SubstituenteffectsintheDiels–Alderreactions
ofbutadienes,cyclopentadienes,furansand
pyroleswithmaleicanhydride
YonggeQiu
a
Inthisstudy,activationenergiesintheDiels–Alderreactionsofaseriesofsubstitutedbutadienes,cyclopentadienes,fu-
ransandpyroleswithmaleicanhydridewerecalculatedbytheM06-2X/6-31G(d)method.Thesubstituenteffectsonthe
reactivityandtheendo–exoselectivityhavebeenexamined.Thestrengthofreactivityeffecthasanorderof
pyroles>furans>cyclopentadienes>butadienes,whichishighlycorrelatedwiththelowestunoccupiedmolecularorbital
energy,theelectronicchemicalpotentialandtheelectrophilicityofparentdienebutrelativelylesscorrelatedwiththe
highestoccupiedmolecularorbitalenergyandchemicalhardness.Thetrendthatanincreaseofnecleophilicitycaused
byanelectron-donatinggrouponthedienefavorstheendoTSiseffectivewithC2substitution.WithC1substitution,
thetrendisambiguousorevenopposite.Copyright?2015JohnWiley&Sons,Ltd.
Keywords:Diels–Alderreaction;substituenteffect;endo–exoselectivity;substituteddiene;maleicanhydride
INTRODUCTION
TheDiels–Alder(D–A)reactionhasbeenintensivelyinvestigated
andwidelyusedtoformsix-memberedringssinceitwasdiscov-
eredin1928.
[1]
Thiscycloadditioncantakeplacebetweenvari-
ouskindsofdienesanddienophiles,accompanyingwith
complicatedreactivity,regioselectivityandstereoselectivity
problems.
Intheprevailingopinion,theD–Areactionisaconcerted
pericyclicreactionviaasingle,cyclictransitionstate(TS).
[2–6]
Forasubstituteddienophile,therearetwopossibleorienta-
tionsapproachingtothediene,respectivelycorrespondingto
theendoandexoTSs.TheendoTSiswiththesubstituenton
thedienophileorientedtowardthedieneπsystemwhilethe
exoTSiswiththesubstituentorientedawayfromit.Formany
asymmetricallysubstituteddienes,thetwoTSsresultintwodif-
ferentproducts.Empirically,additionbytheendochannelis
usuallypreferredwhenanelectronwithdrawinggroup(EWG)
substituentsuchasacarbonylgroupispresentonthe
dienophile.ThispreferenceisalsocalledtheAlderrule,which
hasbeenregardedasausefulinitialguidetopredictionof
thestereochemistryofaD–Areaction.
[7]
Theendopreference
hasbeenexplainedoriginallyasaresultof“maximumaccumu-
lationofunsaturation”byAlder
[8,9]
andrationalizedlaterwith
thesecondaryorbitalinteraction(SOI).
[10–13]
Cyclopropeneis
thoughttobeanespeciallyattractivedienophilefortesting
theimportanceofSOI.
[14–16]
However,amixtureofbothstereo-
isomersisfrequentlyformed,andsometimes,theexoproduct
predominatesintheexperiments.
[17–20]
Eventheexistenceof
SOIshasbeenquestioned.
[21]
Investigationofendo–exoselec-
tivityintheD–Areactionisstillattractivetochemistsinthe
recentyears.
[13,22,23]
Computationalstudieshaverevealedsomeofthesigni?cant
effectsofLewisacidcatalysisontheendo–exostereoselectivity.
Fortheuncatalyzedreactionofbutadieneandmethylacrylate,
theexoTSsarepreferredovertheendo;whenitisBF
3
-
catalyzed,theendos-transTSisstronglypreferential.
[24]
This
in?uenceofLewisacidcatalysissuggeststhattheendo–exo
selectivitymaybechangedbyincreasingelectrophilicityof
thedienophile.Itmaybeinferredthatanincreaseof
necleophilicityoradecreaseofelectrophilicityforthediene
mayalsofavortheendoTS.However,sofar,thereisnot
anysystematicstudytosupportthat.Herein,weintentto
usemaleicanhydrideasthedienophileandtheoretically
investigatehowtheendo–exoselectivity,aswellasthe
reactivity,isin?uencedbythesubstituentelectroniceffects
intheD–Areactionswithsubstituteddienes.Thesedienes
includethefollowing:(E)-1-X-butadienes(BDs)and2-X-BDs,
1-X-cyclopentadienes(CPs)and2-X-CP,α-X-furansandβ-X-
furans,α-X-pyrolesandβ-X-pyroles(theirconcertedexoand
endoTSsareillustratedinchart1).Itisknownthatnumerous
D–AreactionsofdifferentdieneswithMAhavebeeninvesti-
gatedexperimentallyandtheoreticallyfromdifferentas-
pects,
[17,19,22,25–28]
,butinvestigationsofthesubstituent
electroniceffectsontheendo–exoselectivityhavebeenfew
documentedinourknowledge.
COMPUTATIONALMETHODS
Amonganumberofcomputationalmethodsevaluatedforstudying
D–Areactions,thedensityfunctionaltheoryB3LYPmethod
[29,30]
is
oneofthemostfrequentlyused.
[5,22,31–35]
However,themethodhas
asystematicerrorintreatingπ→σtransformations.
[36]
Inrecentyears,
theM06-2Xmethodbecomesmoreandmorewidelyacceptedforthe
Correspondenceto:YonggeQiu,DepartmentofChemistry,HanshanNormal
University,GuangdongProvince,ChaozhouCity,521041,China.
