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Partial Synthesis of Fe(III) - Tetraamido Macrocyclic Ligands as Potential Green Oxidation Catalysts

Permanent Link: http://ncf.sobek.ufl.edu/NCFE004473/00001

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Title: Partial Synthesis of Fe(III) - Tetraamido Macrocyclic Ligands as Potential Green Oxidation Catalysts
Physical Description: Book
Language: English
Creator: Andreansky, Eric
Publisher: New College of Florida
Place of Publication: Sarasota, Fla.
Creation Date: 2011
Publication Date: 2011

Subjects

Subjects / Keywords: Green Chemistry
Organic Synthesis
Catalysts
Genre: bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The goal of green chemistry is to decrease the environmental footprint of chemical activities. One significant problem faced is the remediation of complex organic compounds that are released into the environment. Current wastewater treatments rely upon methods, such as ozonolysis and chlorinolysis, that both require unsafe chemicals and that can often produce degradation products that are more toxic than their precursors.
Statement of Responsibility: by Eric Andreansky
Thesis: Thesis (B.A.) -- New College of Florida, 2011
Electronic Access: RESTRICTED TO NCF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE
Bibliography: Includes bibliographical references.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Local: Faculty Sponsor: Scudder, Paul

Record Information

Source Institution: New College of Florida
Holding Location: New College of Florida
Rights Management: Applicable rights reserved.
Classification: local - S.T. 2011 A52
System ID: NCFE004473:00001

Permanent Link: http://ncf.sobek.ufl.edu/NCFE004473/00001

Material Information

Title: Partial Synthesis of Fe(III) - Tetraamido Macrocyclic Ligands as Potential Green Oxidation Catalysts
Physical Description: Book
Language: English
Creator: Andreansky, Eric
Publisher: New College of Florida
Place of Publication: Sarasota, Fla.
Creation Date: 2011
Publication Date: 2011

Subjects

Subjects / Keywords: Green Chemistry
Organic Synthesis
Catalysts
Genre: bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The goal of green chemistry is to decrease the environmental footprint of chemical activities. One significant problem faced is the remediation of complex organic compounds that are released into the environment. Current wastewater treatments rely upon methods, such as ozonolysis and chlorinolysis, that both require unsafe chemicals and that can often produce degradation products that are more toxic than their precursors.
Statement of Responsibility: by Eric Andreansky
Thesis: Thesis (B.A.) -- New College of Florida, 2011
Electronic Access: RESTRICTED TO NCF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE
Bibliography: Includes bibliographical references.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Local: Faculty Sponsor: Scudder, Paul

Record Information

Source Institution: New College of Florida
Holding Location: New College of Florida
Rights Management: Applicable rights reserved.
Classification: local - S.T. 2011 A52
System ID: NCFE004473:00001


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PartialSynthesisofFe(III)-TetraamidoMacrocyclicLigandsasPotentialGreenOxidationCatalystsByEricAndreanskyAThesisSubmittedtotheDivisionofNaturalSciencesNewCollegeofFloridaInpartialfulllmentoftherequirementsforthedegreeofBachelorofArtsUnderthesponsorshipofDr.PaulScudderSarasota,FloridaMay,2011

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AcknowledgementsForemost,Iwouldliketogivethankstomyadvisor,Dr.PaulScudder,forhiscontin-uouspatienceandsupportduringmanyaspectsofmyeducationatNewCollege,fromthisprojectwhichIhaveworkedonsinceISPofmysecondyeartothemanytutorialsandISPsIhavedonewithhimrelatedtoorganicchemistry.Withouthiscriticalin-sight,asignicantamountofprogresswithboththisprojectandmypersonalgrowthwouldhavenotbeenpossible.Iwouldalsoliketodeeplythanktheothermembersofmycommittee.IfDr.Shermanwouldnothavepersuadedmetotrytotakeorganicchemistryduringmyrstyear,IwouldprobablynotbewhereInowamacademically.Dr.Shipmanhasalwaysbeenanexcellentsourceofupliftingconversation,freshinsight,andunfetteredenthusiasmthatgivesyouabreakfromalltheinsanitythatconstitutesyourthirdandfourthyear.IwouldalsoliketothankallthosewhohaveworkedinbothDr.Scudder'sandDr.Sherman'slabduringthetimeIworkedonthisproject.Thesepeopleunderstandthesignicantamountofworkthatisnecessarytomakeanyprogressonachemistryproject.Thesenseofcamaraderieproducedfromthisunderstandingissomethingthatoftenkeptusworkingwhilefacingwhatoftenfeltlikedefeat.Specically,IwouldliketothankErinnBrigham,RichardDecal,AdamFlowerday,BenKriegel,KaitlinLovering,JackieWindsor,andJustinSpengler.Iwouldalsoliketothankmyfamilyandfriendsformybeingmysupport,forlifeii

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iiidoesn'talwayshavetoinvolvechemistry.IwouldespeciallyliketothankDouglasGrayforbeingoneofthebestpeopletoenjoylifewith.Lastly,IwouldliketothanktheNewCollegeFoundationandtheCouncilforAca-demicAairs,whoprovidedthefundingtomakethisprojectpossible.

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Contents1Introduction11.1GreenChemistry.............................11.1.1HistoryofEnvironmentalRegulationofToxicWaste.....11.1.2WhatisGreenChemistry?....................41.2LookingtoNatureforInspiration:Peroxidase,Catalase,andCy-tochromeP450EnzymesasNature'sCatalyticOxidants.......71.2.1CytochromeP450Enzymes...................81.2.2PeroxidaseandCatalaseEnzymes................101.3TAMLOxidationCatalysts.......................111.3.1TAMLCatalystDesign......................121.3.2Fe(III)-TAMLs:StructureandMechanism...........151.3.2.1Fe(III)-TAMLCatalystSolid-StateStructure....161.3.2.2CoordinationofFe(III)-TAMLsinAqueousSolution171.3.2.3OxidizedFormsofFe(III)-TAMLs-Fe(IV)andFe(V)Species.........................181.3.2.4TAMLOxidationMechanisms:Peroxidase-andCatalase-likeActivity.......................211.3.2.5TAMLDeactivationMechanisms-AcidandBuerDemetallationMechanisms..............281.3.2.6OxidativeDegradationofFe(III)-TAMLs.......31iv

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CONTENTSv1.3.3ApplicationsofTAMLSystems.................331.3.3.1DegradationofPolychlorinatedPhenols.......331.3.3.2DegradationofOrganophosphorousPesticides....351.3.3.3DegradationofAnthraxSpores............361.3.3.4DestructionofEstrogens................381.4Second-GenerationTAMLLigands...................401.5GoalsofThesis..............................412Experimental452.1SynthesisofMalonateFragment.....................462.1.1methylpropargylmalonate,diethylester(2)..........462.1.2methylpropargylmalonicacid(3)................472.1.3methylpropargylmalonyldichloride(4)............492.2Synthesisof2,2'-DiaminooxanilideFragment..............502.2.12-(carbamate,tert-butylester)aniline(6)............502.2.22,2'-(dicarbamate,tert-butylester)oxanilide(7)........522.2.32,2'-diaminooxanilide(8).....................532.3N,N'-1,2-phenylenebis(2,2-dimethylpropanamide)...........542.3.12-phthalimidoisobutyricacid(10)................543ResultsandDiscussion563.1RetrosyntheticAnalysisandPreviousSyntheses............563.2SynthesisofMalonateFragment.....................593.2.1methylpropargylmalonate,diethylester(2)..........593.2.2methylpropargylmalonicacid(3)................623.2.3methylpropargylmalonyldichloride(4)............653.3Synthesisof2,2'-DiaminooxanilideFragment..............673.3.12-(carbamate,tert-butylester)aniline..............68

