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Chapter8
NucleophilicSubstitution8.1
FunctionalGroup
TransformationByNucleophilic
SubstitutionY:–RXYR++:X–nucleophileisaLewisbase(electron-pairdonor)oftennegativelychargedandusedas
Na+orK+saltsubstrateisusuallyanalkyl
halide
NucleophilicSubstitutionSubstratecannotbeanavinylichalideoranarylhalide,exceptundercertainconditionstobediscussedinChapter23.XCCXNucleophilicSubstitution+RXgivesanetherAlkoxideionasthenucleophile..O:..R'–+:XR..O..R'–Table8.1ExamplesofNucleophilicSubstitution(CH3)2CHCH2ONa+CH3CH2BrIsobutylalcohol(CH3)2CHCH2OCH2CH3+NaBrEthylisobutylether(66%)Example+RXgivesanesterCarboxylateionasthenucleophile..O:..R'C–+:XR..O..R'C–OOTable8.1ExamplesofNucleophilicSubstitutionOK+CH3(CH2)16CCH3CH2Iacetone,water+KIOCH2CH3CH3(CH2)16CEthyloctadecanoate(95%)OOExample+RXgivesathiolHydrogensulfideionasthenucleophile..S:..H–+:XR..S..H–Table8.1ExamplesofNucleophilicSubstitutionKSH+CH3CH(CH2)6CH3Brethanol,water+KBr2-Nonanethiol(74%)CH3CH(CH2)6CH3SHExample+RXgivesanitrileCyanideionasthenucleophile–+:XR–CN::CN:Table8.1ExamplesofNucleophilicSubstitutionDMSOCyclopentylcyanide(70%)BrNaCN+CN+NaCNExample+RXgivesanalkylazideAzideionasthenucleophile+:XR–..–NNN..::–+..NNN..:–+Table8.1ExamplesofNucleophilicSubstitutionNaN3+CH3CH2CH2CH2CH2I2-Propanol-waterCH3CH2CH2CH2CH2N3+NaIPentylazide(52%)Example+RXgivesanalkyliodideIodideionasthenucleophile+:XR––..:I....:I..:Table8.1ExamplesofNucleophilicSubstitutionNaIissolubleinacetone;
NaClandNaBrarenot
solubleinacetone.acetone+NaICH3CHCH3Br63%+NaBrCH3CHCH3IExample8.2
RelativeReactivityofHalideLeavingGroupsRIRBrRClRFmostreactiveleastreactiveGeneralizationReactivityofhalideleavinggroupsinnucleophilicsubstitutionisthesameasforelimination.BrCH2CH2CH2Cl+NaCNAsingleorganicproductwasobtainedwhen
1-bromo-3-chloropropanewasallowedtoreact
withonemolarequivalentofsodiumcyanidein
aqueousethanol.Whatwasthisproduct?BrisabetterleavinggroupthanClProblem8.2BrCH2CH2CH2Cl+NaCNAsingleorganicproductwasobtainedwhen
1-bromo-3-chloropropanewasallowedtoreact
withonemolarequivalentofsodiumcyanidein
aqueousethanol.Whatwasthisproduct?CH2CH2CH2Cl+NaBrCN:Problem8.28.3
TheSN2MechanismofNucleophilicSubstitutionManynucleophilicsubstitutionsfollowa
second-orderratelaw.
CH3Br+HO–
ÆCH3OH+Br–
rate=k[CH3Br][HO–]
inference:rate-determiningstepisbimolecularKineticsHO–CH3Br+HOCH3Br–+onestep
concerted
BimolecularmechanismHO–CH3Br+HOCH3Br–+onestep
concerted
BimolecularmechanismHO–CH3Br+HOCH3Br–+onestep
concertedHOCH3Brd-d-transitionstate
Bimolecularmechanism8.4
StereochemistryofSN2ReactionsNucleophilicsubstitutionsthatexhibit
second-orderkineticbehaviorare
stereospecificandproceedwith
inversionofconfiguration.Generalizationnucleophileattackscarbon
fromsideoppositebond
totheleavinggroupInversionofConfigurationnucleophileattackscarbon
fromsideoppositebond
totheleavinggroupthree-dimensional
arrangementofbondsin
productisoppositeto
thatofreactantInversionofConfigurationAstereospecificreactionisoneinwhich
stereoisomericstartingmaterialsgive
stereoisomericproducts.Thereactionof2-bromooctanewithNaOH
(inethanol-water)isstereospecific.