E-mail:qiuyongge@hstc.edu.cn
aY.Qiu
DepartmentofChemistry,HanshanNormalUniversity,GuangdongProvince,
ChaozhouCity521041,China
ResearchArticle
Received:6August2014,Revised:26December2014,Accepted:13January2015,PublishedonlineinWileyOnlineLibrary
(wileyonlinelibrary.com)DOI:10.1002/poc.3421
J.Phys.Org.Chem.2015Copyright?2015JohnWiley&Sons,Ltd.
cycloaddition.
[37–41]
B3LYPactivationbarriersarehigherthanM06-2X
resultsbyafewkcal/mol.
[41]
TheM06-2Xmethodwasemployedat
the6-31G(d)basissetlevelinthecurrentwork.Allthecalculations
wereperformedbytheGaussian09suiteofprograms.
[42]
(E)-1-X-BDs
and2-X-BDs,1-X-CPsand2-X-CPs,α-X-furansandβ-X-furans,α-X-
pyrolesandβ-X-pyroles(X?OH,OCH
3
,CH
3
,CH?CH
2
,H,Cl,CHO,CF
3
,
CNandNO
2
)werefullyoptimizedtoobtaintheirstablegeometries.
Thesecommonsubstituentswerechosenprimarilybasedontherange
oftheirelectroniceffectsquanti?edbyHammettconstantsσ
p
[43]
and
withrelativelylessstericeffects.ThegeometriesofconcertedTSswere
optimizedbyusingtheBernyalgorithm.Eachofthegeometrieswas
con?rmedbyfrequencyanalysistohaveoneornoneofimaginaryfre-
quency.Incaseofmorethanonestableconformerbyrotationofthe
C–Xbond,themoststableonewasusedtocalculatetheactivation
energy.
RESULTSANDDISCUSSION
TheGibbsfreeenergiesat298.15Kand1atmfordienes,
dienophilesandtheirconcertedTSsarecollectedinTableS-
1~8.FreeenergyofactivationΔG
act
isde?nedasthefreeenergy
differencebetweentheTSandthereactantsdienophileanddi-
ene.However,for(E)-1-X-BDsand2-X-BDs,ΔG
act
andΔG′
act
are
calculatedrespectivelyasthefollowing:
ΔG
act
?GTSeTC0GdienophileeTC0Gdieneins-transeT
ΔG’
act
?GTSeTC0GdienophileeTC0Gdieneins-ciseT
Foranacyclicdiene,thes-transconformationneedtotrans-
formintothes-cisform(alsocalleds-gauche)toparticipatein
theconcertedcycloaddition.
[17,44]
Reactionsof(E)-1-X-butadienesand2-X-butadienes
ActivationenergiesΔG
act
andΔG′
act
ofthereactionsof(E)-1-X-
BDsand2-X-BDsarecalculatedseparatelywithrespecttoexo
andendoTSsandlistedinTable1.
Inthereactionsof(E)-1-X-BDsandMA,ΔG
act
(exo)ranges
from20.38to29.73kcal/molandΔG
act
(endo)isfrom18.48to
27.70kcal/mol.Obviously,thesubstitutionhasastrongin?u-
enceonthereactivity.BothΔG
act
(exo)andΔG
act
(endo)in-
creasewithanincreaseofHammettconstantσ
p
inagood
linearcorrelation(Fig.1):
ΔG
act
exoeT?7:27σ
p
t24:83;R
2
?0:9299
ΔG
act
endoeT?6:72σ
p
t22:65;R
2
?0:9073
Itisdemonstratedthatthereactionisfavoredbyan
electron-donatinggroup(EDG)onthediene.Thetrendhas
beencon?rmedforalongtime.
[7,25]
Accordingtotheclassi?-
cationofD–Areactions,
[45]
theyarethenormalelectron
demand.
ΔG′
act
revealstheactualenergybarrierofcycloadditionby
separatings-trans→s-cistransformationenergyfromΔG
act
.The
transformationenergiesareca.3kcal/molfor(E)-1-X-BDs,differ-
entslightlyfromeachother.ThevariationsofΔG′
act
withσ
p
are
almostparalleledtothoseofΔG
act
.
Assumedthatthereactionsarekineticallycontrolled,the
endo–exoselectivityisjudgeddirectlyfromthedifferenceof
ΔG
act
(exo)andΔG
act
(endo)(ΔG
act
(exo-endo)),whichisequalto
Table1.ActivationfreeenergiesΔG
act
andΔG′
act
(inparen-
theses)intheD–Areactionsof(E)-1-X-BDsand2-X-BDswith
MAbytheM06-2X/6-31G(d)method(kcal/mol)
X(E)-1-X-BD2-X-BD
(σ
p
)ExoEndoExoWndo
OH20.3818.4825.5422.72
(C00.37)(17.74)(15.84)(22.98)(20.16)
OCH
3
23.7921.2526.5823.27
(C00.27)(21.07)(18.53)(24.07)(20.77)
CH
3
24.0321.9525.1622.12
(C00.17)(21.30)(19.21)(22.72)(19.68)
Vi24.5022.9922.9020.36
(C00.04)(22.30)(20.79)(22.90)(20.36)
H25.0222.6525.0222.65
(0.00)(22.62)(20.25)(22.62)(20.25)
Cl27.5025.4925.9225.20
(0.23)(24.85)(22.85)(23.66)(22.94)
CHO27.6825.3124.0422.01
(0.42)(24.80)(22.44)(23.86)(21.83)
CF
3
29.0725.5925.1524.78
(0.54)(26.32)(22.84)(23.74)(23.37)
CN29.5827.7026.4525.96
(0.66)(26.69)(24.80)(23.71)(23.22)
NO
2
29.7327.0223.0022.69
(0.78)(26.76)(24.05)(24.15)(23.84)
Figure1.PlotofΔG
act
versusσ
p
inthereactionsof(E)-1-X-butadienes
withmaleicanhydride
Chart1.
