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Chapter 19Aromatic Substitution Reactions
Organic ChemistrySecond Edition
David Klein
Copyright©2015JohnWiley&Sons,Inc.Allrightsreserved. Klein, Organic Chemistry 2e
19.1IntroductiontoElectrophilicAromaticSubstitution
• Inchapter18,wesawhowaromaticC=Cdoublebondsarelessreactivethantypicalalkene doublebonds
• Considerabromination reaction
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19.1IntroductiontoElectrophilicAromaticSubstitution
• WhenFeisintroducedareactionoccurs
• Isthereactionsubstitution,elimination,additionorpericyclic?
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• Similarreactionsoccurforaromaticringsusingotherreagents
• SuchreactionsarecalledElectrophilicAromaticSubstitution(EAS)
• ExplaineachtermintheEAStitle
19.1IntroductiontoElectrophilicAromaticSubstitution
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Description of Mechanism Using Resonance Structures
Step 1: Attack by the ElectrophileTwo π-electrons form a σ-bond to the incoming electrophile yielding a delocalized carbocation intermediate called an arenium ion.
E Aδ+ δ-H
E+
HE
+
HE
+
These resonance structures show the distribution of positive charge in the arenium ion.
The arenium ion is non-aromatic, but it is reasonably stable because of charge dispersal over the carbons ortho and para to the site of attachment of the electrophile.
HE
δ+
δ+ δ+
- A:-
Step 2: Deprotonation of the Arenium Ion and Re-aromatization
HE
++ A:- + H-A
E
The Lewis base that attacks and removes the proton may, as shown, be the conjugate base of the electrophile or some other Lewis base that may be present.
Free-Energy Diagram for an Electrophilic Aromatic Substitution Reaction
The much larger energy of activation requirement for Step 1 makes it the slow, rate-determining step.
The Arenium Ion Intermediate
HE
δ+
δ+ δ+
A calculated structure for the resonance-stabilized (but non-aromatic) arenium ion intermediate, a delocalized cyclohexadienyl cation, is shown on the right. The blue coloration at the para and the two ortho
sp3 carbon
carbons, suggesting low electron densities there, is in line with the partial positive charge locations in the resonance hybrid shown on the left above.
19.2Halogenation• Doyouthinkanaromaticringismorelikelytoactasanucleophile oranelectrophile?WHY?
• DoyouthinkBr2 ismorelikelytoactasanucleophile oranelectrophile?WHY?
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19.2Halogenation• TopromotetheEASreactionbetweenbenzeneandBr2,wesawthatFeisnecessary
•
• DoesthisprocessmakeBromineabetterorworseelectrophile?HOW?
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19.2Halogenation
• TheFeBr3 actsasaLewisacid.HOW?
• AlBr3 issometimesusedinsteadofFeBr3
• Aresonance-stabilizedcarbocation isformed
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19.2Halogenation• TheresonancestabilizedcarbocationiscalledaSigmaComplexorarenium ion
• Drawtheresonancehybrid
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19.2Halogenation• TheSigmaComplexisre-aromatized
• DoestheFeBr3 actascatalyst?
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19.2Halogenation• Substitutionoccursratherthanaddition.WHY?
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19.2Halogenation• Cl2 canbeusedinsteadofBr2
• DrawtheEASmechanismforthereactionbetweenbenzeneandCl2 withAlCl3 asaLewisacidcatalyst
• Fluorinationisgenerallytooviolenttobepractical,andiodinationisgenerallyslowwithlowyields
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19.2Halogenation• NotethegeneralEASmechanism
• Practicewithconceptualcheckpoint19.1
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• Therearemanydifferentelectrophiles thatcanbeattackedbyanaromaticring
• FumingH2SO4 consistsofsulfuricacidandSO3 gas• SO3 isquiteelectrophilic.HOW?
19.3Sulfonation
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19.3Sulfonation• Let’sexamineSO3 inmoredetail• TheS=Odoublebondinvolvesp-orbitaloverlapthatislesseffectivethantheorbitaloverlapinaC=Cdoublebond.WHY?
• Asaresult,theS=OdoublebondbehavesmoreasaS-Osinglebondwithformalcharges.WHATarethecharges?