(+)-2-BromooctaneÆ(–)-2-Octanol
(–)-2-BromooctaneÆ(+)-2-OctanolStereospecificReactionCHCH3BrCH3(CH2)5CHCH3HO(CH2)5CH3NaOH(S)-(+)-2-Bromooctane(R)-(–)-2-OctanolStereospecificReactionTheFischerprojectionformulafor(+)-2-bromooctane
isshown.WritetheFischerprojectionofthe
(–)-2-octanolformedfromitbynucleophilicsubstitution
withinversionofconfiguration.Problem8.4HBrCH3CH2(CH2)4CH3TheFischerprojectionformulafor(+)-2-bromooctane
isshown.WritetheFischerprojectionofthe
(–)-2-octanolformedfromitbynucleophilicsubstitution
withinversionofconfiguration.HOHCH3CH2(CH2)4CH3Problem8.48.5
HowSN2ReactionsOccur:BrCH....–....HOCH3(CH2)5H3C:BrCH....–....HOCH
Brd–....HO:....d–CH3(CH2)5H3CCH3(CH2)5
CH3:BrCH....–....HOCH
Brd–....HO:....d–CHHO....–....:BrCH3(CH2)5H3C(CH2)5CH3CH3(CH2)5
CH3CH38.6
StericEffectsinSN2ReactionsTherateofnucleophilicsubstitution
bytheSN2mechanismisgoverned
bystericeffects.Crowdingatthecarbonthatbears
theleavinggroupslowstherateof
bimolecularnucleophilicsubstitution.CrowdingattheReactionSiteRBr+LiIÆRI+LiBrAlkyl Class Relative
bromide rateCH3Br Methyl 221,000CH3CH2Br Primary 1,350(CH3)2CHBr Secondary 1(CH3)3CBr Tertiary toosmall
tomeasureTable8.2ReactivitytowardsubstitutionbytheSN2mechanismCH3BrCH3CH2Br(CH3)2CHBr(CH3)3CBrDecreasingSN2ReactivityCH3BrCH3CH2Br(CH3)2CHBr(CH3)3CBrDecreasingSN2ReactivityTherateofnucleophilicsubstitution
bytheSN2mechanismisgoverned
bystericeffects.Crowdingatthecarbonadjacent
totheonethatbearstheleavinggroup
alsoslowstherateofbimolecular
nucleophilicsubstitution,butthe
effectissmaller.CrowdingAdjacenttotheReactionSiteRBr+LiIÆRI+LiBrAlkyl Structure Relative
bromide rateEthyl CH3CH2Br 1.0Propyl CH3CH2CH2Br 0.8Isobutyl (CH3)2CHCH2Br 0.036Neopentyl (CH3)3CCH2Br 0.00002Table8.3EffectofchainbranchingonrateofSN2substitution8.7
NucleophilesandNucleophilicityThenucleophilesdescribedinSections8.1-8.6
havebeenanions.....HO:–....CH3O:–....HS:––CN::etc.NucleophilesThenucleophilesdescribedinSections8.1-8.6
havebeenanions.Notallnucleophilesareanions.Manyareneutral.....HO:–....CH3O:–....HS:––CN::etc.....HOHCH3OH....NH3:forexampleNucleophilesThenucleophilesdescribedinSections8.1-8.6
havebeenanions.Notallnucleophilesareanions.Manyareneutral.Allnucleophiles,however,areLewisbases.....HO:–....CH3O:–....HS:––CN::etc.....HOHCH3OH....NH3:forexampleNucleophiles....HOHCH3OH....forexampleManyofthesolventsinwhichnucleophilicsubstitutionsarecarriedoutarethemselves
nucleophiles.NucleophilesThetermsolvolysisreferstoanucleophilicsubstitutioninwhichthenucleophileisthesolvent.Solvolysis+substitutionbyananionicnucleophileR—X+:Nu—R—Nu+:X—solvolysisR—X+:Nu—HR—Nu—H+:X—stepinwhichnucleophilic
substitutionoccursSolvolysis+substitutionbyananionicnucleophileR—X+:Nu—R—Nu+:X—solvolysisR—X+:Nu—HR—Nu—H+:X—R—Nu+HXproductsofoverallreactionSolvolysisR—X–H+Methanolysisisanucleophilicsubstitutionin
whichmethanolactsasboththesolventand
thenucleophile.Theproductisamethylether.HOCH3::+HOCH3:R+O:CH3R..Example:Methanolysissolvent productfromRX