Y.QIU
wileyonlinelibrary.com/journal/pocCopyright?2015JohnWiley&Sons,Ltd.J.Phys.Org.Chem.2015
therelativestabilityoftheexoandendoTSs.Forall(E)-1-X-BDs,
thereactionsareendo-selectiveinsomedegreeandthereisno
obvioustrendfortheendo–exoselectivityresultingfromdonat-
ingorwithdrawingabilityofsubstituents.FortheparentBD,the
exoandendoTSsresultinasamecycloadduct,butΔG
act
(endo)
islessthanΔG
act
(exo)by2.37kcal/mol.Ithasbeenfoundprevi-
ouslythatthereactionofdeuterium-labeledBDwithMAreveals
an85/15preferenceforendoadducts(ΔG
act
(exo-endo)
~1.2kcal/mol).
[46]
Inthereactionsof2-X-BDsandMA,ΔG
act
(exo)andΔG
act
(endo)almosthavenocorrelationwithσ
p
.However,forΔG′
act
(exo)andΔG′
act
(endo),thecorrelationsbecomemuchbetterin
quality,indicatingthattheelectronicfactorofsubstituentplays
asigni?cantroleactuallyduringthecycloadditionprocess.Both
ΔG′
act
(exo)andΔG′
act
(endo)increasewithanincreaseofσ
p
at
relativelysmallrates(Fig.2):
ΔG’
act
exoeT?0:849σ
p
t23:291;R
2
?0:3586
ΔG’
act
endoeT?3:5207σ
p
t21:016;R
2
?0:8219
Transformationofs-trans→s-cisisquitedifferentinenergy
for2-X-BDs,whichisresponsibleforpoorcorrelationsof
ΔG
act
(exo)andΔG
act
(endo)withσ
p
.For2-vi-BD,themoststa-
bleconformationis(s-cis,s-trans)amongthreeconformations
(theothertwoare(s-trans,s-trans)and(s-cis,s-cis)).Itcanpar-
ticipateinthecycloadditiondirectlywithoutthetransforma-
tion.Therefore,ΔG
act
isequaltoΔG′
act
.For2-NO
2
-BD,thes-
cisformismorestablethanthes-trans.So,ΔG
act
iseven
smallerthanΔG′
act
.
TheΔG
act
(exo-endo)valuesindicatethatthereactionsare
endo-selectivewithallsubstituents.Theendopreferenceis
moresigni?cantwithaEDGonthedieneandthecorelation
resultis
ΔG
act
exoC0endoeT?C02:6717σ
p
t2:2754;R
2
?0:8221
Reactionsof1-X-CPsand2-X-CPswithMA
For1-X-CPs,ΔG
act
(exo)isintherangefrom15.52to26.02kcal/
molandΔG
act
(endo)isfrom15.68to23.88kcal/mol(Table2).
AnEDGonthedieneisinfavorofthereaction,namelyboth
ΔG
act
(exo)andΔG
act
(endo)increasewithanincreaseofσ
p
.Their
correlationsareexcellentinquality(Fig.3):
ΔG
act
exoeT?8:06σ
p
t20:46;R
2
?0:9169
ΔG
act
endoeT?6:74σ
p
t18:58;R
2
?0:9416
Theendoperferenceissigni?cantforallsubstituentsexcept
forX?OH.However,theelectronicfactorshowsapoorcorrela-
tionwiththeendo–exoselectivitytrend.ForunsubstitutedCP,
ΔG
act
(endo)is2.07kcal/mollessthanΔG
act
(exo),whichmeans
anoverestimatedendopreferencecomparedwiththeexperi-
mentalresults.
[17,46]
ΔG
act
(endo)forX?OHisobviouslydeviated
fromthetrendlineandresultsinaslightexopreference(ΔG
act
(exo-endo)C00.15kcal/mol).ByexaminingtheexoTSstructure,
itisfoundthathydroxygroupisgauchetowardMAwithadihe-
dralangleC
2
?C
1
–O–H151.8°andthedistancebetweenHatom
inC0OHandOatominC?Ois1.991?.Thegeometrysuggests
thatahydrogenbondinteractionispresentbetweenthediene
anddienophileunits,whichmaycontributeanadditionalstabili-
zationtotheexoTS.Incontrast,suchinteractionisnotfoundin
theendoTS.