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19.3Sulfonation• TheSatominSO3 carriesagreatdealofpositivecharge
• Thearomaticringisstable,butitisalsoelectron-rich
• WhentheringattacksSO3,theresultingcarbocationisresonancestabilized
• Drawtheresonancecontributorsandtheresonancehybrid
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19.3Sulfonation
• AsineveryEASmechanism,aprotontransferre-aromatizesthering
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• Thespontaneityofthesulfonation reactiondependsontheconcentration
• Wewillexaminetheequilibriumprocessinmoredetaillaterinthischapter
• Practicewithconceptualcheckpoints19.2and19.3
19.3Sulfonation
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19.4Nitration• Amixtureofsulfuricacidandnitricacidcausestheringtoundergonitration
• Thenitronium ionishighlyelectrophilicCopyright©2015JohnWiley&Sons,Inc.Allrightsreserved. 19-22 Klein, Organic Chemistry 2e
19.4Nitration• Theringattacksthenitronium ion
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19.4Nitration• Thesigmacomplexstabilizesthecarbocation
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19.4Nitration• AswithanyEASmechanism,theringisre-aromatized
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19.4Nitration• Anitrogroupcanbereducedtoformanamine
• Combiningthereactionsgivesusa2-stepprocessforinstallinganaminogroup
• Practicewithconceptualcheckpoint19.4Copyright©2015JohnWiley&Sons,Inc.Allrightsreserved. 19-26 Klein, Organic Chemistry 2e
19.5Friedel-CraftsAlkylation• DoyouthinkthatanalkylhalideisaneffectivenucleophileforEAS?
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• InthepresenceofaLewisacidcatalyst,alkylationisgenerallyfavored
• WhatroledoyouthinktheLewisacidplays?
19.5Friedel-CraftsAlkylation
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19.5Friedel-CraftsAlkylation
• Acarbocationisgenerated• Theringthenattacksthecarbocation• Showafullmechanism
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19.5Friedel-CraftsAlkylation• Primarycarbocationsaretoounstabletoform,yetprimaryalkylhalidescanreactunderFriedel-Craftsconditions
• FirstthealkylhalidereactswiththeLewisacid– showtheproduct
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19.5Friedel-CraftsAlkylation• Thealkylhalide/Lewisacidcomplexcanundergoahydrideshift
• Showhowthemechanismcontinuestoprovidethemajorproductofthereaction
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19.5Friedel-CraftsAlkylation• Thealkylhalide/Lewisacidcomplexcanalsobeattackeddirectlybythearomaticring
•• Showhowthemechanismprovidestheminorproduct
• Whymightthehydrideshiftoccurmorereadilythanthedirectattack?
• Whyarereactionsthatgivemixturesofproductsoftenimpractical?
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19.5Friedel-CraftsAlkylation• TherearethreemajorlimitationstoFriedel-Craftsalkylations1. Thehalideleavinggroupmustbeattachedtoansp3
hybridizedcarbon
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19.5Friedel-CraftsAlkylation• TherearethreemajorlimitationstoFriedel-Craftsalkylations2. Polyalkylationcanoccur
Wewillseelaterinthischapterhowtocontrolpolyalkylation
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19.5Friedel-CraftsAlkylation• TherearethreemajorlimitationstoFriedel-Craftsalkylations3. Somesubstitutedaromaticringssuchasnitrobenzeneare
toodeactivatedtoreact
Wewillexploredeactivatinggroupslaterinthischapter
• Practicewithconceptualcheckpoints19.5,19.6,and19.7
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Limitations of the Friedel-Crafts Reactions(1) Rearrangements during Alkylations
Whenever carbocation intermediates are formed, they are subject to rearrangements that produce more stable species.Example: During the Friedel-Crafts reaction of benzene with butyl bromide a 1,2-hydride shift, possibly concurrent with dissociation, produces some of the more stable sec-butyl carbocation. A mixture of products results.