water(HOH) ROHmethanol(CH3OH) ROCH3ethanol(CH3CH2OH) ROCH2CH3formicacid(HCOH) aceticacid(CH3COH) ROCCH3OROCHOOOTypicalsolventsinsolvolysisTable8.4comparestherelativeratesofnucleophilicsubstitutionofavarietyofnucleophilestowardmethyliodideasthesubstrate.Thestandardofcomparisonismethanol,whichisassignedarelative
rateof1.0.NucleophilicityisameasureofthereactivityofanucleophileRank Nucleophile Relative
ratestrong I-,HS-,RS- >105good Br-,HO-,
104
RO-,CN-,N3-fair NH3,Cl-,F-,RCO2- 103weak H2O,ROH 1veryweak RCO2H 10-2Table8.4Nucleophilicitybasicitysolvationsmallnegativeionsarehighly
solvatedinproticsolventslargenegativeionsarelesssolvatedpolarizabilityMajorfactorsthatcontrolnucleophilicityRank Nucleophile Relative
rategood HO–,RO– 104
fair RCO2– 103weak H2O,ROH 1Whentheattackingatomisthesame(oxygen
inthiscase),nucleophilicityincreaseswith
increasingbasicity.Table8.4Nucleophilicitybasicitysolvationsmallnegativeionsarehighly
solvatedinproticsolventslargenegativeionsarelesssolvatedpolarizabilityMajorfactorsthatcontrolnucleophilicitySolvationofachlorideionbyion-dipoleattractive
forceswithwater.Thenegativelychargedchloride
ioninteractswiththepositivelypolarizedhydrogens
ofwater.Figure8.4Rank Nucleophile Relative
ratestrong I- >105good Br- 104fair Cl-,F- 103Atightsolventshellaroundanionmakesit
lessreactive.Largerionsarelesssolvatedthan
smalleronesandaremorenucleophilic.Table8.4Nucleophilicitybasicitysolvationsmallnegativeionsarehighly
solvatedinproticsolventslargenegativeionsarelesssolvatedpolarizabilityMajorfactorsthatcontrolnucleophilicityRank Nucleophile Relative
reactivitystrong I- >105good Br- 104fair Cl-,F- 103Morepolarizableionsaremorenucleophilicthan
lesspolarizableones.Polarizabilityincreases
withincreasingionicsize.Table8.4Nucleophilicity8.8
UnimolecularNucleophilicSubstitution
SN1Tertiaryalkylhalidesareveryunreactivein
substitutionsthatproceedbytheSN2mechanism.
Dotheyundergonucleophilicsubstitutionatall? Yes.ButbyamechanismdifferentfromSN2.
Themostcommonexamplesareseenin
solvolysisreactions.Aquestion...++HBr....:O::HHCCH3CH3CH3BrCOH........:CH3CH3CH3Exampleofasolvolysis.Hydrolysisoftert-butylbromide.++HBr....:O::HHC++O:HHBr....::–CH3CH3CH3CCH3CH3CH3BrCOH........:CH3CH3CH3Exampleofasolvolysis.Hydrolysisoftert-butylbromide.+O::HHC++O:HHBr....::–CH3CH3CH3CCH3CH3CH3Br....:Thisisthenucleophilicsubstitution
stageofthereaction;theonewith
whichweareconcerned.Exampleofasolvolysis.Hydrolysisoftert-butylbromide.+O::HHC++O:HHBr....::–CH3CH3CH3CCH3CH3CH3Br....:Thereactionrateisindependent
oftheconcentrationofthenucleophile
andfollowsafirst-orderratelaw. rate=k[(CH3)3CBr]Exampleofasolvolysis.Hydrolysisoftert-butylbromide.+O::HH+Br....::–C+O:HHCH3CH3CH3CCH3CH3CH3Br....:Themechanismofthisstepis
notSN2.ItiscalledSN1and
beginswithionizationof(CH3)3CBr.Exampleofasolvolysis.Hydrolysisoftert-butylbromide.rate=k[alkylhalide]First-orderkineticsimpliesaunimolecular
rate-determiningstep.