Figure2.PlotofΔG′
act
versusσ
p
inthereactionsof2-X-butadieneswith
maleicanhydride
Table2.ActivationenergiesΔG
act
intheD–Areactionsof1-
X-CPsand2-X-CPswithMAtheM06-2X/6-31G(d)method
(kcal/mol)
X1-X-CP2-X-CP
ExoEndoExoEndo
OH15.5215.6819.7516.84
OCH
3
19.1215.9420.3417.70
CH
3
19.2717.8319.7017.41
Vi20.6619.2519.9318.63
H20.6518.5720.6518.57
Cl22.7620.6421.1321.10
CHO25.1621.5322.4321.38
CF
3
24.4321.2522.1822.66
CN26.0223.8822.8722.94
NO
2
25.4223.2223.1223.90
Figure3.PlotofΔG
act
versusσ
p
inthereactionsof1-X-
cyclopentadieneswithmaleicanhydride
DIELS–ALDERREACTIONSOFSUBSTITUTEDDIENESWITHMALEICANHYDRIDE
J.Phys.Org.Chem.2015Copyright?2015JohnWiley&Sons,Ltd.wileyonlinelibrary.com/journal/poc
Inthereactionsof2-X-CPswithMA,ΔG
act
(exo)isintherange
from19.70to23.12kcal/molandΔG
act
(endo)isfrom16.84to
22.94kcal/mol(Table2).BothE
a
(exo)andΔG
act
(endo)increase
withanincreaseofσ
p
.Theircorrelationswithσ
p
areexcellent
(Fig.4):
ΔG
act
exoeT?3:15σ
p
t20:65;R
2
?0:9245
ΔG
act
endoeT?6:27σ
p
t19:00;R
2
?0:9791
Obviously,thereactionisalsofavoredbyanEDGonthediene
ingeneral.ΔG
act
(endo)ismoresensitivelyin?uencedbythe
electroniceffectofsubstituent.Anegativecorrelationisfound
betweenΔG
act
(exo-endo)andσ
p
:
ΔG
act
exoC0endoeT?C03:13σ
p
t1:65;R
2
?0:8759
Thebalancepointofendo–exoselectivityisatσ
p
=0.52,corre-
spondingtoamoderateEWG.ThetrendpredictsthatanyEDG
mayleadtosigni?cantendoselectivitywhileonlyastrong
EWGmayhaveexoselectivity.
Reactionsofα-X-furansandβ-X-furanswithMA
Forα-X-furans,ΔG
act
(exo)variesfrom17.03to30.96kcal/moland
ΔG
act
(endo)isfrom20.56to29.48kcal/mol(Table3).Correlation
withσ
p
resultsin(Fig.5):
ΔG
act
exoeT?9:65σ
p
t23:40;R
2
?0:8693
ΔG
act
endoeT?6:11σ
p
t24:30;R
2
?0:7736
BothΔG
act
(exo)andΔG
act
(endo)increasewithanincreasing
σ
p
,indicatingthatthereactionisalsofavoredbyanEDGon
thediene.ForthereactionofunsubstitutedfuranandMA,a
previoustheoreticalstudyshowedthattheendoTSisslightly
favoredby0.2kcal/mol,
[47]
whichisconsistenttothisstudy.
However,morerecently,aslightexoselectivitywasfoundex-
perimentallybasedonthekineticconstants.
[19]
ForX?OH,a
hydrogenbondbetweenOHandC?OintheexoTSmayalso
beresponsiblefortheabnormallylargedifferenceofΔG
act
(exo)
andΔG
act
(endo)aliketothereactionofα-OH-CP.Correlationof
ΔG
act
(exo-endo)withσ
p
tendstobepositivebutpoorin
quality.
Forβ-X-furans,ΔG
act
(exo)variesfrom21.25to27.92kcal/mol
andΔG
act
(endo)isfrom19.50to29.73kcal/mol(Table3).Corre-
lationwithσ
p
resultsin(Fig.6):
ΔG
act
exoeT?5:36σ
p
t23:46;R
2
?0:8801
ΔG
act
endoeT?8:36σ
p
t23:24;R
2
?0:9502
ΔG
act
(exo)andΔG
act
(endo)increasewithanincreaseofσ
p
,
andso,thereactionisfavoredbyanEDGonthediene.Like
thereactionsof2-X-BDsand2-X-CPs,thereisanegativecorrela-
tioninagoodqualitybetweenΔG
act
(exo-endo)andσ
p
forβ-X-
furans:
ΔG
act
exoC0endoeT?C03:00σ
p
t0:22;R
2
?0:8401
Theendo–exobalancepointisclosetotheparentfuran
(σ
p
=0).Therefore,astrongelectronicdonatingorwithdraw-
ingsubstituentmayresultinsigni?cantendoorexo
preference.
Figure4.PlotofΔG
act
versusσ
p
inthereactionsof2-X-
cyclopentadieneswithmaleicanhydride
Table3.ActivationenergiesΔG
act
intheD–Areactionsofof
MAwithα-X-furansandβ-X-furansbytheM06-2X/6-31G(d)
method(kcal/mol)
X1-X-furan2-X-furan
ExoEndoExoEndo
OH17.0322.3721.2520.27
OCH
3
20.6420.5621.5119.50
CH
3
22.1924.9223.3422.25
Vi25.1124.1922.8423.19
H24.2324.1924.2324.19
Cl26.4425.2724.4825.50
CF
3
27.8225.9824.5726.45
CN30.9629.4827.6729.15
CHO27.9928.8626.3127.05
NO
2
28.7528.0927.9229.73
Figure5.PlotofΔG
act
versusσ
p
inthereactionsofα-X-furanswithma-
leicanhydride
Y.QIU
wileyonlinelibrary.com/journal/pocCopyright?2015JohnWiley&Sons,Ltd.J.Phys.Org.Chem.2015
Reactionsofα-X-pyrolesandβ-X-pyroleswithMA
Inthereactionsofα-X-pyroles,ΔG
act
(exo)rangesfrom18.04to
34.43kcal/molandΔG
act
(endo)isfrom23.30to34.89kcal/mol
(Table4).Theircorrelationswithσ
p
resultin(Fig.7):
ΔG
act
exoeT?12:09σ
p
t25:77;R
2
?0:8519
ΔG
act
endoeT?9:37σ
p
t27:71;R
2
?0:8512
BothΔG
act
(exo)andΔG
act
(endo)increasewithanincrease
ofσ
p
,andso,thereactionisfavoredbyanEDGinthediene.
