Organic Chemistry - Faculté des sciences - Faculty of...

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

Copyright©2015JohnWiley&Sons,Inc.Allrightsreserved. 19-2 Klein, Organic Chemistry 2e


• WhenFeisintroducedareactionoccurs

• Isthereactionsubstitution,elimination,additionorpericyclic?


• Similarreactionsoccurforaromaticringsusingotherreagents

• SuchreactionsarecalledElectrophilicAromaticSubstitution(EAS)

• ExplaineachtermintheEAStitle



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?


19.2Halogenation• TopromotetheEASreactionbetweenbenzeneandBr2,wesawthatFeisnecessary

•

• DoesthisprocessmakeBromineabetterorworseelectrophile?HOW?


19.2Halogenation

• TheFeBr3 actsasaLewisacid.HOW?

• AlBr3 issometimesusedinsteadofFeBr3

• Aresonance-stabilizedcarbocation isformed


19.2Halogenation• TheresonancestabilizedcarbocationiscalledaSigmaComplexorarenium ion

• Drawtheresonancehybrid


19.2Halogenation• TheSigmaComplexisre-aromatized

• DoestheFeBr3 actascatalyst?


19.2Halogenation• Substitutionoccursratherthanaddition.WHY?


19.2Halogenation• Cl2 canbeusedinsteadofBr2

• DrawtheEASmechanismforthereactionbetweenbenzeneandCl2 withAlCl3 asaLewisacidcatalyst

• Fluorinationisgenerallytooviolenttobepractical,andiodinationisgenerallyslowwithlowyields


19.2Halogenation• NotethegeneralEASmechanism

• Practicewithconceptualcheckpoint19.1


• Therearemanydifferentelectrophiles thatcanbeattackedbyanaromaticring

• FumingH2SO4 consistsofsulfuricacidandSO3 gas• SO3 isquiteelectrophilic.HOW?

19.3Sulfonation


19.3Sulfonation• Let’sexamineSO3 inmoredetail• TheS=Odoublebondinvolvesp-orbitaloverlapthatislesseffectivethantheorbitaloverlapinaC=Cdoublebond.WHY?

• Asaresult,theS=OdoublebondbehavesmoreasaS-Osinglebondwithformalcharges.WHATarethecharges?


19.3Sulfonation• TheSatominSO3 carriesagreatdealofpositivecharge

• Thearomaticringisstable,butitisalsoelectron-rich

• WhentheringattacksSO3,theresultingcarbocationisresonancestabilized

• Drawtheresonancecontributorsandtheresonancehybrid


19.3Sulfonation

• AsineveryEASmechanism,aprotontransferre-aromatizesthering


• Thespontaneityofthesulfonation reactiondependsontheconcentration

• Wewillexaminetheequilibriumprocessinmoredetaillaterinthischapter

• Practicewithconceptualcheckpoints19.2and19.3

19.3Sulfonation


19.4Nitration• Amixtureofsulfuricacidandnitricacidcausestheringtoundergonitration

• Thenitronium ionishighlyelectrophilicCopyright©2015JohnWiley&Sons,Inc.Allrightsreserved. 19-22 Klein, Organic Chemistry 2e

19.4Nitration• Theringattacksthenitronium ion


19.4Nitration• Thesigmacomplexstabilizesthecarbocation


19.4Nitration• AswithanyEASmechanism,theringisre-aromatized


19.4Nitration• Anitrogroupcanbereducedtoformanamine

• Combiningthereactionsgivesusa2-stepprocessforinstallinganaminogroup

• Practicewithconceptualcheckpoint19.4Copyright©2015JohnWiley&Sons,Inc.Allrightsreserved. 19-26 Klein, Organic Chemistry 2e

19.5Friedel-CraftsAlkylation• DoyouthinkthatanalkylhalideisaneffectivenucleophileforEAS?


• InthepresenceofaLewisacidcatalyst,alkylationisgenerallyfavored

• WhatroledoyouthinktheLewisacidplays?

