DielsAlderreactions

TheDielsAlderreaction:the[4+2]cycloadditionreaction
In 1906, Wieland discovered that 1,3dienes would react with alkenes to form a cyclohexenes.
However,thestructuresofmanyoftheproductsremainedunknownuntilthe1920's,whenOttoDielsand
KurtAlderfinallydeterminedthem.Theirsystematicexplorationofthescopeofthe"dienesynthesis,"as
itwasthencalledestablishedthereactionnowalmostuniversallyknownastheDielsAlderreaction
asamajormethodforthesynthesisofsixmemberedrings.Partoftheirlegacyistheterminologythat
wenowusetodescribethetwoparticipatingreactants:thedieneandthedienophile(from"diene"and
theGreek,,philos,loving).
TheDielsAlderreactionhasbeenthesubjectofconsiderableresearchsincethepioneeringstudiesof
DielsandAlderinthe1920's. Thepreponderanceofevidencesuggeststhatthereactionisconcerted,
althoughalternativestepwisemechanismsforthereactionstillcontinuetobeproposed.Thereactionis
highlyregioselectiveandhighlystereoselective,andsubsequentdevelopmentssuchastheWoodward
Hoffmannrules(conservationoforbitalsymmetry)haveenabledustopredictboththeregiochemistry
andthestereochemistryofthemajorproduct.Infact,itspredictablestereochemicalandregiochemical
outcomes have made the DielsAlder reaction one of the cornerstone reactions of modern organic
synthesis.

InordertoachieveeffectiveHOMOLUMOoverlap,thelobesattheendsofthedienemustoverlap
withthelobesattheendsofthedienophile. Atthesametime,thegeometryoftheactivatedcomplex
geometrymustallowthesimultaneousformationofthetwonewbondsandthenewbondinasix
memberedring.Forthesereasons,theDielsAlderreactionmustoccurthroughthescisconformerofthe
diene.ReactingthroughthestransconformationwouldrequireHOMOLUMOoverlapatunreasonably
large distances, and the reaction would result in the formation of a transcyclohexene, which is
prohibitivelystrained. Cyclicdieneswhicharelockedbytheringinthe scis conformation(e.g.1,3
cyclopentadieneand1,3cyclohexadiene)tendtobemuchmorereactivethanacyclicdienes,whiledienes
suchas4methyl1,3pentadiene,whichcanattainthe scis conformationonlywithdifficulty,tendto
react only extremely slowly if at all. Dienes which cannot achieve the scis geometry (e.g
bicyclo[4.4.0]deca1,6diene,below)donotreactintheDielsAlderreactionatall.

Me H
Me

1,3cyclopentadiene1,3cyclohexadiene

4methyl1,3pentadiene bicyclo[4.4.0]deca1,6diene

TheformationoftheproductinaDielsAlderreactionrequiresthattwonewbondsbeformedat
theexpenseoftwobonds,andthatfournewsp3centersbeformedattheexpenseoffoursp 2centers.
Therefore,theDielsAlderreactionbetweensubstituteddienesanddienophilescanleadtothegeneration
ofuptofournewchiralcentersintheproduct:thepossibilityofgeometricisomerisminthereactants
becomesthepossibilityfordiastereoisomerismintheproduct.Forexample,when(E,E)2,4heptadiene
reactswithmaleicanhydride(aZalkene),fournewchiralcenters(indicatedbelowwithanasterisk)are

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DielsAlderreactions
generated,sothat(inprinciple,atleast)therearesixteen(2 4)stereoisomericcompoundsthatmightbe
formed. Obviously not all these isomers are formed, or the reaction would not have achieved its
importanceinmodernsynthesis.So...howmanyisomersareformed,andwhichonesarethey?
O
+

O
*

*
* *

O
O

(E,E)2,4heptadiene

O
O

maleicanhydride

TheDielsAlderreactionproceedsstereospecificallywithrespecttobothcomponentreactants.We
haveusedthisterminologybeforewithoutdefiningexactlywhatwemeanbythetermsstereospecificand
stereoselective.Nowitistimetodoso.Astereospecificreactionisoneinwhichonestereoisomerofa
reactantgivesexclusivelyonestereoisomerintheproduct,andinwhichanotherstereoisomerofthe
reactantgivesadifferentstereoisomeroftheproduct.Agoodexampleofastereospecificreactionisthe
SN2substitutionreaction:becauseitproceedswithinversionofconfiguration,oneenantiomerofthe
reactantgivesonlyoneenantiomeroftheproduct.Astereoselectivereaction,ontheotherhand,isonein
whichonestereoisomerofthereactantgivespredominantly,butnotexclusively,onestereoisomerof
theproduct.
O
+