Fortheparentandα-substitutedpyroles,thereactionsareal-
waysexo-selectiveindifferentdegrees.Theabnormallylarge
magnitudeofΔG
act
(exo-endo)forX?OH(over5kcal/mol)
mayalsocomefromanadditionalstabilizationofhydrogen
bondbetweenOHandC?OintheexoTS.Correlationof
ΔG
act
(exo-endo)withσ
p
tendstobepositivebutpoorin
quality.
Inthereactionsofβ-X-pyroles,ΔG
act
(exo)rangesfrom21.70to
30.88kcal/molandΔG
act
(endo)isfrom22.34to35.40kcal/mol
(Table4).Correlationwithσ
p
resultsin(Fig.8):
ΔG
act
exoeT?7:85σ
p
t25:02;R
2
?0:9060
ΔG
act
endoeT?10:49σ
p
t27:12;R
2
?0:9558
BothΔG
act
(exo)andΔG
act
(endo)increasewithanincreaseof
σ
p
,andso,thereactionisfavoredbyanEDGsubstituenton
thediene.Fortheparentandninesubstituteddienes,allreac-
tionsareexo-selective.Formostofthem,thepreferenceisquite
strong.Similartotheotherβ-substituteddienes,agoodnegative
correlationisfoundbetweenΔG
act
(exo-endo)andσ
p
:
ΔG
act
exoC0endoeT?C02:63σ
p
C02:10;R
2
?0:8052
Therelativestabilityofexoandendoalsodecreaseswithan
increasingσ
p
.Theendo–exobalancepointisatσ
p
=C00.80,
whichiscorrespondingtoanextremelystrongEDGandoutof
therangeofsubstituentsconsideredhere.Therefore,although
trendisapprovedthattheendoTSismorefavoredbyanEDG,
itispredictedthatthereactionsshouldremainexo-selective
forcommonsubstitutedpyroles.
Table4.ActivationenergiesΔG
act
intheD–Areactionsofα-
X-pyrolesandβ-X-pyroleswithMAbytheM06-2X/6-31G(d)
method(kcal/mol)
Xα-X-pyroleβ-X-pyrole
ExoEndoExoEndo
OH18.0423.7921.9323.44
OCH
3
22.1823.3021.7022.34
CH
3
25.2227.1324.7426.14
Vi27.3728.9224.4927.24
H26.2928.1126.2928.11
Cl28.2129.0826.5729.61
CHO34.1134.1428.8431.75
CF
3
29.9130.1027.1831.50
CN34.4334.8930.8834.35
NO
2
33.3834.3431.5235.40
Figure7.PlotofΔG
act
versusσ
p
inthereactionsofα-X-pyroleswithma-
leicanhydride
Figure8.PlotofΔG
act
versusσ
p
inthereactionsofβ-X-pyrolesandma-
leicanhydride
Figure6.PlotofΔG
act
versusσ
p
inthereactionsofβ-X-furanswithma-
leicanhydride
DIELS–ALDERREACTIONSOFSUBSTITUTEDDIENESWITHMALEICANHYDRIDE
J.Phys.Org.Chem.2015Copyright?2015JohnWiley&Sons,Ltd.wileyonlinelibrary.com/journal/poc
Thestrengthofsubstituenteffectonthereactivity
Theforegoingresultshaveindicatedthatwemayhaveagood
predictionbytheelectroniceffectofsubstituentfromthehighly
correlationofΔG
act
orΔG′
act
withσ
p
foreachsetofreactions.It
hasfoundpreviously
[48]
thattheexperimentalreactivityofthe
D–Areactionishighlyrelatedwiththechargetransfer(CT)be-
tweenthedieneanddienophileunitsintheTS.Forthereac-
tionshere,theelectrontransferdirectionisfromthedieneto
MA.AnEDGonthedieneishelpfultotheCTandthenlower
ΔG
act
orΔG′
act
whileanEWGhasanoppositeeffect.ΔG
act
or
ΔG′
act
hasagoodcorrelationwiththeCTforeachsetofreac-
tions(datanotshown).Therefore,themechanismissupported
thattheelectroniceffectofsubstituentworksbyin?uencing
theCTintheTS.
Accordingtothefrontiermolecularorbital(FMO)andpertur-
bationtheory,highestoccupiedmolecularorbital–lowestunoc-
cupiedmolecularorbital(HOMO–LUMO)interactionsbetween
thedieneanddienophilecontributetolowertheactivationen-
ergyintheD–Areaction.
[49,50]
TheHOMOandLUMOenergies
ofthedieneslinearlycorrelateinsomedegreewithΔG
act
or
ΔG′
act
foreachsetofreactions(datanotshown,similartrends
werefoundpreviously).
[44]
Theelectrophilicityindexωisanotherindexappliedinthe
quantitativeanalysisforD–Areactionsintherecentyears.
