chapter 10 synthesis using aromatic...

Chapter10SynthesisUsing

AromaticMaterialsELECTROPHILICAROMATICSUBSTITUTIONAND

DIRECTEDORTHOMETALATION

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10.2p BondsActingasNucleophiles



AsdescribedinChapter8,thep bondofanalkenecanactasanucleophile.

Example:


Whenbenzeneismixedwithbromine,noreactionhappens.

Additionofacatalystcaninducereactivity.

10.3ElectrophilicAromaticSubstitution



Electrophilicaromaticsubstitution(SEAr)reactionsproceedbyageneraltwo-stepmechanism:

1. additionofanelectrophile(Chapter8)

2. elimination(explainedindetailinChapter12)


Secondsteprestoresaromaticity.

Thisdrivesreactiontowardsubstitutioninsteadofnucleophilicattack.

10.4TypesofElectrophilesUsedinElectrophilicAromatic

Substitution


10.4.1Halogenation


Aromaticringscanbehalogenatedwithbromine,chlorine,oriodineusingaLewisacidcatalyst.


Theactivatedelectrophilichalogenreactswiththearomaticringtoformthearenium intermediate.

OneofthebrominesofFeBr4− actsasabasetoremoveaproton.

10.4.2Nitration


Ahydrogenatomisreplacedwithanitrogroup(–NO2)viaSEAr.

Theelectrophileinthisreactionisthenitronium ion(NO2+).

ItisgeneratedbydehydrationofHNO3 withH2SO4.


Nitrationmechanism:

Providesaroutetoaromaticamines(detailsinCh.19)

10.4.3Sulfonation


Ahydrogenonthearomaticringisreplacedbyasulfonicacidgroup(–SO3H).

TheactiveelectrophileislikelySO3H+.


FormationofSO3H+:


Sulfonation mechanism:

Sulfonation canbereversedusingastrongacid(e.g.,H2SO4)inwater.

10.4.4Friedel–Craftsalkylation


ThisisatypeofSEAr foraddingalkylgroupstoaromaticrings.

AlCl3 =Lewisacid


Friedel–Craftsalkylationmechanism:

10.4.5LimitationsoftheFriedel–Craftsalkylation


1. Carbocations arenotreactiveenoughtocouplewithweaklynucleophilicaromaticrings.


2. Becausealkylgroupsareelectrondonating,theproductofaFriedel–Craftsalkylationisusuallymorenucleophilic(morereactive)thanthestartingreactant.

Over-alkylationiscommonforFriedel–Craftsalkylation.


3. Carbocations canrearrangeandleadtoproductmixtures.

Carbocationrearrangements(recallChapter8):


Twocompetingmechanismsresultintheformationofthetwoproducts:

10.4.6Friedel–Craftsacylation


VerysimilartoFriedel–Craftsalkylation,butaddsanacyl groupinstead.

Thisinvolvestheformationofanacylium ion.


TheproductofFriedel–Craftsacylationislessreactivethanreactantbecauseacylgroupiselectronwithdrawing.

Therefore,singleacylations arehighlyfeasible.

Canprovideroutetosingly-alkylatedproductviasubsequentreduction:


Friedel–Craftsacylationcanuseanhydrideinsteadofacidchloride:

Itcannotproducearomaticaldehydes.


Gatterman–Kochreactioncanyieldaromaticaldehydes:

10.5AromaticNomenclatureand

MultipleSubstituents



Manyaromaticcompoundshavetrivialnames:

Onaromaticcompoundswithmultiplesubstituents,relativepositionsdesignatedbynumbersorGreekwords:

10.6DirectingGroupsinElectrophilicAromatic

Substitution



ExistingsubstituentsaffecttheoutcomeofSEAr reactionswithrespecttothefollowing:

• rateofreaction

• regioselectivity

Functionalgroupsareclassifiedaccordingtoparticularproperties:

1. Activatingvs.deactivating


2. Ortho/paravs.metadirectors

Ortho/para directors:• Favour theformationofortho andpara regioisomers

Meta directors:• Favour theproductionofthemeta regioisomer

10.6.1Ortho/para directinggroups


Electron-donatinggroupstendtodirectregioselectivitytowardortho and/orpara products.

10.6.1.1Strongortho/para directors


Substituentlonepairsstabilizearenium ionforortho/parasubstitution:


Ifinitialadditionoccursatmeta position,lonepaircannotstabilizearenium.


10.6.1.2Moderateortho/para directors

Insomecases,lonepaironsubstituentmayalreadybeengagedindelocalization.


