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–

?CH3OH+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-Bromooctane?(–)-2-Octanol

(–)-2-Bromooctane?(+)-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+LiI?RI+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+LiI?RI+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