[48,51–
53]
Itisameasureofreactant’selectrophilicpowerdeveloped
in1999byParretal.
[54]
andhasbeenfoundtobehighlycorre-
latedwithreactivityandbioactivity.
[55–57]
Theelectrophilicityin-
dexωiscalculatedbythefollowingequation:
ω?μ
2
=2ηeVeT
wheretheelectronicchemicalpotential
[58–61]
μ≈(E(HOMO)+E
(LUMO))/2andthechemicalhardness
[62]
η≈(E(LUMO)C0E
(HOMO).Itisfoundthattheelectrophilicityindicesofthedienes
alsolinearlycorrelateinsomedegreewithΔG
act
(exo)orΔG
act
(endo)(forsubstitutedBDs,ΔG′
act
isused)respectivelyineach
setofreactions(datanotshown).
Here,wearemoreinterestedtoexploreifanyfactorisrelated
withthestrengthofreactivityeffect,whichisquanti?edbythe
slope(ρ)of?ttinglinefromthelinearcorrelationofΔG
act
with
σ
p
.Obviously,itisapprovedthatC1substitutiongenerallyhas
alargerreactivityeffectthanC2substitution.Therulecanbede-
rivedfromearlyexperimentaldatawithsubstitutedBDsand
CPs.
[25]
Ingeneral,thestrengthorderfortheseparentdienesis
pyroles>furans>CPs>BDs.
TheHOMOandLUMOenergies,aswellastheirderivedindi-
ces:η,μandω,areusedasdescriptorstoanalyzequantitatively
variationoftheslopesρwithfourparentdienes.Thevaluesof
theseindicesarelistedinTable5.Thecorrelationresultsofthe
slopesρwiththeseindicesaresummarizedinTable6.
AccordingtotheFMOtheory,forthesenormalelectronde-
mandD–Areactions,theinteractionofHOMO
diene
andLUMO
MA
isdominant.Theirenergygapissmaller,thestrongerthesubstit-
uenteffect.
[7]
Thetrendnodoubtiscon?rmedbyourresults.
However,thedominantinteractiondoesnotmeanagoodpre-
diction.Thecorrelationqualityofthereactivityeffectstrength
(ρ)withHOMOenergiesoftheparentdienesisfarfromdesirable
(theaverageR
2
0.6687).Thecorrelationisalsonotgoodforη(R
2
0.6037intheaverage).Itbecomesquitegoodorevenextremely
excellentforΕ(LUMO),μandω(R
2
0.8561,0.9019and0.8791re-
spectivelyintheaverage).Especially,thestrengthofreactivity
effectatC2substitutionmaybewellpredictedfromthethreein-
dicesoftheparentdiene(Table6).
CONCLUSIONS
Basedontheactivationenergiescalculated,thesubstituentef-
fectsonthereactivityandendo–exoselectivityhavebeeninves-
tigatedfortheD–Areactionsofsubstituteddieneswithmaleic
anhydride.Themainconclusionsincludethefollowing:
EachsetofthereactionsisfavoredbyanEDGsubstituentand
disfavoredbyanEWGonthediene.Allofthemarethenormal
electrondemandD–Areactions.However,thesubstituenteffect
onthereactivityisdifferentinstrength,dependingonthesub-
stitutionpositionandtheparentdiene.Ingeneral,C1substitu-
tionisstrongerthanC2substitutionwithasameparentdiene.
Thestrengthhasanorderofpyroles>furans>CPs>BDs.Itis
highlycorrelatedwiththeLUMOenergy,theelectronicchemical
potentialandtheelectrophilicityofparentdienewhereasless
correlatedwiththeHOMOenergyandthechemicalhardness.
WithC1subsitution,theendoselectivityisdemonstratedfor
allBDsandamajorityofCPs.Theendoorexoselectivityisfound
fordifferentfuranswhiletheexoselectivityalwaysremains
Table5.Ε(ΗΟΜΟ),Ε(LUΜΟ),η,μandωoftheparentdienes
(eV)
DieneΕ(ΗΟΜΟ)Ε(LUΜΟ)ημω
BD(s-cis)C07.810.568.37C03.620.78
CPC07.240.828.06C03.210.64
FuranC07.551.789.32C02.890.45
PyroleC06.912.599.51C02.160.25
MAC010.12C02.028.10C06.072.27
Table6.Correlationresultsofthestrengthofreactivityef-
fect(ρ)withE(HOMO),E(LUMO),η,μandωoftheparent
dienes
ρsourceFittinglineR
2
C1-exoρ=4.65E(HOMO)+43.510.6494
ρ=2.37E(LUMO)+5.770.9809
ρ=2.72ηC014.840.7451
ρ=3.59μ+19.860.9932
ρ=C09.47ω+14.190.9878
C1-endoρ=3.30E(HOMO)+31.490.7236
ρ=1.20E(LUMO)+5.420.5597
ρ=1.10ηC02.560.2701
ρ=2.01μ+13.110.6861
ρ=C04.76ω+9.670.5523
C2-exoρ=6.25E(HOMO)+50.420.6481
ρ=3.15E(LUMO)C00.240.9589
ρ=3.60ηC027.460.7206
ρ=4.79μ+18.540.9760
ρ=C012.78ω+11.070.9960
C2-endoρ=6.22E(HOMO)+53.070.6536
ρ=3.07E(LUMO)+2.740.9249
ρ=3.47ηC023.410.6789
ρ=4.69μ+21.100.9522
ρ=C012.57ω+13.810.9803
Y.QIU
wileyonlinelibrary.com/journal/pocCopyright?2015JohnWiley&Sons,Ltd.J.Phys.Org.Chem.2015
unchangedforallpyroles.Forfuransandpyroles,thetrendap-
pearsthattheendoTSismorefavoredbyanEWGandtheexo
TSismorefavoredbyanEDG,butthecorrelationqualityis
unsatisfatory.