19.5Friedel-CraftsAlkylation


19.5Friedel-CraftsAlkylation

• Acarbocationisgenerated• Theringthenattacksthecarbocation• Showafullmechanism


19.5Friedel-CraftsAlkylation• Primarycarbocationsaretoounstabletoform,yetprimaryalkylhalidescanreactunderFriedel-Craftsconditions

• FirstthealkylhalidereactswiththeLewisacid– showtheproduct


19.5Friedel-CraftsAlkylation• Thealkylhalide/Lewisacidcomplexcanundergoahydrideshift

• Showhowthemechanismcontinuestoprovidethemajorproductofthereaction


19.5Friedel-CraftsAlkylation• Thealkylhalide/Lewisacidcomplexcanalsobeattackeddirectlybythearomaticring

•• Showhowthemechanismprovidestheminorproduct

• Whymightthehydrideshiftoccurmorereadilythanthedirectattack?

• Whyarereactionsthatgivemixturesofproductsoftenimpractical?


19.5Friedel-CraftsAlkylation• TherearethreemajorlimitationstoFriedel-Craftsalkylations1. Thehalideleavinggroupmustbeattachedtoansp3

hybridizedcarbon


19.5Friedel-CraftsAlkylation• TherearethreemajorlimitationstoFriedel-Craftsalkylations2. Polyalkylationcanoccur

Wewillseelaterinthischapterhowtocontrolpolyalkylation


19.5Friedel-CraftsAlkylation• TherearethreemajorlimitationstoFriedel-Craftsalkylations3. Somesubstitutedaromaticringssuchasnitrobenzeneare

toodeactivatedtoreact

Wewillexploredeactivatinggroupslaterinthischapter

• Practicewithconceptualcheckpoints19.5,19.6,and19.7


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


19.6Friedel-CraftsAcylation• Acylation proceedsthroughanacylium ion


19.6Friedel-CraftsAcylation• Theacylium ionisstabilizedbyresonance

• Theacylium iongenerallydoesnotrearrangebecauseoftheresonance

• Drawacompletemechanismforthereactionbetweenbenzeneandtheacylium ion


• SomealkylgroupscannotbeattachedtoaringbyFriedel-Craftsalkylationbecauseofrearrangements

• Anacylation followedbyaClemmensen reductionisagoodalternative



• Unlikepolyalkylation,polyacylation isgenerallynotobserved.WewilldiscussWHYlaterinthischapter

• Practicewithconceptualcheckpoint19.8through19.10



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


• SubstitutedbenzenesgenerallyundergoEASreactionsregioselectively



• Therelativepositionofthemethylgroupandtheapproachingelectrophileaffectsthestabilityofthesigmacomplex

• Iftheringattacksfromtheortho position,thefirstresonancecontributorofthesigmacomplexisstabilized.HOW?

• Isthetransitionstatealsoaffected?



• Therelativepositionofthemethylgroupandtheapproachingelectrophileaffectsthestabilityofthesigmacomplex



• Explainthetrendbelow

• Theortho productpredominatesforstatisticalreasonsdespitesomeslightstericcrowding




• Themethoxy groupinanisoleactivatesthering400timesmorethanbenzene

• Throughinduction,isamethoxy groupelectronwithdrawingordonating?HOW?

• Themethoxy groupdonatesthroughresonance

• Whichresonancestructurecontributesmosttotheresonancehybrid?



• Themethoxy groupactivatestheringsostronglythatpolysubstitution isdifficulttoavoid

• Activatorsaregenerallyortho-para directors



• Theresonancestabilizationaffectstheregioselectivity



• Howwillthemethoxy groupaffectthetransitionstate?

• Thepara productisthemajorproduct.WHY?



• Allactivatorsareortho -para directors• Givereactantsnecessaryfortheconversionbelow




• Thenitrogroupiselectronwithdrawingthroughbothresonanceandinduction.ExplainHOW

• Withdrawingelectronsfromtheringdeactivatesit.HOW?

• Willwithdrawingelectronsmakethetransitionstateortheintermediatelessstable?

19.8DeactivatingGroups


• Themeta productpredominatesbecausetheotherpositionsaredeactivated




19.9Halogens:TheException• Allelectrondonatinggroupsareortho-para directors• Allelectronwithdrawinggroupsaremeta-directorsEXCEPTthehalogens

• Halogenswithdrawelectronsbyinduction(deactivating)• Halogensdonateelectronsthroughresonance(ortho-para directing)


19.9Halogens:TheException• Halogensdonateelectronsthroughresonance


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?




