Rearrangements and Reactive Intermediates 34

Rearrangements and Reactive Intermediates1A Organic Chemistry

Handout 2 - Carbenes and Nitrenes

http://burton.chem.ox.ac.uk/teaching.html

jonathan.burton@chem.ox.ac.uk

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''