10.6.1.3Weakortho/paradirectors

1. Alkylgroups

Ø haveweakelectron-donatingcharacter(hyperconjugation)

2. Aromaticrings

10.6.2Deactivatingortho/para directors


Halogensdeactivatedueto

• highelectronegativity

• poororbitaloverlapbetween2pringorbitalsandlonepairporbitalsforCl,Br,andI(3p,4p,and5prespectively)

Theyactasortho/para directorsduetoweakresonanceeffect.

10.6.3Meta directinggroups


Electron-withdrawinggroupstypically:• deactivateanaromaticringtowardSEAr• favourmeta regioisomer


10.6.3.1Moderatelydeactivatingmeta directorsThesegroupscontainpolarp bondsconnectedtoelectronegativeatomsandconjugatedtothering.

10.6.3.2Stronglydeactivatingmeta directors

Substituentsthatareelectronwithdrawingduetostronginductiveeffects.

10.6.4Modifyingreactivityinelectrophilicaromaticsubstitutions


Substituentscanbetemporarilymodifiedtocontrolreactivity.


Insomecases,incidentalmodificationcanleadtounexpectedproducts.

10.6.5Strengthofactivationonpolysubstituted benzenes


Whenmultiplesubstituentsarepresent,thecollectiveeffectsofdirectinggroupsmustbeconsidered.

10.7ElectrophilicAromaticSubstitutionof

PolycyclicandHeterocyclicAromatic

Compounds


10.7.1Reactivityofpolycyclicaromaticcompounds


Regioselectivity iscontrolledbystabilityofarenium ion.

Thesetwoproductsresultfromthemoststablearenium ions.


Mechanismforformationof1-nitronaphthalene:


Mechanismforformationof2-nitronaphthalene:


10.7.1.1Reactivityofsubstitutedpolyaromatics

Directinggroupeffectsstillapply.

Example:

Becausethemethylgroupiselectrondonating,theringtowhichitisattachedismorenucleophilic.

10.7.2Reactivityofheterocycliccompounds


Thepresenceofheteroatomscanhaveastronginfluenceonreactivityandregioselectivity.

Examples:


Mechanismforfurannitration:


Indolepreferentiallyreactsviapaththatpreservesaromaticity:


Pyridineisanelectron-pooraromaticring.

Theelectrophilicnitrogenatomdestabilizesthepositivechargeintheadditionintermediate.

10.8DirectedOrthoMetalationasanAlternativeto

ElectrophilicAromaticSubstitution



Directedorthometalation(DOM):• analternateroutetoaromaticsubstitution• stepsoccurinoppositeorderrelativetoSEAr

DMG=directedmetalationgroup:• asubstituentthatfavours deprotonationattheadjacent

ortho position


Acloserlook:

Averystrongbasemustbeusedinthefirststep.

Recall:BuLi =n-butyllithuim

TMEDA(tetramethylethylenediamine)isusedtoenhancebasicityofBuLi (complexeswithLi).

DMGstabilizesaryllithium (ArLi).

10.8.1Commondirectedmetalationgroups


ManyDMGsarecarbonyl-basedfunctionalgroups:

Othersarederivedfromheteroatomsubstituents:


Onceanaryllithium intermediatehasformed,avarietyofelectrophilescanbeadded.

10.9RetrosyntheticAnalysisinAromatic

Synthesis



Synthesis:• assemblingnewsubstancesbyreactingdifferent

moleculestocombineinacontrolledmanner

Retrosynthesis:• techniqueforplanningsynthesisinwhichthetargetis

analyzedintermsofwhatitcanbemadefrom

Disconnection:• aretrosyntheticstep,animaginary“reverse”reaction


Retrosyntheses forp-nitroisopropylbenzene:

Forwardsynthesis:

10.9.1Usingsynthonsinsynthesis


Synthon:• animaginarycomponentthatcapturestheoverall

reactivitypatternofaseriesofcompounds

10.10PatternsinElectrophilicAromaticSubstitutionReactions


Generalreaction:

Chaptersummary


• AromaticringscanbemodifiedviaSEAr.

• Thesereactionsallfollowthesamegeneralmechanism.

• Friedel–Craftsalkylationandacylationcanbeusedtointroducealkylandacylgroups,respectively.

• Substituentscanbeactivatingordeactivating;ortho/paradirectingormeta directing.

• Retrosynthesisiscommonlyusedinplanningchemicalsynthesis.

chapter 10 synthesis using aromatic...

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