WithC2substitution,theselectivityisendoforallBDsand
shiftsfromendotoexowhenthesubstituentischangedfrom
EDGtoEWGforCPsandfurans.Theexoselectivityisfoundfor
allpyroles.ForallfoursetsofC2-substituteddienes,thetrend
thattheendoTSismorefavoredbyanEDGhasagoodcorrela-
tionquality.
Ourresultsindicatethattheinferencethatanincreaseof
necleophilicitycausedbyanEDGonthedienefavorstheendo
TSiseffectiveonlywithC2substitution.WithC1substitution,
thetrendisambiguousorevenopposite.
Theelectroniceffectofsubstituentexitsthemostuniversally
andintrinsicallyamongpossiblein?uencingfactorswhensubsti-
tutiononaspeci?cdiene-dienophilesystemisconsidered.We
supposethatthisstudymaybehelpfultofurtherunderstand
andapplytheD–Areaction.
Acknowledgements
Theauthorisgratefulfor?nancialsupportfromHanshanNormal
University(GeneralResearchProgram).
REFERENCES
[1]O.Diels,K.Alder,JustusLiebigsAnn.Chem.1928,460,98.
[2]J.Sauer,R.Sustmann,Angew.Chem.Int.Ed.Engl.1980,19,779.
[3]M.J.Dewar,S.Olivella,J.J.Stewart,J.Am.Chem.Soc.1986,108,
5771.
[4]K.Houk,Y.T.Lin,F.K.Brown,J.Am.Chem.Soc.1986,108,554.
[5]R.D.Bach,J.J.McDouall,H.B.Schlegel,G.J.Wolber,J.Org.Chem.
1989,54,2931.
[6]K.N.Houk,J.Gonzalez,Y.Li,Acc.Chem.Res.1995,28,81.
[7]F.A.Carey,R.J.Sundberg,AdvancedOrganicChemistry:PartA:Struc-
tureandMechanism,5thed.,Springer,NewYork,2007.
[8]K.Alder,G.Stein,Angew.Chem.1937,50,510.
[9]K.Alder,JustusLiebigsAnn.Chem.1951,571,157.
[10]R.Hoffmann,R.B.Woodward,J.Am.Chem.Soc.1965,87,4388.
[11]K.Houk,TetrahedronLett.1970,11,2621.
[12]A.Arrieta,F.P.Cossio,B.Lecea,J.Org.Chem.2001,66,6178.
[13]C.S.Wannere,A.Paul,R.Herges,K.N.Houk,H.F.SchaeferIII,P.V.R.
Schleyer,J.Comput.Chem.2007,28,344.
[14]Y.Apeloig,E.Matzner,J.Am.Chem.Soc.1995,117,5375.
[15]M.Imade,H.Hirao,K.Omoto,H.Fujimoto,J.Org.Chem.1999,64,
6697.
[16]M.Sodupe,R.Rios,V.Branchadell,T.Nicholas,A.Oliva,J.J.
Dannenberg,J.Am.Chem.Soc.1997,119,4232.
[17]J.G.Martin,R.K.Hill,Chem.Rev.1961,61,537.
[18]J.Furukawa,Y.Kobuke,T.Fueno,J.Am.Chem.Soc.1970,92,6548.
[19]L.Rulí?ek,P.?ebek,Z.Havlas,et.al.,J.Org.Chem.2005,70,6295.
[20]Y.Lam,P.H.Cheong,J.M.BlascoMata,S.J.Stanway,V.Gouverneur,
K.N.Houk,J.Am.Chem.Soc.2009,131,1947.
[21]J.I.García,J.A.Mayoral,L.Salvatella,Acc.Chem.Res.2000,33,658.
[22]G.Gayatri,G.N.Sastry,J.Phys.Chem.A2009,113,12013.
[23]C.Chiappe,M.Malvaldi,C.S.Pomelli,J.Chem.TheoryComput.2009,
6,179.
[24]J.I.García,J.A.Mayoral,L.Salvatella,Tetrahedron1997,53,6057.
[25]D.Craig,J.J.Shipman,R.B.Fowler,J.Am.Chem.Soc.1961,83,2885.
[26]M.J.Dewar,A.B.Pierini,J.Am.Chem.Soc.1984,106,203.
[27]M.C.Kloetzel,TheDiels-AlderReactionwithMaleicAnhydride,John
Wiley&Sons,Inc.,HobokenNJ,2004.
[28]Y.W.Goh,B.R.Pool,J.M.White,J.Org.Chem.2008,73,151.
[29]A.D.Becke,J.Chem.Phys.1993,98,1372.
[30]W.Kohn,A.D.Becke,R.G.Parr,J.Phys.Chem.1996,100,12974.
[31]T.C.Dinadayalane,R.Vijaya,A.Smitha,G.N.Sastry,J.Phys.Chem.A
2002,106,1627.
[32]M.Linder,T.Brinck,Phys.Chem.Chem.Phys.2013,15,5108.
[33]S.M.Bakalova,J.Kaneti,J.Phys.Chem.A2008,112,13006.