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CONTENTSvi3.3.22,2'-(dicarbamate,tert-butylester)oxanilide..........703.3.32,2'-diaminooxanilide.......................723.4N,N'-1,2-phenylenebis(2-aminoisobutyramide).............743.4.12-phthalimidoisobutyricacid...................743.5MacrocyclizationReactions.......................764Conclusion80ASpectra82

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ListofFigures1.1ValleyoftheDrums,1979.........................11.2MechanismofCytochromeP450activationofoxygen..........91.3Proposedschemeforperoxidaseactivity.................101.4IterativeprogressionofTAMLdesign..................131.5Designsofrst-generationTAMLcatalystsystems...........141.6Crystalstructuresofselectrst-generationFe(III)-TAMLcatalysts.161.7StepwiseligandsubstitutionforFe(III)-TAMLinaqueoussolution..171.8Bis-Fe(IV)--oxocomplexformeduponairoxidationofFe(III)-TAMLligands...................................181.9UV-VisspectralchangesofanFe(III)-TAMLcatalystinthepresenceofaqueoushydrogenperoxide......................191.10ProposedmechanismofFe(IV)-oxospeciesformationinaqueoussolution191.11Peroxidase-andcatalase-likeactivityofFe(III)-TAMLcomplexes..211.12Three-dimensionalkineticplotofFe(III)-TAMLcatalyst.......221.13DyesusedtotracethekineticsofFe-TAMLcomplexes........231.14CharacteristicpHproleforTAMLligandsatvarioustemperatures.231.15ProposedmechanismforpHdependenceofperoxidaticactivity....241.16HammettplotbetweenEWGcharacterandperoxidase-likeactivity.251.17Catalase-likeactivitydecreasewithincreasingSafranineO......271.18TheHOMOandsHOMOofTAMLcatalysts..............29vii

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LISTOFFIGURESviii1.19Proposedmechanismforbuer-catalyzeddemetallationofFe-TAMLcatalysts..................................301.20ProposedequilibriaforFe-TAMLdemetallationbypicolinicacid...311.21CompletemechanisticpictureforFe(III)-TAMLactivity.......321.22LinearfreeenergyrelationshipbetweenkIIandki...........331.23DegradationofchlorophenolsbyTAMLcatalysts...........341.24PesticidesdegradedbyTAMLcatalysts.................351.25DegradationofFenitrothionbyTAMLcatalysts............361.26DegradationofanthraxbyTAMLcatalysts...............371.27EstrogencompoundstobetestedwithFe(III)-TAMLcatalysts....391.28DegradationofestrogensbyanFe-TAMLcatalyst...........401.29Designofsecond-generationofTAMLcatalystsystems........401.30Targetstructuresforsynthesis......................432.1Synthesisofmethylpropargylmalonate,diethylester(2).......462.2Synthesisofmethylpropargylmalonicacid(3)............472.3Synthesisofmethylpropargylmalonyldichloride(4).........492.4HClgastrapsetup............................502.5Synthesisof2-(carbamate,tert-butylester)aniline(6).........502.6Synthesisof2,2'-(dicarbamate,tert-butylester)oxanilide(7).....522.7Synthesisof2,2'-diaminooxanilide(8)..................532.8Synthesisof2-phthalimidoisobutyricacid(10).............543.1Retrosyntheticanalysisofsecond-generationliganddesign......563.2Previousrouteto2,2'-diaminooxanilide.................583.3Synthesisofmethylpropargylmalonyldichloride............593.4Synthesisofmethylpropargylmalonate,diethylester(2).......593.5Selectivityissueswithrespecttomalonatealkylation.........60

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LISTOFFIGURESix3.61H-NMRspectrumofmethylpropargylmalonate,diethylester(CDCl3)623.7Synthesisofmethylpropargylmalonicacid(3)............623.81H-NMRspectrumofmethylpropargylmalonicacid(d6-DMSO)...643.9Predicted1H-NMRspectrumforpotentialdecarboxylationproduct..653.10Synthesisofmethylpropargylmalonyldichloride(4).........653.11GeneralschemeforDMF-catalyzedacylchlorideformationusingoxalylchloride...................................663.121H-NMRspectrumofmethylpropargylmalonyldichloride(d6-DMSO).673.13Synthesisof2,2'-diaminooxanilide....................673.14Synthesisof2-(carbamate,tert-butylester)aniline(6).........683.151H-NMRspectrumof2-(carbamate,tert-butylester)aniline(d6-DMSO)693.16Synthesisof2,2'-(dicarbamate,tert-butylester)oxanilide(7).....703.17Proposedreactionofwaterwithmonosubstitutedoxanilideleadingtodecomposition...............................713.181H-NMRspectrumof2,2'-(dicarbamate,tert-butylester)oxanilide(d6-DMSO)..................................713.19Synthesisof2,2'-diaminooxanilide(8)..................723.201H-NMRspectrumof2,2'-diaminooxanilide(d6-DMSO)........733.21RoutetothesynthesisofN,N'-1,2-phenylenebis(2-aminoisobutyramide)743.22Synthesisof2-phthalimidoisobutyricacid(10).............743.231H-NMRspectrumof2-phthalimidoisobutyricacid(d6-DMSO).Ace-toneispresent2.2ppm,whileanunknownimpurityispresentat1.2ppm.(LargerversionisavailableingureA.23).............763.24MacrocyclizationReaction.Conditions:Et3N,THF,CH2Cl2......763.25Typical1H-NMRspectrumoftheisolatedproductforamacrocycliza-tionreaction................................78

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LISTOFFIGURESxA.11H-NMRspectrumofmethylpropargylmalonate,diethylester(2)(CDCl3)..................................83A.213C-NMRspectrumofmethylpropargylmalonate,diethylester(2)(d6-DMSO)................................84A.3IRspectrumofmethylpropargylmalonate,diethylester(2)......85A.4Predicted1H-NMRand13C-NMRspectraformethylpropargylmal-onate,diethylester(2)..........................86A.51H-NMRspectrumofmethylpropargylmalonicacid(3)(d6-DMSO)87A.613C-NMRspectrumofmethylpropargylmalonicacid(3)(d6-DMSO).88A.7IRspectrumofmethylpropargylmalonicacid(3)...........89A.8Predicted1H-NMRand13C-NMRspectraofmethylpropargylmalonicacid(3)...................................90A.91H-NMRspectrumofmethylpropargylmalonyldichloride(4)(CDCl3)91A.1013C-NMRspectrumofmethylpropargylmalonyldichloride(4)(CDCl3).92A.11IRspectrumofmethylpropargylmalonyldichloride(4)........93A.12Predicted1H-NMRand13C-NMRspectraformethylpropargylmal-onyldichloride(4).............................94A.131H-NMRspectrumfor2-(carbamate,tert-butylester)aniline(6)(d6-DMSO)..................................95A.1413C-NMRspectrumfor2-(carbamate,tert-butylester)aniline(6)(d6-DMSO)...................................96A.15IRspectrumfor2-(carbamate,tert-butylester)aniline(6).......97A.161H-NMRspectrumfor2,2'-(dicarbamate,tert-butylester)oxanilide(7)(d6-DMSO)................................98A.1713C-NMRspectrumfor2,2'-(dicarbamate,tert-butylester)oxanilide(7)(d6-DMSO)..............................99A.18IRspectrumfor2,2'-(dicarbamate,tert-butylester)oxanilide(7)...100