3. WEAKactivators.WHATmakesthemweak?

4. WEAKdeactivators.WHATmakesthemweak?




5. Moderatedeactivators.WHATmakesthemmoderate?

6. STRONGdeactivators.WHATmakesthemstrong?



• Forthecompoundbelow,determinewhetherthegroupiselectronwithdrawingordonating

• Also,determineifitisactivatingordeactivatingandhowstronglyorweakly

• Finally,determinewhetheritisortho,para,ormetadirecting

• PracticewithSkillBuilder 19.1


19.11MultipleSubstituents• ThedirectingeffectsofallsubstituentsattachedtoaringmustbeconsideredinanEASreaction

• PredictthemajorproductforthereactionbelowandEXPLAIN


19.11MultipleSubstituents• PredictthemajorproductforthereactionbelowandEXPLAIN



19.11MultipleSubstituents• Considersterics inadditiontoresonanceandinductiontopredictwhichproductbelowismajorandwhichisminor


19.11MultipleSubstituents• Considersterics inadditiontoresonanceandinductiontopredictwhichproductbelowismajorandwhichisminor

• Substitutionisveryunlikelytooccurinbetweentwosubstituents.WHY?



19.11MultipleSubstituents• Whatreagentsmightyouuseforthefollowingreaction?

• Isthereawaytopromotethedesiredortho substitutionoversubstitutionatthelesshinderedpara position?

• Maybeyoucouldfirstblockoutthepara position


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


19.12SyntheticStrategies• Tosynthesizedi-substitutedaromaticcompounds,youmustcarefullyanalyzethedirectinggroups

• Howmightyoumake3-nitrobromobenzene?• Howmightyoumake3-chloroaniline?• Suchareactionismuchmorechallenging,because–NH2and–Cl groupsarebothpara directing

• Ameta directorwillbeusedtoinstallthetwogroups• Oneofthegroupswillsubsequentlybeconvertedintoitsfinalform– useexamplesonthenextslide


19.12SyntheticStrategies


19.12SyntheticStrategies• Designasynthesisforthemoleculebelowstarting

frombenzene


19.12SyntheticStrategies• Whendesigningasynthesisforapolysubstituted

aromaticcompound,oftenaretrosyntheticanalysisishelpful

• Designasynthesisforthemoleculebelow

• WhichgroupwouldbetheLASTgroupattached?• WHYcan’tthebromooracylgroupsbeattachedlast?


• Oncetheringonlyhastwosubstituents,itshouldbeeasiertoworkforward

19.12SyntheticStrategies

• Explainwhyotherpossiblesyntheticroutesarenotlikelytoyieldasmuchofthefinalproduct

• ContinueSkillBuilder 19.6


19.13NucleophilicAromaticSubstitution

• Considerthereactionbelowinwhichthearomaticringisattackedbyanucleophile

• Istherealeavinggroup?



• Aromaticringsaregenerallyelectron-rich,whichallowsthemtoattackelectrophiles (EAS)

• Tofacilitateattackbyanucleophile:1. Aringmustbeelectronpoor.WHY?

Aringmustbesubstitutedwithastrongelectronwithdrawinggroup

2. Theremustbeagoodleavinggroup3. TheleavinggroupmustbepositionedORTHO orPARA tothe

withdrawinggroup.WHY?Wemustinvestigatethemechanism– seenextslide



• Drawalloftheresonancecontributorsintheintermediate



• Inthelaststepofthemechanism,theleavinggroupispushedoutastheringre-aromatizes



• Howwouldthestabilityofthetransitionstateandintermediatedifferforthefollowingmolecule?



• Theexcesshydroxidethatisusedtodrivethereactionforwardwilldeprotonate thephenol,soacidmustbeusedaftertheNASstepsarecomplete

• Practicewithconceptualcheckpoints19.35through19.37


19.14EliminationAddition• Withoutthepresenceofastrongelectronwithdrawing

group,mildNASconditionswillnotproduceaproduct

• Significantlyharsherconditionsarerequired


19.14EliminationAddition• Thereactionworksevenbetterwhenastronger

nucleophileisused

• WhyisNH2- astrongernucleophilethanOH-?


• Givetheproductsforthereactionbelowandacompletemechanism

AdditionalPracticeProblems


• Predictthemajorproductforeachreactionbelow



• Givenecessaryreagentsforthesynthesisbelow



AdditionalPracticeProblems• Fillintheblanksbelow


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