroup
Rearrangements and Reactive Intermediates 54
R N
OO
HRNH2
R'
O
OH NR •
O
water
- CO2
◼ otherrearrangementstoelectrondeficientnitrogen– theserearrangementsareunlikelytoinvolvenitrenes
◼ Hoffmanrearrangement
R N
OH
H
Br2, OHRNH2
R N
O
H
Br Br
R N
OBr
H
OHR N
OBr N
R •O
OH
NR
O
OH
HOH
HN
RO
OH
◼ Lossen rearrangement
R N
OO R'
OR N
OO R'
O
NR •
O
Rearrangements and Reactive Intermediates 55
O NN
NHO N
NN
NHON2
N
O
H - H
◼ Schmidtrearrangement
R
O
NHNH2 R
O
OHHNO2
R
O
NNN HN3
O•NR
◼ Schmidtrearrangementwithketones(aldehydesgivenitriles)
O
R R
HN3 OH
R R
N3
R R
HO N N N
R R
HO N N NH
H
R R
NN2
R N R
R N RH2O
R
OH2
NR± H
R
O
NR
H
H
R
O
NR
H
- H
◼ IntramolecularSchmidtrearrangementwithalkylazides
◼ stereochemistry
N
O
NHON2
Rearrangements and Reactive Intermediates 56
N ClAgNO3, MeOH
N N
MeO
◼ Beckmannrearrangement ◼ thegroupantitotheleavinggroupmigrates(σC-Ctoσ*N-O)
◼ oximescanundergoE/Z isomerisationundertheacidicreactionsconditions
◼migrationwithretentionofconfiguration
N
R R
N
R RR N R
R N RH2O
R
OH2
NR± H
R
O
NR
H
H
R
O
NR
H
- H
OHH
OH2
◼ Beckmannrearrangement– synthesisofcaprolactam,precursortonylon6
ONH2OH
NOH
H2SO4 NH
O
carpolactam◼ Neber rearrangement– substituentpossessingmostacidichydrogenmigrates
R'NOTs
RH
ORN
RR'H2O
HN
RR'
OH O
RNH2
R'
◼ Stieglitzrearrangement
Ag
N
Me
HO
H2SO4
HNO Me
moststableoxime withbulkygroupstrans
ketonetoamidebyNHinsertion
Rearrangements and Reactive Intermediates 57
BuHO O
O
O
R''H
O OH
OR''O
Bu O
O
Bu
◼ Baeyer-Villiger
R'
O
RO O
HOR''
R'
O
OR
◼ orderofmigrationA.K.Amigratoryaptitude3° alkyl>2° alkyl>aryl>1° alkyl>methyli.e.thegroupwhichbestsupportsapositivechargemigrates
◼ witharomaticgroups,electrondonatinggroupsincreasemigratoryaptitude
◼migrationoccurswithretentionofconfigurationinthemigratinggroup
◼ withaldehydesmigrationof“H”usuallyoccurstogivecarboxylicacids
H
OH
Bu BuHO O
O
OH
R''± H
O
OH
Bu
- R''CO2H
- H
◼ transitionstateiselectrondeficient(electronwithdrawinggrouponoxygen)
◼ electronreleasinggroupsstabilisethetransitionstategivingtheorderofmigratoryaptitudeabove
BuHO O
O
OH
R''
(+)
(+)
δ+Bu
HO OO
O
R''
(-)
(+)
δ+
conversionofaketoneintoanesterbyoxygeninsertion
OOHO R''
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