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LISTOFFIGURESxiA.19Predicted1H-NMRand13C-NMRspectrafor2,2'-(dicarbamate,tert-butylester)oxanilide(7)..........................101A.201H-NMRspectrumfor2,2'-diaminooxanilide(8)(d6-DMSO)......102A.2113C-NMRspectrumfor2,2'-diaminooxanlide(8)(d6-DMSO).....103A.26Predicted1H-NMRand13C-NMRspectrafor2-phthalimidoisobutyricacid(10)..................................104A.22IRspectrumfor2,2'-diaminooxanilide(8)................105A.231H-NMRspectrumof2-phthalimidoisobutyricacid(10)(d6-DMSO).106A.2413C-NMRspectrumof2-phthalimidoisobutyricacid(10)(d6-DMSO).107A.25IRspectrumof2-phthalimidoisobutyricacid(10)............108

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AbstractThegoalofgreenchemistryistodecreasetheenvironmentalfootprintofchemicalac-tivities.Onesignicantproblemcurrentlyfacedistheremediationofcomplexorganiccompoundsthatarereleasedintotheenvironment.Currentwastewatertreatmentsrelyuponmethods,suchasozonolysisorchlorinolysis,thatbothrequireunsafechem-icalsandthatcanoftenproducedegradationproductsthataremoretoxicthantheirprecursors.Livingorganismshavetheirownmethodfordealingwithcomplexorganiccom-poundsthatinvolvesactivatingoxygenspecieswithiron.Basedupontheseenzymaticsystems,anumberofsyntheticligandshavebeendeveloped.Specically,asetofironcatalystsystemsusingTetraamidoMacrocyclicLigands(TAML)havebeendevelopedbyTerryCollinsofCarnegieMellonUniversitytoactivatehydrogenperoxide.How-ever,thesecatalystsundergoeventualoxidativedegradation.Thisthesisdetailsthedevelopmentandpartialsynthesisofasystemforattachingtheseligandstoasolidsupportusinga1,2,3-triazolelinkage.Twofragmentsofthemacrocycleweresynthesized,butproblemsoccuredwithrespecttoringclosure.Anewroutetothemacrocylehasbeenproposed.xiiDr. Paul Scudder

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Chapter1Introduction1.1GreenChemistry1.1.1HistoryofEnvironmentalRegulationofToxicWaste Figure1.1:ValleyoftheDrums,1979.[1]Onethingunderstoodbyanypracticingsyntheticchemististheamountoftoxicwasteproduceddailyduringanyoftheirwork.Manyofthecommonlyusedreagentsandsolventsaredisposedofinlargebottlesthatarethenpickedupbyahazardouswastedisposalcompanyandneverseenagain.However,thisdistancelessensthe1

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CHAPTER1.INTRODUCTION2apparentimpactcausedbythesignicantamountofwasteproducedbymoststandardchemistry.UndertheToxicReleaseInventory(TRI),theenvironmentalreleaseof596chemicalsand30chemicalcategoriesarerequiredtobetracked.In2009,3.37billionpoundsoftoxicchemicalstrackedbytheTRIwerereleasedintotheenvironment,equivalenttothereleaseofmorethanthreetonsoftoxicwasteeveryminute.[2]Thechemicalstrackedonlyrepresentasmallfractionofthe75,000compoundsusedregularlyincommercialapplications.Formanyofthesechemicalswedonotfullyunderstandthepotentialshort-andlong-termenvironmentaleects,andthereforehavenobasisfortheirregulation.Thetotalamountofsyntheticchemicalswereleaseintotheenvironmentonadailybasisismostlikelyenormousinproportion.Thisisnottodetractfromthebenetschemistryhasprovidedtosociety.Inmanyways,thedevelopmentofchemistryhasledtodrasticimprovementsinqualityoflifeforpeopleallaroundtheworld.Chemistrybreakthroughshaveledtoamazingbene-tsinhealthcarebyallowingustonallytreatdiseasesthathavebeenaroundsincethebeginningofmankind.Theusageofchemistryhasalsoleadtoincreasedyieldsinfoodproduction,allowinggreaternutritionforpeopletheworldover.However,thedevelopmentandmanufactureofsuchchemicalsthatbenettheenvironmentoftenleadtotheproductionoftoxicbyproductsthatmustbedisposedofaswaste.AfterWorldWarII,almostnoregulationexistedonthemanufacture,use,andreleaseoftoxicchemicals.Thechemicalindustryalsoboomedduetotheincreaseinthepopulationanddemandforamoreextravagantlifestyleinpost-warAmerica.Itwasn'tuntiltheearlysixtiesthatconcerndevelopedregardingthepotentialeectofchemicalsontheenvironment.OneoftherstmomentswasthemedicalcrisiscausedbytheusageofthalidomideinEurope.Thissedativewasusedasatreatmentformorningsickness,butwasthenfoundtopotentiallybeacauseforanestimated10,000-20,000birthdefects,5,000inGermanyalone.Thismedicalcatastrophecreatedasignicantamountoffearwithinthegeneralpublicastothesafetyof

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CHAPTER1.INTRODUCTION3syntheticchemicalsandtheirpotentialunknowneects.[3]In1962,RachelCarsonpublishedherpivotalwork,SilentSpring,thatdetailedtheeectsofDDTontheeggsofbirds.Beforethistime,littlewasknownofthepotentialforchronictoxicity,bioaccumulation,andcarcinogenicityofmanysubstances.[4]Evenforchemicalswheretheharmfuleectswereknown,itwaspreviouslybelievedthattheirunpleasanteectswereminimizedbydilutionuponreleasetotheenvironment.Nowadays,thisisknownnottobethecase.Itwasn'tuntilseveralmajorincidencesinthe1960s,1970s,and1980sthatsig-nicantenvironmentalregulationcameintobeing.InNiagaraFalls,NewYork,toxicchemicalsbeganleachingoutofaclay-cappeddumpandintothegroundwaterandsoilthatnowhadacommunitysittingonit.Thearea,knownasLoveCanal,wascontaminatedby82chemicals,includingsuspectedcarcinogenssuchabenzene,chlori-natedhydrocarbons,anddioxin.[5]WithinthecommunityofTimesBeach,Missouri,thedirtroadsweresprayedwithoilthatunknowninglycontainedsignicantlevelsofdioxins.Thecommunityoodsregularly,andoneoftheseoodscoatedthecom-munity'shomeswithdioxin-lacedmud.ThiseventuallyleadtotheEPAbuyingtheentiretownfor$32million.[6]InLouisville,Kentucky,ahazardouswastedumpdubbedtheValleyoftheDrumsbecameapoignantvisualizationoftheproblemwhenseveralofthedrumsonthesitestartedleakingorspontaneouslycaughtre.[1]TheseincidencesledtotheestablishmentoftheSuperfundin1980,atrustfundfromataxonpetroleumandchemicalsthatisusedtocleanupmajortoxicwastesites,manythatwerepreviouslyabandonedsothatnoparticularpartycanbeheldresponsible.ThisdemonstratesthePolluterPaysprinciplethatisthefoundationofmuchoftheenvironmentallegislationaroundtheworld.AquickglanceatthelistofSuperfundsitesforanystatesdemonstratesthesignicantprevalenceofthishazardouswastesites.[7]Intheearly1970s,theCuyahogariverinOhiowascontaminatedbysomuch