O
O

H O
()

O
H O

endo(majorproduct)

H O
+

()

O
H O

exo(minorproduct)

WhentheDielsAlderreactionbetween(E,E)2,4heptadieneandmaleicanhydrideisactuallycarried
out,onlytwodiastereomericracematesareisolated,andone(designatedastheendoisomer)isformedin
greatpreponderanceovertheother(designatedastheexoisomer).Theobservedstereochemistryofthese
twoproductscanberationalizedonlyintermsofasuprafacialadditionwithrespecttobothparticipating
reactants.Consequently,thestereochemistryofthereactantsismirroredintheproducts:groupswhich
aretranstoeachotherinthedienophilearetranstoeachotherintheproduct,andgroupsthataretransto
thecenterCCbondofthedienearecistoeachotherintheproduct.Thedifferencebetweentheendo
and exo productsarisesfromthedifferentrelativeorientationsofthedieneandthedienophileasthey
approacheachothertoestablishtheinitialHOMOLUMOoverlap.
Thedifferencebetweenthetwoproductsofthereactionabovearisesfromtherelativeorientationof
thetworeactantsastheyapproacheachother.SincetheDielsAlderreactionproceedsthroughthescis
conformerofthediene,thedieneitselfmaybesaidtoresembleasetofjawswiththetwo cisgroupsas
"teeth." IfthedienophileisorientedasshownontheleftinFigure10.11,thecarbonylgroupsonthe
dienophileareinsidethejaws;thisorientationleadstoendoisomer(Latinendo,inside).Thealternative
orientation,whichhasthetwocarbonylgroups outside thejaws,leadstothe exo isomer(Latin exo,
outside).Intheexamplesbelow,the"teeth"andthegroupsoutsidethejawsthosegroupsenclosedin
theloopfinishupcistoeachotherintheproduct.

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DielsAlderreactions

CH3
O H

endo

CH3
H
H

O
O

exo

O
H

CH2CH3

CH2CH3

Figure10.11 TheorientationsofthereactantsthatleadtothetwoisomericproductsoftheDiels
Alderreactionbetweenmaleicanhydrideand(E,E)2,4heptadiene.
The terms endo and exo were first used by Bredt in his work with the bicyclo[2.2.1]heptane
(norbornane)ringsystem. Thisringsystemhasbothaconvexandaconcavesurface. Theconvex
surface,fromwhichallsubstituentsprojectoutfromthesurface,iscalledtheexosurface.Theconcave
surface,fromwhichallsubstituentsprojectintothecavity,iscalledtheendosurface(Figure10.12).

convex surface
exo

concave surface

endo

Figure10.12Theexoandendosurfacesofthebicyclo[2.2.1]heptane(norbornane)ringsystem.
TheregiochemistryoftheDielsAlderreactionisalsoquitepredictable,andthesepredictionscanbe
madeonthebasisoftheelectronicnatureofthesubstituentonthedieneorthedienophile. Electron
withdrawinggroupstendtoreducetheelectrondensityattheterminalcarbonatomofthedienophileby
resonance,asshowninFigure10.15foracrolein.Similarly,electronreleasinggroupstendtoincrease
theelectrondensityattheterminalcarbonofthedienebyresonance,asalsoshowninFigure10.15forE
1methoxy1,3butadiene.