AlCl3-+
ComplexBr
Br AlCl3- BrAlCl3-
H
Butylbenzene (32-36%) sec-Butylbenzene (64-68%)
• Acylation andalkylationbothformanewcarbon-carbonbond
• Acylation reactionsarealsogenerallycatalyzedwithaLewisacid
19.6Friedel-CraftsAcylation
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19.6Friedel-CraftsAcylation• Acylation proceedsthroughanacylium ion
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19.6Friedel-CraftsAcylation• Theacylium ionisstabilizedbyresonance
• Theacylium iongenerallydoesnotrearrangebecauseoftheresonance
• Drawacompletemechanismforthereactionbetweenbenzeneandtheacylium ion
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• SomealkylgroupscannotbeattachedtoaringbyFriedel-Craftsalkylationbecauseofrearrangements
• Anacylation followedbyaClemmensen reductionisagoodalternative
19.6Friedel-CraftsAcylation
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• Unlikepolyalkylation,polyacylation isgenerallynotobserved.WewilldiscussWHYlaterinthischapter
• Practicewithconceptualcheckpoint19.8through19.10
19.6Friedel-CraftsAcylation
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Activating Groups: Ortho-Para DirectorsThe methyl and other alkyl groups are in this category.
Example: Nitration of toluene proceeds faster than that of benzene and gives predominantly ortho and para nitrotoluene products.
CH3
Toluene
HNO3
H2SO4
More reactivethan benzene
CH3 CH3 CH3NO2
NO2
NO2
+ +
o-Nitrotoluene p-Nitrotoluene m-Nitrotoluene59% 37% 4%
Alkyl groups are also activating and ortho/para directing in other electrophilic aromatic substitutions.
Additional Activating and Ortho/Para Directing Groups
OCH3 NHCCH3
O=OH NH2
Methoxy Acetamido Hydroxyl Amino
Nitrobenzene
HNO3
H2SO4
Much less reactivethan benzene
NO2 NO2 NO2NO2
NO2NO2
o-Dinitrobenzene p-Dinitrobenzene
+ +
m-Dinitrobenzene6% 1% 93%
Deactivating Groups: Meta DirectorsThe nitro group, -NO2, is an example.
Nitration of nitrobenzene proceeds at a rate approximately 10-8 times the rate of nitration of benzene, and the major product is m-dinitrobenzene.
NO2
Other deactivating and meta-directing groups are:
COOH SO3H C-R CF3
O=
Carboxyl Sulfonic acid Acyl Trifluoromethyl
Halogen Substituents: Deactivating but Ortho/Para Directing
Chloro and bromo substituents are unique in decreasing reactivity in electrophilic aromatic substitution but producing mostly ortho and para products.
Cl
Chlorobenzene
E+Cl Cl Cl
E
EE
ortho(%)
para(%)
meta(%)
+ +
Reaction:Chlorination 39 55 6Bromination 11 87 2Nitration 30 70 --Sulfonation -- 100 --
• SubstitutedbenzenesmayundergoEASreactionswithfasterRATES thanunsubstituted benzene.Whatisrate?
• Tolueneundergoesnitration25timesfasterthanbenzene
• Themethylgroupactivatestheringthroughinduction(hyperconjugation).ExplainHOW
19.7ActivatingGroups
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• SubstitutedbenzenesgenerallyundergoEASreactionsregioselectively
19.7ActivatingGroups
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• Therelativepositionofthemethylgroupandtheapproachingelectrophileaffectsthestabilityofthesigmacomplex
• Iftheringattacksfromtheortho position,thefirstresonancecontributorofthesigmacomplexisstabilized.HOW?
• Isthetransitionstatealsoaffected?
19.7ActivatingGroups
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• Therelativepositionofthemethylgroupandtheapproachingelectrophileaffectsthestabilityofthesigmacomplex
19.7ActivatingGroups
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• Explainthetrendbelow
• Theortho productpredominatesforstatisticalreasonsdespitesomeslightstericcrowding
• Practicewithconceptualcheckpoint19.11
19.7ActivatingGroups
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• Themethoxy groupinanisoleactivatesthering400timesmorethanbenzene
• Throughinduction,isamethoxy groupelectronwithdrawingordonating?HOW?
• Themethoxy groupdonatesthroughresonance
• Whichresonancestructurecontributesmosttotheresonancehybrid?