ProposedmechanismiscalledSN1,whichstandsfor
substitutionnucleophilicunimolecularKineticsandMechanism+Br–..::..unimolecular
slowCCH3CH3CH3Br....:CH3CCH3CH3+Mechanismbimolecular
fastCH3CCH3CH3+O::HHC+O:HHCH3CH3CH3
Mechanismproton
transferROH2+carbocation
formationR+ROHcarbocation
captureRXfirstorderkinetics:rate=k[RX]unimolecularrate-determiningstepcarbocationintermediateratefollowscarbocationstabilityrearrangementssometimesobservedreactionisnotstereospecificmuchracemizationinreactionsof
opticallyactivealkylhalidesCharacteristicsoftheSN1mechanism8.9
CarbocationStabilityandSN1ReactionRatesTherateofnucleophilicsubstitution
bytheSN1mechanismisgoverned
byelectroniceffects.Carbocationformationisrate-determining.
Themorestablethecarbocation,thefaster
itsrateofformation,andthegreaterthe
rateofunimolecularnucleophilicsubstitution.ElectronicEffectsGovernSN1RatesRBrsolvolysisinaqueousformicacidAlkylbromide Class Relativerate CH3Br Methyl 1CH3CH2Br Primary 2(CH3)2CHBr Secondary 43(CH3)3CBr Tertiary 100,000,000Table8.5ReactivitytowardsubstitutionbytheSN1mechanismCH3BrCH3CH2Br(CH3)2CHBr(CH3)3CBrDecreasingSN1Reactivity8.10
StereochemistryofSN1ReactionsNucleophilicsubstitutionsthatexhibit
first-orderkineticbehaviorare
notstereospecific.GeneralizationR-(–)-2-BromooctaneHCCH3BrCH3(CH2)5(R)-(–)-2-Octanol(17%)HCCH3OHCH3(CH2)5CHCH3HO(CH2)5CH3(S)-(+)-2-Octanol(83%)H2OStereochemistryofanSN1ReactionIonizationstep
givescarbocation;three
bondstostereogenic
centerbecomecoplanar+Figure8.8Leavinggroupshields
onefaceofcarbocation;
nucleophileattacks
fasteratoppositeface.+Figure8.8Morethan50%Lessthan50%+8.11
CarbocationRearrangements
inSN1Reactionscarbocationsareintermediates
inSN1reactions,rearrangements
arepossible.Because...CH3CHCHCH3BrCH3H2OCH3COHCH2CH3CH3(93%)ExampleCH3CHCHCH3CH3CH3CCHCH3CH3CH3CHCHCH3BrCH3H2OCH3COHCH2CH3CH3(93%)+H+Example8.12
SolventEffectsSN1ReactionRatesIncrease
inPolarSolventsIngeneral...Solvent Dielectric Relative constant rateaceticacid 6 1methanol 33 4formicacid 58 5,000water 78 150,000Table8.6
SN1ReactivityversusSolventPolarityR+RXd+
RXd-energyofRX
notmuch
affectedby
polarityof
solventtransition
state
stabilizedby
polarsolventR+RXd+
RXd-energyofRX
notmuch
affectedby
polarityof
solventtransition
state
stabilizedby
polarsolventactivationenergy
decreases;rateincreasesSN2ReactionRatesIncreasein
PolarAproticSolventsAnaproticsolventisonethatdoes
nothavean—OHgroup.Ingeneral...Solvent Type Relative
rateCH3OH polarprotic 1H2O polarprotic 7DMSO polaraprotic 1300DMF polaraprotic 2800Acetonitrile polaraprotic 5000CH3CH2CH2CH2Br+N3–Table8.7
SN2ReactivityversusTypeofSolventMechanismSummary
SN1andSN2When...primaryalkylhalidesundergonucleophilic
substitution,theyalwaysreactbytheSN2
mechanismtertiaryalkylhalidesundergonucleophilic
substitution,theyalwaysreactbytheSN1
mechanismsecondaryalkylhalidesundergonucleophilic
substitution,theyreactbytheSN1mechanisminthepresenceofaweak
nucleophile(solvolysis)SN2mechanisminthepresenceofagood
nucleophile8.13
SubstitutionandElimination
asCompetingReactionsAlkylhalidescanreactwithLewisbasesintwodifferent