[34]S.M.Bakalova,A.G.Santos,J.Org.Chem.2004,69,8475.
[35]G.O.Jones,V.A.Guner,K.Houk,J.Phys.Chem.A2006,110,1216.
[36]S.N.Pieniazek,F.R.Clemente,K.N.Houk,Angew.Chem.-Int.Edit.
2008,47,7746.
[37]S.Osuna,J.Morera,M.Cases,K.Morokuma,M.Solà,J.Phys.Chem.A
2009,113,9721.
[38]R.S.Paton,S.Kim,A.G.Ross,S.J.Danishefsky,K.Houk,Angew.
Chem.-Int.Edit.2011,50,10366.
[39]R.S.Paton,J.L.Mackey,W.H.Kim,J.H.Lee,S.J.Danishefsky,K.N.
Houk,J.Am.Chem.Soc.2010,132,9335.
[40]S.E.Wheeler,A.J.McNeil,P.Müller,T.M.Swager,K.N.Houk,J.Am.
Chem.Soc.2010,132,3304.
[41]K.Black,P.Liu,L.Xu,C.Doubleday,K.N.Houk,Proc.Natl.Acad.Sci.
U.S.A.2012,109,12860.
[42]M.J.Frisch,G.W.Trucks,H.B.Schlegel,G.E.Scuseria,M.A.Robb,J.
R.Cheeseman,G.Scalmani,V.Barone,B.Mennucci,G.A.Petersson,
H.Nakatsuji,M.Caricato,X.Li,H.P.Hratchian,A.F.Izmaylov,J.
Bloino,G.Zheng,J.L.Sonnenberg,M.Hada,M.Ehara,K.Toyota,
R.Fukuda,J.Hasegawa,M.Ishida,T.Nakajima,Y.Honda,O.Kitao,
H.Nakai,T.Vreven,J.J.A.Montgomery,J.E.Peralta,F.Ogliaro,M.
Bearpark,J.J.Heyd,E.Brothers,K.N.Kudin,V.N.Staroverov,R.
Kobayashi,J.Normand,K.Raghavachari,A.Rendell,J.C.Burant,S.
S.Iyengar,J.Tomasi,M.Cossi,N.Rega,J.M.Millam,M.Klene,J.E.
Knox,J.B.Cross,V.Bakken,C.Adamo,J.Jaramillo,R.Gomperts,R.
E.Stratmann,O.Yazyev,A.J.Austin,R.Cammi,C.Pomelli,J.W.
Ochterski,R.L.Martin,K.Morokuma,V.G.Zakrzewski,G.A.Voth,
P.Salvador,J.J.Dannenberg,S.Dapprich,A.D.Daniels,O.Farkas,
J.B.Foresman,J.V.Ortiz,J.Cioslowski,D.J.Fox,RevisionA,02ed.,
Gaussian,Inc.,WallingfordCT,2009.
[43]C.Hansch,A.Leo,R.Taft,Chem.Rev.1991,91,165.
[44]R.Robiette,J.Marchand-Brynaert,D.Peeters,J.Org.Chem.2002,67,
6823.
[45]X.Jiang,R.Wang,Chem.Rev.2013,113,5515.
[46]L.M.Stephenson,D.E.Smith,S.P.Current,J.Org.Chem.1982,47,
4170.
[47]S.Calvo-Losada,D.Suárez,J.Am.Chem.Soc.2000,122,390.
[48]L.R.Domingo,J.A.Sáez,Org.Biomol.Chem.2009,7,3576.
[49]R.Sustmann,PureAppl.Chem.1974,40,569.
[50]K.N.Houk,Acc.Chem.Res.1975,8,361.
[51]L.R.Domingo,M.J.Aurell,P.Pérez,R.Contreras,Tetrahedron2002,
58,4417.
[52]L.R.Domingo,E.Chamorro,P.Perez,J.Phys.Chem.A2008,112,
4046.
[53]Y.Xia,D.Yin,C.Rong,Q.Xu,D.Yin,S.Liu,J.Phys.Chem.A2008,112,
9970.
[54]R.G.Parr,L.v.Szentpály,S.Liu,J.Am.Chem.Soc.1999,121,1922.
[55]P.K.Chattaraj,U.Sarkar,D.R.Roy,Chem.Rev.2006,106,2065.
[56]P.K.Chattaraj,D.R.Roy,Chem.Rev.2007,107,PR46.
[57]P.K.Chattaraj,S.Giri,S.Duley,Chem.Rev.2011,111,PR43.
[58]R.G.Parr,L.J.Bartolotti,J.Am.Chem.Soc.1982,104,3801.
[59]R.G.Parr,L.J.Bartolotti,J.Phys.Chem.1983,87,2810.
[60]R.G.Parr,W.Yang,J.Am.Chem.Soc.1984,106,4049.
[61]C.Pérez-Méndez,P.Fuentealba,R.Contreras,J.Chem.Theory
Comput.2009,5,2944.
[62]G.Makov,J.Phys.Chem.1995,99,9337.
SUPPORTINGINFORMATION
Additionalsupportinginformationmaybefoundintheonline
versionofthisarticleatthepublisher’swebsite
DIELS–ALDERREACTIONSOFSUBSTITUTEDDIENESWITHMALEICANHYDRIDE
J.Phys.Org.Chem.2015Copyright?2015JohnWiley&Sons,Ltd.wileyonlinelibrary.com/journal/poc
|
|