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CHAPTER1.INTRODUCTION4chemicalpollutionthatitcaughtonre.[8]Aroundthissametime,acommonsightinmanymajorUScitieswasthebrownhazeofsmogthatlaidlikeablanketabovethecity.ThesesightsledtothepassageoftheCleanWaterActandtheCleanAirActinthe1970s.Inthe1980s,thevisualizationofaholeformingintheozonelayerledtotheimplementationoftheMontrealProtocol,whichbeganthephasingoutoftheusageofchlorouorocarbonsaroundtheworld.ThehugechemicaldisasterinBhopal,India,resultinginthereleaseofmethylisocyanate,thedeathofthousandsofpeople,andhealtheectswithinthecommunityfordecadestocome,leadtopassageoftheEmergencyPlanningandCommunityRight-to-KnowActin1986.[9]Muchoftheearlierregulationaimedtolimittheamountofchemicalsbeingre-leasedbyregulatingtheirlevelsandrequiringthetreatmentofmanychemicalsbeforetheirreleaseintotheenvironment.Thistreatmentwasthroughsuchmeansastheneutralizationofacids,theusageofscrubbersforairpollutants,andincinerationoftoxiccompounds.However,thepassageofthePollutionPreventionActof1990movedthefocusfromtreatingtoxicwastetochangingindustrialmethodsinordertopreventtheproductionoftoxicwasteintherstplace.[10]Thisalterationisprobablythemostfundamentalaspectoftheparadigminwhatisknownasgreenchemistry:chemistsshouldtrytofocusondevelopingmethodstopreventthepro-ductionoftoxicwasteintherstplaceinsteadoftryingtogureoutwhattodowithitonceithasbeenmade.Moreandmoreinthefuturethisoutlookwillcolorthewaychemistsdesignnewmethodsintheirresearch.ItssignicancecanbeseenhowPaulAnastas,consideredbymanytobethefounderoftheGreenChemistrymovement,willnowheadR&DattheEnvironmentalProtectionAgency.[11]1.1.2WhatisGreenChemistry?GreenChemistryisthedesignofchemicalproductsorprocessesthatreduceorelim-inatetheuseorgenerationofhazardoussubstances.[12]Theprinciplesthatserveas

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CHAPTER1.INTRODUCTION5guidelinesareoutlinedinPaulAnastas'GreenChemistry:TheoryandPractice.[13] TheTwelvePrinciplesofGreenChemistry1.)Itisbettertopreventwastethantotreatorcleanupwasteafteritisformed.2.)Syntheticmethodsshouldbedesignedtomaximizetheincorporationofallma-terialsusedintheprocessintothenalproduct.3.)Whereverpracticable,syntheticmethodologiesshouldbedesignedtouseorgener-atesubstancesthatpossesslittleornotoxicitytohumanhealthandtheenvironment.4.)Chemicalproductsshouldbedesignedtopreserveecacyorfunctionwhilereducingtoxicity.5.)Theuseofauxillarysubstances(e.g.solvents,separationagents,etc.)shouldbemadeunnecessarywhereverpossibleand,innocuouswhenused.6.)Energyrequirementsshouldberecognizedfortheirenvironmentalandeconomicimpactsandshouldbeminimized.Syntheticmethodsshouldbeconductedatambienttemperatureandpressure.7.)Arawmaterialfeedstockshouldberenewableratherthandepletingwherevertechnicallyandeconomicallypracticable.8.)Unnecessaryderivatization(blockinggroup,protection/deprotection,temporarymodicationorphysical/chemicalprocesses,etc.)shouldbeavoidedwheneverpossi-ble.9.)Catalyticreagents(asselectiveaspossible)aresuperiortostoichiometricreagents.10.)Chemicalproductsshouldbedesignedsothatattheendoftheirfunctiontheydonotpersistintheenvironmentandbreakdownintoinnocuousdegradationproducts.11.)AnalyticalMethodologiesneedtobefurtherdevelopedtoallowforreal-time,in-processmonitoringandcontrolpriortotheformationofhazardoussubstances.12.)Substancesandtheformofasubstanceinachemicalprocessshouldbechosensoastominimizethepotentialforchemicalaccidents,includingreleases,explosions,andres.[13] Whilegreenchemistrymayalsobeaboutthedevelopmentofmethodsthatpro-ducetheleastpossibleenvironmentalimpact,italsoisaboutdevelopingtechnologiestodealwithpollutionproblemsthatcurrentlyexist.AnothersetofguidelinesforgreenchemistryistheThreeR's,orrecovery,reuse/recycling,andregeneration.[13]Recoverymeansthatsolvents,reagents,andcatalystsforareactionsystemcanbeisolatedandreused,leadingtoonelesschemicalenteringthewastestream.Areagentthatcanberecoveredwithoutpuricationcanbereused,whilecompoundsthatneedpuricationareknowntoberecycled.Ifareagentcanberegenerated,

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CHAPTER1.INTRODUCTION6lesschemicalsenterthewastestreamandlessenergyandchemicalsarerequiredtoproducethecompound.Catalystscanbeconsideredoneofthemosteectivemeansofmakingacertainchemicalreactiongreener.Acatalystisachemicalsubstancethatincreasestherateofachemicalreactionwithoutbeingconsumeditself.Acatalystlowerstheactivationenergyforareaction,inturnboostingthespeedandallowinglessenergytobeinputintothereaction.Reactionswithoutcatalystsusuallyrequirestoichiometricamountsofreagentsthatendupaswastefulbyproductsiftheydonotbecomeacomponentofthedesiredproduct.Acatalystthereforeisbenecialbecauseonlyasmallamountofitisrequiredforareactiontooccuranditutilizeslessenergy.Anidealcatalystsignicantlyacceleratesareaction,isonlyneededinminuteamounts,ishighlyselectivewithrespecttoitsreactionpathway,andlastsforever.Aminuteamountisdesirablebecauseverylittleofthecatalystwouldenterthewastestream.However,itisevenmoredesirabletohavethecatalystberecoverablefromsolution.Oneareaofgreenchemistrythathassomewhatlaggedisthedevelopmentofoxidationchemistry.Manyoftheclassicoxidationmethodsusedinsynthesisinvolvestoichiometricamountsofreagentsthataregenerallyveryhazardoustohandleanddispose,theprototypicalexamplebeingCr(VI)reagents.Also,oxidativetreatmentofwastewaterhasalsobeenlacking,withozoneandchlorinegasbeingtheonlymethodsavailabletodestroycomplexorganiccompoundsanddisinfectwastewater.Thisisinstarkcontrasttoreductivechemistry,whichhasforyearsbeenmainlybasedoncatalyticreagentsthatactivatehydrogengas;handlinghydrogencomeswithit'sownrisks,buttheamountofwastedisposedissignicantlylesscomparedtomodernoxidationmethods.Also,reductionusuallyinvolvesanadditionmechanismtoacompound,leadingtogreateratomeconomyduetoincorporationofmorereagentcomponentsintotheproduct.Directreductiveadditionofhydrogenacrossanalkeneorcarbonyldoublebondisveryatomeconomicwhendonecatalytically.