19.7ActivatingGroups
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• Themethoxy groupactivatestheringsostronglythatpolysubstitution isdifficulttoavoid
• Activatorsaregenerallyortho-para directors
19.7ActivatingGroups
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• Theresonancestabilizationaffectstheregioselectivity
19.7ActivatingGroups
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• Howwillthemethoxy groupaffectthetransitionstate?
• Thepara productisthemajorproduct.WHY?
19.7ActivatingGroups
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• Allactivatorsareortho -para directors• Givereactantsnecessaryfortheconversionbelow
• Practicewithconceptualcheckpoint19.12
19.7ActivatingGroups
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• Thenitrogroupiselectronwithdrawingthroughbothresonanceandinduction.ExplainHOW
• Withdrawingelectronsfromtheringdeactivatesit.HOW?
• Willwithdrawingelectronsmakethetransitionstateortheintermediatelessstable?
19.8DeactivatingGroups
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19.8DeactivatingGroups
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• Themeta productpredominatesbecausetheotherpositionsaredeactivated
• Practicewithconceptualcheckpoint19.13
19.8DeactivatingGroups
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19.9Halogens:TheException• Allelectrondonatinggroupsareortho-para directors• Allelectronwithdrawinggroupsaremeta-directorsEXCEPTthehalogens
• Halogenswithdrawelectronsbyinduction(deactivating)• Halogensdonateelectronsthroughresonance(ortho-para directing)
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19.9Halogens:TheException• Halogensdonateelectronsthroughresonance
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The Anomolous Halo Groups: Ortho-Para Directing But Rate Retarding.
The apparent contradiction in behavior of the halogen substituents is explained by opposing electronic influences of the inductive and resonance effects.
Inductive EffectThe halogens are electronegative relative to carbon, so they all withdraw electrons inductively from the benzene ring. This polarization deactivates the aromatic ring towards electrophilic addition.
:X:
:δ-δ+
Resonance Effect
As the electrophile E+ begins to add, a pair of nonbonding electrons on the halogen interacts with the developing positive charge through the polarizable p electrons. This interaction stabilizes the developing arenium ion. But this interaction is only possible when the electrophile attaches ortho or para to the halogen, as illustrated below.
:X:
:
E+
para addition
:X:
:
H E
+
:X:
:H E
+:X:
:
H E+
X::
E
+
HAn important contributor
E+
meta addition
:X:
:
:X::
HE
+
:X:
:
HE
+:X:
:
HE
+
No supplemental resonance stabilization by halogen
19.10DeterminingtheDirectingEffectsofaSubstituent
• Let’ssummarizethedirectingeffectsofmoresubstituents
1. STRONGactivators.WHATmakesthemstrong?
2. Moderateactivators.Whatmakesthemmoderate?
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19.10DeterminingtheDirectingEffectsofaSubstituent
• Let’ssummarizethedirectingeffectsofmoresubstituents
3. WEAKactivators.WHATmakesthemweak?
4. WEAKdeactivators.WHATmakesthemweak?
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19.10DeterminingtheDirectingEffectsofaSubstituent
• Let’ssummarizethedirectingeffectsofmoresubstituents
5. Moderatedeactivators.WHATmakesthemmoderate?
6. STRONGdeactivators.WHATmakesthemstrong?
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19.10DeterminingtheDirectingEffectsofaSubstituent
• Forthecompoundbelow,determinewhetherthegroupiselectronwithdrawingordonating
• Also,determineifitisactivatingordeactivatingandhowstronglyorweakly
• Finally,determinewhetheritisortho,para,ormetadirecting
• PracticewithSkillBuilder 19.1
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19.11MultipleSubstituents• ThedirectingeffectsofallsubstituentsattachedtoaringmustbeconsideredinanEASreaction
• PredictthemajorproductforthereactionbelowandEXPLAIN
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19.11MultipleSubstituents• PredictthemajorproductforthereactionbelowandEXPLAIN
• PracticewithSkillBuilder 19.2
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19.11MultipleSubstituents• Considersterics inadditiontoresonanceandinductiontopredictwhichproductbelowismajorandwhichisminor
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19.11MultipleSubstituents• Considersterics inadditiontoresonanceandinductiontopredictwhichproductbelowismajorandwhichisminor
• Substitutionisveryunlikelytooccurinbetweentwosubstituents.WHY?