Me

Me

Me

H
O

1-methoxy-1,3-butadiene

acrolein

Figure10.15Theresonancecontributorstothehybridofadienebearingatypicalelectrondonating
group (1methoxy1,3butadiene) and a dienophile bearing a typical electronwithdrawing group

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DielsAlderreactions
(acrolein).
Inthereactionbetweenanunsymmetricallysubstituteddieneandanunsymmetricallysubstituted
dienophile (e.g. the reaction between E1methoxy1,3butadiene and acrolein), two possible endo
productscanbeformed.Themajorregioisomerobtainedwillbethatinwhichthereisthebestmatch
betweentheformalchargesintheminorresonancecontributors(Figure10.16).

matched
lower energy

MeO

mis-matched
higher energy

OMe

OMe

CH=O

CH=O

(major)
()

OMe

CH=O

(minor)
()

OMe

Figure 10.16 The regiochemistry of the major product of the DielsAlder reaction between an
unsymmetrically substituted diene (e.g. 1methoxy1,3butadiene) and an unsymmetrically substituted
dienophile(e.g.acrolein)canbepredictedonthebasisoftheresonancecontributorsofeachreactant.
Themajorproductcorrespondstotheendoisomerinwhichtheformalchargesattheterminioftheminor
contributorstothestructureofthedieneandthedienophilearematched.
OttoPaulHermannDiels(18761954).DielswasborninHamburgandeducatedattheUniversity
ofBerlin,wherehestudiedunderEmilFischer.Aftergraduating,hejoinedthefacultyatBerlin,wherehe
rosethroughtherankstpprofessor.In1916hemovedtotheUniversityofKiel,wherehespenttherestof
hisprofessionallife,retiringin1945.LikemanyGermanscientistduringWorldWarII,Dielsalsofeltthe
impactofwarpersonallyhelosttwosonsontheRussianfront,andsawhishomeandlaboratoriesboth
destroyedbyalliedbombing.AlthoughDielsdiscoveredcarbonsuboxide,C 3O2,hewillberemembered
mostforhisaccomplishmentsincollaborationwithhisassistant,KurtAlder.Inthetwoyearperiod1927
1928, they took a rather obscure reaction the diene synthesis and turned it into oneof the most
importantmethodsavailabletothesyntheticorganicchemist.DielsandAldersharedthe1950NobelPrize
inChemistryfortheirdevelopmentofthereactionthatnowbearstheirname.
KurtAlder(19021958).AlderwasbornthesonofateacherinKnigshtta,Silesia(nowChorzw,
Poland;GermanywasforcedtocedeSilesiatoPolandafterWorldWarI).Heobtainedhisundergraduate
educationattheUniversityofBerlin,andstudiedforhisPh.D.underOttoDielsattheUniversityofKiel.
HeobtainedhisPh.D.in1926,andthencontinuedworkingwithDielsforthenexteightyears,during
whichtimetheirNobelPrizewinningresearchwascarriedout.In1934,AlderjoinedthefacultyatKielas
professor,andin1936hebecamedirectorofresearchfortheGermanchemicalgiantI.G.Farben.In1940,
hemovedtoCologneasprofessorofchemistry,andheremainedtherefortherestofhislife. Alder's
contributionstotheDielsAlderreactionwere seminal,andin1950heshared theNobel Prizefor its
developmentwithhismentor.Alderwasquiteyoungwhenhediedin1958lessthanthreeweeksbefore
his56thbirthday.

Becauseofitsimportanceasasyntheticmethod,itisworthwhilespendingconsiderableeffortto
mastertheDielsAlderreaction.Oftenthereactionlookshopelesslycomplextothebeginningstudent,

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DielsAlderreactions
butitispossibletoarriveatthecorrectproductstructurebyfollowingafewsimplerules.Letusexamine
twoexamples,onewhereacyclicdieneisused,andonewhereanacyclicdieneisused.
Example1:E1Methoxy1,3butadiene+acrolein.

MeO

CH=O

LetususethisreactionbetweenthedieneanddienophileusedinFigures10.15and10.16asourfirst
example.TheproductofaDielsAlderreactionisalwaysacyclohexene,soonebeginsbydrawingthe
cyclohexene,asshowninFigure10.17.