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CHAPTER1.INTRODUCTION7Probablythegreenestoxidizingagentishydrogenperoxide,duetoitsdecomposi-tionintowaterandoxygenupondegradation.However,theuseofhydrogenperoxideislimitedduetoitstemperedreactivity;thisisduetothestrengthoftheperoxideO-Obond(51kcal/mol).Therefore,signicantinteresthasbeenputintothepossibilitytocatalyzethereactionofhydrogenperoxidewithvarioussubstrates.1.2LookingtoNatureforInspiration:Peroxidase,Catalase,andCytochromeP450EnzymesasNa-ture'sCatalyticOxidantsLivingorganismsusethechemistryofironinordertoactivatebothoxygenandhydrogenperoxideforreactivity.Ironinsolutionreactsreadilywithhydrogenper-oxide,buttendstoformsperoxyandhydroxyradicals,speciesthataremuchmorediculttocontrolandthereforetendstogobyundesiredpathways.ThistypeofreactionisknownasFentonChemistry.Inaddition,chainreactionstendtobecharacteristicofradicals,withmanythousandsofstepsoccuringbeforeterminationoftheprocess.Radicalsarealsoveryharmfultolivingorganisms,somuchsothatcellshavespecicsystemsfordealingwiththesereactivespecies,suchassuperoxidedismutase.Therefore,organismsusecoordinatedhigh-valentironintheircatalyticprocessestotempertheformationofradicals.Thisnon-Fenton-typechemistryisalsowhatwouldbedesiredinasyntheticcatalystsystemthatwouldactivatehydrogenperoxide.Therefore,naturecouldbeagoodinspirationforecientgreencatalyststhatutilizethereactivityofhydrogenperoxide.[14]Livingthingsnaturallyproducehydrogenperoxidecontinuallyasanunintendedbyproductofoxygenmetabolism.Inmanyprocesses,oxygenisreduceddowntowaterorotheroxygenspeciesbycatalysisataporphyrin-boundiron.Acommon

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CHAPTER1.INTRODUCTION8intermediateinmanyoftheseprocessesisahydroperoxidespeciesthatwillsometimesescapebinding.Ourbodieshavedevelopedaseriesofenzymes,theperoxidasesandcatalases,thatcatalyzethedegradationofthesespeciesinordertopreventextensivedamagefrombeingdonetoourcells.Thesesystemsprovideinterestingbiologicalmodelsforhowhydrogenperoxidecouldbeactivatedbysyntheticcatalysts.[15]Theenzymessystemsdiscussed,theCytochromeP450,peroxidase,andcatalaseenzymes,herewereselectedduetotheirsimilarcatalyticcyclestothegreenoxidationsystemsthatwillbediscussedinlatersectionsinthischapter.1.2.1CytochromeP450EnzymesCytochromeP450enzymesareadiversefamilyofenzymesthatcatalyzeabroadvarietyofoxidationreactionsonbothendogenousandexogenouscompoundsinbothprokaryoticandeukaryoticorganisms.Theseenzymesarethemainwayhumansoxidizemostxenobiotics,suchaspharmaceuticals,sothattheselipophiliccompoundsbecomemorewatersolubleandeasiertoexcrete.Greaterthan90%ofdrugsconsumedbyhumansaremetabolizedbyacytochromeP450enzyme;thisgeneralreactivityhasledtoextensivestudyofthisenzymesystemfordecades.Theseenzymesareabletoperformavarietyofreactions,suchasthehydroxylationofsp3andaromaticcarbons,theepoxidationofolens,oxidationatnitrogenandsulfur,anddealkylationatnitrogenandoxygen.CatalyticactivityisperformedbyanFe(III)-porphyrincoenzymeboundtotheenzymebyacysteinecoordinatingtooneoftheaxialpositionsontheiron.Theotheraxialpositionisoccupiedbywaterintherestingstate.[16]

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CHAPTER1.INTRODUCTION9 Figure1.2:MechanismofCytochromeP450activationofoxygen.Notethatthehy-drogenperoxideshuntwouldcausethismechanismtobeginonstructureE',removingthenecessaryelectrondonationsteps.[16]Bindingoftheoxidizingsubstrateleadstoconformationalchangesthatcausethelossoftheaxialwaterligandoniron.ThischangestheironfromalowspinS=1/2species(A)toahighspinS=5/2species(B).ThischangeinelectronicstatemakestheironmorereceptivetoelectrontransferbyCytochromeP450reductase,leadingtothechangeofFe(III)(B)toFe(II)(C).Thisstepthenleadstoformationofthedioxygencomplex(D),leadingbacktoanFe(III)oxidationstate.AsecondelectrontransferstepleadstotheformationofanucleophilicFe-(III)-peroxospecies(E),whichreadilydeprotonatesneighboringwatermoleculestwice(E').Thisdihydroperoxo-Fe(III)speciesthenreadilydecomposesintotheiron-oxointermediate(F),themainreactivespecies,withlossofwater.Thisironspeciesthenreactswiththesubstrate,leadingbacktoformationofthefreeFe(III)intermediate(A).CytochromeP450enzymescanreactdirectlywithhydrogenperoxidetoproducethehydroperoxo-Fe(III)speciesbyaprocessknownasthehydrogenperoxideshunt.Thisspeciesdecomposes

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CHAPTER1.INTRODUCTION10tothereactiveiron-oxospecieswithoutelectrondonation.[17]Originally,theiron-oxospecieswasbelievedtobeanFe(V)-oxospecies.However,Recentstudieshaveactuallycapturedspectroscopicevidenceofthemainreactiveoxointermediate,andithasbeenfoundtoactuallybeanFe(IV)-oxointermediatewitharadicalformedoneithertheporphyrinringorthethiolateligandfromtheaxialcysteine.[18]1.2.2PeroxidaseandCatalaseEnzymesPeroxidasesandcatalasesalsoinduceheterolyticcleavageoftheperoxideO-Obond,butinsteadtypicallyusehydrogenperoxideasthesubstrateinsteadofreducingoxy-gentoformaperoxidespecies.Thesespeciesusetheactivatedintermediatetoeitheroxidizevarioussubstratesortodeactivateperoxidespeciesthroughoxidizingasub-strate.Theactivesitestructureisverysimilartocytochromep450enzymes,exceptthattheaxialaminoacidisahistidineimidazoleinperoxidasesandthephenolateionofatyrosineresidueincatalases.Figure1.3:ProposedSchemeforperoxidaseactivity.[14]Peroxidaseenzymestypicallyconsumeperoxidesbyoxidizingaseparatespecies.Theperoxidasemechanismisstillasubjectofdebate,butisknowntoconsistofthreesteps.InitialreactionofhydrogenperoxidewiththeFe(III)-hemeactivesiteleadstoformationofanFe(IV)-oxohemewitharadicalcationformedoneitherthehemeoratryptophanresidueintheprotein(compoundI).Waterisformedasaproductofthis

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CHAPTER1.INTRODUCTION11step.Inthenextstep,theradicalcationformedoxidizesonemoleculeofthesubstrateintoaradical,formingtheFe(IV)-oxospecieswithnoradicalresidues(compoundII).Thisspeciesthencatalyzestheoxidationofanothermoleculeofsubstrateintoaradicalspecies,formingwaterandregeneratingtheoriginalFe(III)species.[14]Catalasehasasimilarmechanismtoperoxidaseenzymes,butinsteadcompoundIundergoesatwoelectronreductioncausedbyasecondmoleculeofhydrogenperoxideasthesubstrate.Therefore,nocompoundIIisisolated.Thissecondmoleculeofhydrogenperoxideisconvertedintomolecularoxygen,aspeciesthatismuchmoretameinitsreactivitythanhydrogenperoxide.[14]1.3TAMLOxidationCatalystsDr.TerrenceJ.CollinsatCarnegieMellonhasworkedforthepastthirtyyearsonthedevelopmentofgreenoxidationcatalysts.Thesesystemsmimicmanyoxygen-activatingsystemsinthattheyuseFe(III)coordinatedtoaplanarporphyrin-likeligand.Collinshasusedaniterativeprocessindesigningthesecatalysts,analyzingthedegradativebyproductsofproposedcompondstodeterminepointsofweaknesswithinthepreviousliganddesignandthenredesigningthenextligandtohaveadditionalstabilityatthepointofcleavage.ThishasleadCollinstodevelopseveralrulesforthedevelopmentofgreenoxidationcatalysts.Fe(III)-TAMLcatalystshavebeenfoundtohavebothstructuralandmechanisticfeaturesthataresimilartothoseseeninCytochromeP450,peroxidase,andcatalaseenzymes.Catalyticcyclesdevelopedbyenzymesaresomeofthemostecientknown,sousingourmechanisticknowledgeoftheseenzymescanbeusedtodevelopsyntheticcatalyststhathavesimilarreactivitiesthatwewouldliketoutilize.