• PracticewithSkillBuilder 19.3
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19.11MultipleSubstituents• Whatreagentsmightyouuseforthefollowingreaction?
• Isthereawaytopromotethedesiredortho substitutionoversubstitutionatthelesshinderedpara position?
• Maybeyoucouldfirstblockoutthepara position
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19.11MultipleSubstituents• BecauseEASsulfonation isreversible,itcanbeusedasatemporaryblockinggroup
• PracticewithSkillBuilder 19.4Copyright©2015JohnWiley&Sons,Inc.Allrightsreserved. 19-71 Klein, Organic Chemistry 2e
19.12SyntheticStrategies• Reagentsformonosubstituted aromaticcompounds
• Practicewithconceptualcheckpoints19.28and19.29
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19.12SyntheticStrategies• Tosynthesizedi-substitutedaromaticcompounds,youmustcarefullyanalyzethedirectinggroups
• Howmightyoumake3-nitrobromobenzene?• Howmightyoumake3-chloroaniline?• Suchareactionismuchmorechallenging,because–NH2and–Cl groupsarebothpara directing
• Ameta directorwillbeusedtoinstallthetwogroups• Oneofthegroupswillsubsequentlybeconvertedintoitsfinalform– useexamplesonthenextslide
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19.12SyntheticStrategies
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19.12SyntheticStrategies• Designasynthesisforthemoleculebelowstarting
frombenzene
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19.12SyntheticStrategies• Whendesigningasynthesisforapolysubstituted
aromaticcompound,oftenaretrosyntheticanalysisishelpful
• Designasynthesisforthemoleculebelow
• WhichgroupwouldbetheLASTgroupattached?• WHYcan’tthebromooracylgroupsbeattachedlast?
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• Oncetheringonlyhastwosubstituents,itshouldbeeasiertoworkforward
19.12SyntheticStrategies
• Explainwhyotherpossiblesyntheticroutesarenotlikelytoyieldasmuchofthefinalproduct
• ContinueSkillBuilder 19.6
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19.13NucleophilicAromaticSubstitution
• Considerthereactionbelowinwhichthearomaticringisattackedbyanucleophile
• Istherealeavinggroup?
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19.13NucleophilicAromaticSubstitution
• Aromaticringsaregenerallyelectron-rich,whichallowsthemtoattackelectrophiles (EAS)
• Tofacilitateattackbyanucleophile:1. Aringmustbeelectronpoor.WHY?
Aringmustbesubstitutedwithastrongelectronwithdrawinggroup
2. Theremustbeagoodleavinggroup3. TheleavinggroupmustbepositionedORTHO orPARA tothe
withdrawinggroup.WHY?Wemustinvestigatethemechanism– seenextslide
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19.13NucleophilicAromaticSubstitution
• Drawalloftheresonancecontributorsintheintermediate
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19.13NucleophilicAromaticSubstitution
• Inthelaststepofthemechanism,theleavinggroupispushedoutastheringre-aromatizes
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19.13NucleophilicAromaticSubstitution
• Howwouldthestabilityofthetransitionstateandintermediatedifferforthefollowingmolecule?
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19.13NucleophilicAromaticSubstitution
• Theexcesshydroxidethatisusedtodrivethereactionforwardwilldeprotonate thephenol,soacidmustbeusedaftertheNASstepsarecomplete
• Practicewithconceptualcheckpoints19.35through19.37
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19.14EliminationAddition• Withoutthepresenceofastrongelectronwithdrawing
group,mildNASconditionswillnotproduceaproduct
• Significantlyharsherconditionsarerequired
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19.14EliminationAddition• Thereactionworksevenbetterwhenastronger
nucleophileisused
• WhyisNH2- astrongernucleophilethanOH-?
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• Givetheproductsforthereactionbelowandacompletemechanism
AdditionalPracticeProblems
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• Predictthemajorproductforeachreactionbelow
AdditionalPracticeProblems
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• Givenecessaryreagentsforthesynthesisbelow
AdditionalPracticeProblems
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