CH=O

CH=O

Step 1: draw
cyclohexene

Step 2: add
dienophile
substituents

Step 3: note
diene carbons
OCH3

endo

OCH3

O H
C
H
H
H
H

Step 4: add diene

substituents
remember
regiochemistry

H
H

CH=O

OCH3

CH=O

()
Step 5: assign
stereochemistry

Figure10.17 PredictingthemajorproductoftheDielsAlderreactionbetweenacroleinandE1
methoxy1,3butadiene.
Theoriginaldienophilecontributesthetwocarbonatomsoppositetheproductdoublebond(theones
attheendoftheboldfacebond),soonenowaddsthedienophilesubstituentstothecyclohexene.One
nowaddsthedienesubstituentsattheappropriateplaces(thedienecarbonsarenowmarkedbyboldface
bonds).Theregiochemistryoftheadditionisdeterminedbydrawingtheresonancecontributorstothe
structureofthedieneandthedienophileasinFigure10.16;notethatwehavenotyetworriedaboutthe
stereochemistryofthereaction,butwehavealreadypredictedtheoverallstructureofthemajorproduct
ofthereaction.Finallyonedeterminesthestereochemistryofthereaction,usingthemethodshownin
Figure10.11todeterminewhichsubstituentsonthecyclohexeneringarecistoeachother,andwhichare
trans. Allfourhydrogenatomsare cis toeachother,sothatthetwosubstituentsarealso cis toeach
other.Sincethestartingdieneanddienophilearebothachiral,theproductisracemic.
Example2:1,3Cyclopentadiene+maleicanhydride.

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DielsAlderreactions

Inthisreaction,wearefacedbyasimilarsetofproblems,buttheissueisoftencomplicatedfor
beginningstudentsbythethecyclicdiene(and,inthisexample,thecyclicdienophile).

O
O
Step 1: draw
cyclohexene

O
CH2

Step 2: add
dienophile
substituents

Step 3: note
diene carbons

Step 4: add diene

substituents
remember
regiochemistry

H
O
endo

CH2

CH2

O
O
O

Step 5: assign
stereochemistry

Figure10.18PredictingthestructureofthemajorproductoftheDielsAlderreactionbetween1,3
cyclopentadieneandmaleicanhydride.
Again,webeginbydrawingthecyclohexenefirst(Figure10.18),andthenaddingthedienophile
substituents(inthiscase,thefivememberedringwiththeoxygeninit).Thetwoendcarbonatomsofthe
dieneinthisreactionaresubstitutedbyaCH 2 groupwhichbridgesbothatoms. Therefore,thetwo
positionscorrespondingtothetwoendatomsofthedieneinthecyclohexenemustalsobebridgedbya
CH2group,whichwenowadd.Finally,weagaindeterminethestereochemistryoftheproductbyusing
themethoddetailedinFigure10.11;becausethedienophilecarriestwoconjugatingsubstituents,theendo
isomershouldpredominate(infact,itistheonlyproductisolated),andtheproducthasthetwohydrogens
ofthedienophilecistothebridgingCH 2 groupoftheproduct. Althoughtherearefournewchiral
centersgeneratedduringthisreaction,theproductisopticallyinactivebecauseitisamesocompound.
SampleProblem10.6.PredictthemajorproductofeachofthefollowingDielsAlderreactions.

(a)

CH2=CHCH=CH 2

(b)

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DielsAlderreactions

(c)

(d)

OCH2CH3

Answers:

(b)

(a)
H

Problem10.14.PredictthemajorproductofeachofthefollowingDielsAlderreactions.

(a)

H
CH3

CH3
H

(b)

O
C

(c)

Cl

(d)

(1mole)

(1mole)

Problem 10.15. What combination of diene and dienophile is needed to make each of the
followingcompounds?

(a)

()

(b)

CH=O

()

Cl

CH=O

(c) ()

Br

(d) ()

CO2H

OEt
H
O

H
O

10.28.Whatisthemajororganicproductofeachofthefollowingreactions?Giveyour
reasoning.[Assumethatonemoleofeachreactantisavailableforreaction].

(a)

(b)

CN

(d)

O=CH

(c)

NO2

OMe

CN

CH=O

CO 2H

(e)

O
O

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DielsAlderreactions

(f)

(g)
MeO

10.30.EachofthefollowingcompoundscanbepreparedbyaDielsAlderreaction.Which
dieneanddienophilearerequiredtoformeachproduct?Nocompoundwithmorethansixcarbon
atomsmaybeusedasastartingmaterialorreagentforthepreparationofcompound(i).

(a)

(b)

CHO

CO2H

(c)

CO2H

(d)

(g)

(f)
MeO

(h)
O

Br
O

(e)
O

Me3SiO

(i)
H

2003DavidE.Lewis