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CHAPTER1.INTRODUCTION121.3.1TAMLCatalystDesignTAMLdesignwasdonebyaniterativeprocess.Aligandwassynthesizedanditsoxidativestabilitywasthenanalyzed.Whentheliganddegraded,theproductswereanalyzedinordertodeterminepotentialmechanismsfortheoxidativecleavage.Thesemechanismswerethenusedtoadjustliganddesignstoproperlyprotectthenewiter-ationfromthepreviousdegradation.Fromthisprocess,Collinswasabletodevelopthreemajorrulesthatgovernthedevelopmentofligandsforoxidationcatalysts.[19]Forchelaterings,ahydrogenatomshouldnotbeplacedonanatomthatistoanoxidizingmetalcenter,iftheatomcansupportanincreaseinbondorderwiththe-atom.[19] Aheteroatomshouldnotbeattachedtoavememberringonanatomthatisrtoanoxidizingmetalcenter,iftheheteroatomhasanavailablelonepairthatcanstabilizedevelopingcationiccharacteronther-atomastheendocyclic-rbondisoxidativelycleavedbythemetal.[19]

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CHAPTER1.INTRODUCTION13Aheteroatomshouldbenotemployedasan-donorinavememberchelatering,ifithasanavailablelonepairthatcanstabilizeformingcationiccharacteronthe-atomastheendocyclic-rbondisoxidativelycleavedbythemetal.[19] Thesecharacteristicdegradationpathwayswerediscoveredthroughthehistoricalde-velopmentoftheTAMLcatalystsystemandcanbeusedgenerallyasguidelinesinthefuturedesignofanyligandsystemforanoxidativemetal. Figure1.4:IterativeprogressionofTAMLdesign,witheachprogressingligandbeingmuchmorerobustagainstoxidativedegradationthanthepreviousliganddesign.[20]TAMLshavegonethroughseveraliterationsofdesignsincethe1980s.Theoriginaldesignsinvolvedtwoamidesandtwohydroxylsastheoriginaldonatinggroupsfor

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CHAPTER1.INTRODUCTION14theligand.Theoriginalligand(1980)wasbridgedbyethylenediamine,butthiswasfoundtobedestabilizingbytherstdegradationpathwayandwasreplacedbyphenylenediamine(1982).Thenextmajorchangewastoreplacethehydroxylgroupswithamides(1987),duetotheirgreaterstabilitytooxidativedegradationbythethirddegradationpathway.Thisalsoledtothedevelopmentofamacrocycleringstructurethatmuchmorecloselyresembledthehemeringsinoxidizingenzymesinnature.[20] Figure1.5:Designsofrst-generationTAMLcatalystsystems.[21]Thenewdesignhada5,6,5,6-chelatestructure,whichwasfoundnotbeasstableasa5,5,5,6-chelatestructureusedinlateriterationsduetoitsmuchmorerigidplanarstructure(1989).Fromhere,themaindegradativeproblemsinvolvedtheethylsidechainsonthemalonatefragmentofthering.Thesesubstituentswereswitchedtomethyls(1994),butthisdidnotresultinasignicantincreaseincatalyststability.Thesubstituentswerechangedintoacyclobutane(1996)andcyclopropane(1997)ringtobringthealkylsoutofthewayofthemetal,andnallytouorines(2000),

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CHAPTER1.INTRODUCTION15duetothenotedeectelectron-withdrawingsubstituentshaveonthetailendofthemoleculewithrespecttostabilitytoacid-catalyzeddemetallation.[20]1.3.2Fe(III)-TAMLs:StructureandMechanismIfacatalystismodeledafteranenzyme,thestructureofkeyintermediatesandthemechanisticpathwayofactivityforthecatalystshouldbefairlysimilar.Therefore,theoxidizedstatesofFe(III)-TAMLcatalystswillbereviewedinordertoshowcasestructuralsimilaritiesanddierences.Thecatalyticactivityofthesecatalystswillalsobeexaminedusingakineticmodelbasedoofperoxidaseandcatalaseenzymes.Asimilarkineticprolesuggestspotentialsimilarintermediateswithinthemecha-nism.Catalystmodelsforenzymesoftendisplaydecreasedactivityascomparedtoen-zymesduetotheirhigherexposuretothesolventenvironment.Enzymesactivesitesareusuallyprotectedbytheirpolypeptidechains,andtheidealpHforactivitycanbemaintainedbythepeptideenvironmentwithintheactivesite.Often,syntheticcatalystsneedtohavemorerobuststructuresthantheirenzymaticcounterpartsinordertolastlongenoughtoproducereasonableactivity.Therefore,thepotentialmechanismsfordeactivationofFe(III)-TAMLcatalystswillalsobeexplored.WithinthesestudieswillalsobeexploredhowthestructureoftheTAMLcatalystsisfoundtoaecttheirsuspectibilitytodeactivation.

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CHAPTER1.INTRODUCTION161.3.2.1Fe(III)-TAMLCatalystSolid-StateStructure Figure1.6:Crystalstructuresofselectrst-generationFe(III)-TAMLcatalysts.[21]CrystalizedFe(III)-TAMLcatalystsareve-coordinatetetragonalpyramidalspecieswithasinglecounter-ion(eitheralithiumortetraphenylphosphoniumcation).Theironinthissolid-statespeciesisoutoftheplaneoftheringbyabout0.4.TheFe-Clbondlengthisquitelongascomparedtootherspecies(suchasFeCl4).Theconformationofthesix-memberedchelateringisdependentuponthesubstituentsontheringatthispoint,themalonateend.Alkylsubstituentstendtoleadtoaboatconformation,whileuorinesleadtoachairconformation.Thismayplayaroleintheoxidativestabilityofthediuorospecies.[23]

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CHAPTER1.INTRODUCTION171.3.2.2CoordinationofFe(III)-TAMLsinAqueousSolution Figure1.7:StepwiseligandsubstitutionoftheaxialaqualigandsinanFe(III)-TAMLsysteminaqueoussolution.TheligandLusedwaseitherpyridineorimidazole.[21]ThechlorospeciesofFe(III)-TAMLsundergoquickhydrolysisinwater,leadingtoformationofasix-coordinatedspecieswithtwoaxialaqualigands.Thisquickhy-drolysisisduetothesignicantlengthoftheFe-Clbond,longerthanthatseeninFeCl4.TheUV/VisandEPRspectraisinvariablefrompH5-8,butvariesstronglyfrompH8-11duetothedeprotonationofanaxialaqualigandtothecorrespond-inghydroxospecies.[10]Inaqueoussolution,ligandsubstitutionofsix-coordinatespeciesisastepwiseprocess.ThiswasdeterminedbyobservingtheUV-Visspectralchangesuponadditionofpyridinetoanaqueoussolutionoftheligand.Imidazolewasfoundtobehavesimilarly.Thisstep-wisesubstitutionwillplayasignicantroleingeneral-acid-catalyzeddemetallationofthesesystems.[24]