ways;nucleophilicsubstitutionorelimination.CCHX+Y:–CCYHX:–+CC+HYX:–+b-eliminationnucleophilicsubstitutionTwoReactionTypesHowcanwetellwhichreactionpathwayisfollowed
foraparticularalkylhalide?CCHX+Y:–CCYHX:–+CC+HYX:–+b-eliminationnucleophilicsubstitutionTwoReactionTypesAsystematicapproachistochooseasareference
pointthereactionfollowedbyatypicalalkylhalide
(secondary)withatypicalLewisbase(analkoxide
ion).Themajorreactionofasecondaryalkylhalide
withanalkoxideioniseliminationbytheE2
mechanism.EliminationversusSubstitutionCH3CHCH3BrNaOCH2CH3ethanol,55°CCH3CHCH3OCH2CH3CH3CH=CH2+(87%)(13%)ExampleBrE2Figure8.11CH3CH2O•••••
•–BrSN2Figure8.11CH3CH2O•••••
•–Giventhatthemajorreactionofasecondary
alkylhalidewithanalkoxideioniselimination
bytheE2mechanism,wecanexpectthe
proportionofsubstitutiontoincreasewith: 1) decreasedcrowdingatthecarbonthat
bearstheleavinggroupWhenissubstitutionfavored?Decreasedcrowdingatcarbonthatbearstheleaving
groupincreasessubstitutionrelativetoelimination.
primaryalkylhalideCH3CH2CH2BrNaOCH2CH3ethanol,55°CCH3CH=CH2+CH3CH2CH2OCH2CH3(9%)(91%)UncrowdedAlkylHalidesprimaryalkylhalide+bulkybaseCH3(CH2)15CH2CH2BrKOC(CH3)3tert-butylalcohol,40°C+CH3(CH2)15CH2CH2OC(CH3)3CH3(CH2)15CH=CH2(87%)(13%)Butacrowdedalkoxidebasecanfavoreliminationevenwithaprimaryalkylhalide.Giventhatthemajorreactionofasecondary
alkylhalidewithanalkoxideioniselimination
bytheE2mechanism,wecanexpectthe
proportionofsubstitutiontoincreasewith: 1) decreasedcrowdingatthecarbonthat
bearstheleavinggroup
2)decreasedbasicityofthenucleophileWhenissubstitutionfavored?Weaklybasicnucleophileincreases
substitutionrelativetoeliminationKCNCH3CH(CH2)5CH3ClpKa(HCN)=9.1(70%)DMSOCH3CH(CH2)5CH3CNsecondaryalkylhalide+weaklybasicnucleophileWeaklyBasicNucleophileWeaklybasicnucleophileincreases
substitutionrelativetoeliminationNaN3pKa(HN3)=4.6(75%)secondaryalkylhalide+weaklybasicnucleophileWeaklyBasicNucleophileIN3Tertiaryalkylhalidesaresostericallyhindered
thateliminationisthemajorreactionwithall
anionicnucleophiles.Onlyinsolvolysisreactions
doessubstitutionpredominateoverelimination
withtertiaryalkylhalides.TertiaryAlkylHalides(CH3)2CCH2CH3Br+CH3CCH2CH3OCH2CH3CH3CH2=CCH2CH3CH3CH3C=CHCH3CH3+ethanol,25°C64%36%2Msodiumethoxideinethanol,25°C1%99%Example8.14
SulfonateEsters
as
SubstratesinNucleophilicSubstitutionLeavingGroups wehaveseennumerousexamplesofnucleophilicsubstitutioninwhichXinRXisahalogen
halogenisnottheonlypossibleleavinggroupthoughOtherRXcompoundsROSCH3OOROSOOCH3Alkyl
methanesulfonate
(mesylate)Alkyl
p-toluenesulfonate
(tosylate)undergosamekindsofreactionsasalkylhalidesPreparation(abbreviatedasROTs) ROH+CH3SO2ClpyridineROSOOCH3Tosylatesarepreparedbythereactionof
alcoholswithp-toluenesulfonylchloride
(usuallyinthepresenceofpyridine)TosylatesundergotypicalnucleophilicsubstitutionreactionsHCH2OTsKCNethanol-
waterHCH2CN(86%)ThebestleavinggroupsareweaklybasicTable8.8
ApproximateRelativeReactivityofLeavingGroupsLeavingGroup Relative Conjugateacid Kaof
Rate ofleavinggroup conj.acid
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