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CHAPTER1.INTRODUCTION181.3.2.3OxidizedFormsofFe(III)-TAMLs-Fe(IV)andFe(V)Species Figure1.8:Bis-Fe(IV)--oxocomplexformeduponairoxidationofFe(III)-TAMLligandsdissolvedinorganicsolvents.Therightgureisthecrystalstructureoftheblacksolidisolatedfromthesesolutions.[25]Thephosphoniumsaltsofrst-generationFe(III)-TAMLcatalystsarereadilysolubleinorganicsolventsandformredororangesolutionsthatremainthiscolorunderanitrogenatmosphere.However,uponexposuretoairorbubblingwithO2thesesolutionsinstantlyturnblackwithprecipitate,thespeciesbeingformedinalmostquantitativeyield.Thecrystalstructureoftheseisolatedspeciesshowedthatthecatalystsformedbis-Fe(IV)--oxocomplexes.TheMossbauerspectraofthisspeciesat4.2KrevealfeaturescharacteristicofanS=1Fe(IV)species;however,thesespec-tradonotruleoutthepossibilityofthelocalsitesbeinghighspinS=2Fe(IV).Astudyinvolvingthereactionofthebis-Fe(IV)--oxospecieswithPPh3,wheretheoxidizedTAMLwasformedwithisotopicoxygenandleadingtotheformationoftriphenylphosphineoxide,revealsthatthebridgingoxygenspeciesformsfrommolec-ularoxygen.[25]

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CHAPTER1.INTRODUCTION19 Figure1.9:UV-VisspectralchangesofanFe(III)-TAMLcatalyst(2.5E-5M)inthepresenceof0,2E-6,4E-6,6E-6,8E-6,12E-6,16E-6Mhydrogenperoxide.Theinsetshowsthehydrogenperoxidetitrationcurvesat242,280,and420nmthatdemonstratesthe2:1ratioofFe(III)-TAML:H2O2.[26] Figure1.10:ProposedmechanismfortheformationofanFe(IV)-oxospeciesinaque-oussolution.Notethecleavageofthebis-Fe(IV)--oxocomplexbythebasicsolutiontoformtheFe(IV)-diaquaandFe(IV)-oxocomplex.[26]AdditionofH2O2ort-BuOOHtoanaqueoussolutionofrstgenerationFe(III)-TAMLcatalystsleadstotheformationofbrownish-greensolution.ThechangescanbefollowedbyUV-Visspectroscopy,wherelessthanastoichiometricequivalentofperoxideproducesasignicantspikeinabsorbancebetween350-500nm.ThestabilityofthisabsorbancecomesmuchmorequicklythehigherthepHofthesolution.A

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CHAPTER1.INTRODUCTION20titrationoft-BuOOHwiththeFe-(III)TAMLcatalystsshowsthat0.5equivalentsofhydrogenperoxideareneededtocompletelyformtheoxidizedspecies.TheMossbauerspectrumofafrozenaqueoussolutionofthisspeciesdemonstratespresenceofaFe(IV)specieswhichistheonlyspeciespresentaroundpH14andwhichhasdecreasingstabilityatpH<12.BasedontheUV/Vis,Mossbauer,EPRandEXAFSdataofthesespeciesinaqueoussolution,itappearsthattheperoxideactsasatwoelectronoxidant,convertingtheTAMLsystemintoanFe(V)complex.However,thisspeciesquicklyconproportionateswithafreeFe(III)-TAMLsystemtoproducetheobservedFe(IV)-oxospecies.BaseduponDFTcalculations,thisspeciescouldalsoeasilyexistsasanFe(IV)-diaquaspecies.ThepreferredspinisS=1,ascomparedtothehigh-spinandlow-spinstates.[26]IfthetetraphenylphosphoniumsaltoftheFe(III)-TAMLcomplexisreactedwithm-chloroperbenzoicacidat-60Cinnonaqueousmedia(n-butyronitrile),anFe(V)-oxospeciesisformedafterfteenminutes.ThespecieswascharacterizedbyEPRandMossbauerspectroscopy.Thisspeciesisstableforatleastamonthat77K,butdegradesby10%in90minuteswhenkeptat-60C.BaseduponDFTcalculationsofthestructure,thespinpreferenceisthelowspinstateofS=1/2.

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CHAPTER1.INTRODUCTION211.3.2.4TAMLOxidationMechanisms:Peroxidase-andCatalase-likeAc-tivity Figure1.11:Peroxidase-andcatalase-likeactivityofFe(III)-TAMLcomplexes.kIrepresentstheobservedrateoftheinitialoxidationoftheFe-TAMLcomplex,kIIrepresentstheobservedrateofperoxidaticactivity,andkIIIrepresentstheobservedrateofcatalaticactivity.[21]Fe(III)-TAMLligandsdemonstratesignicantperoxidase-andcatalase-likeactivity.Generally,catalase-likeactivitycanbeignoredwithstrongreducingsubstrates,lead-ingtoasimpliedmodelforperoxidaseactivityoftheenzyme,basedontheequationd[S(red)] dt=kIkII[FeTAML][H2O2][S(red)] kI+kI[H2O2]+kII[S(red)]where[Fe-TAML]isthetotalconcentrationofTAMLcatalystinsolutionand[S(red)]isthereducingsubstrateforthecatalyst..ThisequationimpliesthatTAMLcata-lystsshouldmimicthesteady-stateoxidationcatalyzedbyperoxidaseenzymes.Thisequationisformedbyapplyingthesteady-stateapproximation,asusedinbiochem-

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CHAPTER1.INTRODUCTION22istry,tothestepsingure1.11,ignoringthecatalaticactivity.TheequationhasbeentestedusingOrangeIIdye(gure1.13)andhydrogenperoxideatvaryingconcentra-tionsofthesetwosubstrates.ThesedatasuggestthatkIisnegligibleandthattheratesleveloutwithincreasingreagentconcentrations,aswouldbeexpectedfromtheequationabove.Ascanbedeterminedfromtheaboveequation,lowconcentrationsofhydrogenperoxideleadtothekIstepbeingratelimiting,leadingtotheformofthecurvebeingmainlydependentuponhydrogenperoxideconcentration.However,whenhydrogenperoxideconcentrationsbecomehighcomparedtoOrangeIIconcen-tration,thekIIstepbecomesratelimiting.Thisleadstotheformationofdistinctthree-dimensionalplotsforthesereactions.ThekIandkIIvaluesforthesereactions,3.5103and1.5104M1s1,respectively,showveryhighactivityforFe-TAMLactivators.[27] Figure1.12:Three-dimensionalplotdemonstratingthedistinctivekineticbehaviorofFe(III)-TAMLcatalystswithrespecttoconcentrationofsubstrate(OrangeIIdyehere)andhydrogenperoxide.[27]Inordertoproperlyparameterizetheperoxidase-likeactivityofanFe(III)-TAMLcatalyst,conditionsmustbefoundwherethehydrogenperoxideactivationstepis

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CHAPTER1.INTRODUCTION23ratelimiting,i.e.havingthekIIstepbeextremelyfast.Also,thesubstrateshouldbestableoverawidetemperatureandpHrangeinordertopreventchangesinthesubstratefromaectingtherate.ARu(II)complex(Fig1.13)wasfoundtobethebestsubstrate,beingagoodreducingagent(thusreactingveryquickly)andbeingstableoverawidepHandtemperaturerange.[28] Figure1.13:DyesusedtotracethekineticsofFe-TAMLcomplexes.[21] Figure1.14:CharacteristicpHproleforTAMLligandsatvarioustemperatures.NotehowtheratepeaksaroundpH10.ThedashedlinerepresentsthecalculatedkIII(catalatic)ratewithrespecttopH.NotehowthisrateremainsclosetozerountilthepHreachesnearpH10.[28]

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CHAPTER1.INTRODUCTION24Forthissubstrate,therateswereexaminedoverawidepHrange.TherateswerefoundtobedirectlyproportionaltobothFe(III)-TAMLandhydrogenperox-ideconcentration,whilethesteady-staterateisindependentoftheconcentrationofsubstrate.ThisrelationshipwasfoundtoholdoverthewholepHrangeexamined.[28]Thissuggests,asexpected,thattheratelimitingstepinvolvesthecatalystandhydrogenperoxide,asdesired.Therateconstant,however,appearstovarydepend-ingonthepH.Therateconstantrisessharply,peakingaroundpH10,anddropsathigherpH. Figure1.15:ProposedmechanismforpHdependenceofperoxidaticactivity.Ka1representstheequilibriumconstantfordeprotonationoftheoneoftheaxialdiaqualigandsintheFe-TAMLcatalyst.Ka2representstheequilibriumconstantforde-protonationoftheperoxidespecies.k2isdeemedthelargestrateconstant,betweendeprotonatedcomplexandneutralperoxide.ThisprotonationstateoccursaroundpH10forthetworeactants.[21]ThisbehaviorcanbeanalyzedusinganapproachthatusestheknownpKa'softhecatalystandhydrogenperoxide.Bythisapproach,thediaqua-andaqua/hydroxy-Fe(III)-TAMLcatalysts(Ka1)canreactwithhydrogenperoxideoritsconjugatebase(Ka2)togivefourpotentialrateconstants,k1-k4.Determinedexperimentally,theratesconstantsk1andk4aresignicantlylessthank2byafactorof100and10,respectively.Thevaluesfork3aresosmallthattheycanbedeemedinsignicant.Therefore,thefastestprocessinvolvesneutralperoxideanddeprotonatedcomplex.Thismakessense,sincethemoreelectronrich-2complexwouldbemoreeasilyoxi-dizedthanthe-1complex.AtpH>10.5,wherebothspecieswouldbedeprotonated,

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CHAPTER1.INTRODUCTION25acoulombicrepulsionexplainsthedropoinreactivity.pKa1wasdeterminedtobearound9.3-9.6andpKa2wasdeterminedtobe10.4-10.9.Therefore,a-2chargeonthedeprotonatedcomplexandaneutralperoxidewouldexistaroundpH10.ThiscanhelprationalizetheobservedmaximuminthepHdependenceoftheobservedrateconstantkperobs.[28] Figure1.16:Hammettplotshowingthecorrespondencebetweentheelectron-withdrawingcharacterofthearomaticheadsubstituentsandtheobservedperoxidase-likeactivityofthecomplex.[28]Peroxidaseactivitydependsoncatalystdesign.AHammettplotrevealsthatcatalystswithelectronwithdrawingsubstituentsreactslightlyfasterthandonatingcatalysts.Thisatrstdoesn'tappeartomakeanysense,becauseadonatingligandwouldmoregreatlystabilizetheimportantFe(IV)orFe(V)intermediates.[28]How-ever,thisleadstoanalysisofthestepsthatleadtoconversionofhydrogenperoxideintotheiron-oxointermediate.Coordinationofhydrogenperoxidetoalewis-acidicmetalwouldleadtopolarizationofthehydrogenperoxidebond.Theboundoxygenwouldbecomepositivelycharged,increasingacidityatthissite,leadingtodeproto-nation.Thefurtheroxygenwouldbecomepartiallynegativeincharge,increasingbasicityandallowingforthisoxygentobecomeprotonated.ThispolarizationsetsupfortheeventualdegradationintotheFe-oxospeciesandwater.Therefore,acat-

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CHAPTER1.INTRODUCTION26alystwithhighlewisaciditywouldleadtosignicantpolarizationoftheperoxideO-Obond,increasingtherateofformationforthereactiveiron-oxospecies.Thisisbasicallyabattlebetweenkineticsandthermodynamics.Thearomaticheadsub-stituentsappeartobethemaineectorsofthiscatalyticactivity,whichexplainswhynitro-substitutedTAMLsaresomeofthemostreactive.Whennosubstrateispresent,TAMLcatalystsalsodemonstratecatalase-likeac-tivity,wheretheoxidizedcomplexconvertsonemoleculeofhydrogenperoxideintomolecularoxygen.Inpracticalterms,thisreactionisundesirablebecauseitdegradestwomoleculesofhydrogenperoxidethatotherwisewouldhavedegradedtwomolesofsubstrate.Thereactionstoichiometryisgivenby TherateforthisreactionwasfoundtoberstorderwithboththeTAMLcatalystandoxygen.Therefore,thegeneralrateequationmatchesthatfortheperoxidaseactivity.Thesimilarratelaws,pHproles,andsecond-orderrateconstantssuggestacommonreactiveintermediate.TherateexpressionforperoxidaseactivitywhenaccountingforthecatalaseactivityisgivenbyRate=kIkII[FeTAML][H2O2][S(red)] k1+[H2O2](kI+kIII)+kII[S(red)]whereS(red)isanappropriateelectrondonorsubstrate.IfweassumethatkII[S(red)][H2O2](kI+kIII)g,basedupontheknowledgethatoxidationoftherutheniumdyeusediszeroethorder,theperoxidase-likerateequationbecomesRate [FeTAML][H2O2]=kperobs=kITheCatalase-likeactivityisdescribedby

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CHAPTER1.INTRODUCTION27Rate=kIkIII[FeTAML][H2O2]2 kI+[H2O2](kI+kIII)+kII[S(red)]Duetotherstorderdependenceinhydrogenperoxideforcatalaseactivity,[H2O2](kI+kIII)>>fkI+kII[S(red)]g,andthecatalase-likerateequationsimpliestoRate [FeTAML][H2O2]=kcatobs=kIkIII kI+kIIITherefore,therateequationsbecomebasicallythesameforboththeperoxidase-likeandcatalase-likemechanisms,suggestingthatacommonintermediateispresentforbothofthesemechanisms.Thenextpointofanalysisiswhetherthecatalase-likerate,kIII,isaectedbypH.TheshapeofthecurveforpHdependenceforkIII(dottedlineingure1.14)isrelativelyatbutbeginstoincreaseabovepH10,thepKarangefordeprotonationofhydrogenperoxide.Deprotonatedperoxideisamuchbetterreducingagentduetotheincreasednegativechargeonthespecies,givingreasonableexplanationastowhytherateconstantincreases.[28] Figure1.17:Decreaseincatalase-likeactivityofFe-TAMLcatalystswithincreasingconcentrationofaSafranineO.TherateofoxygenformationwasmeasuredusingaClarkelectrode.[28]

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CHAPTER1.INTRODUCTION28ThisleadstothequestionwhetherTAMLcatalystscanachieve100%eciencyinperoxidaseactivity.Ifbothperoxidase-andcatalase-likeactivitygothroughacommonreactiveintermediate,thisrunstheriskofdecreasedeciencyduetocom-petitionbetweenthesubstrateandthehydrogenperoxidewiththeactivatedcatalyst.Toachievegoodperoxidaseeciency,therateconstantkImustbesignicantlyhigherthantherateconstantkIII,basedontheequationfortherateofcatalaseactivity,thiscanbeachievediftherearesignicantconcentrationsoftheelectrondonatingsubstrate.Thiswasfoundtobethecase,withtherateofoxygenformationde-creasinghyperbolicallywithincreasingconcentrationofsubstrateuponincreasingconcentrationsofaverygoodelectron-donatingsubstrate,SafranineO(gure1.13).[28]Therefore,aslongassucientsubstrateisaround,thesecatalystshavequiteecientperoxidaseactivity.1.3.2.5TAMLDeactivationMechanisms-AcidandBuerDemetallationMechanismsAqueoussolutionsofTAMLcatalystswillremainstableformonthsatneutralpH,butthetypicalUV/Visbandforthecatalysts(360nm)willfadeuponplacingthecatalystsinacidicsolutions(pH3-4).Freeligandcanbeisolatedin>95%yieldwhenthemetallatedcatalystsareplacedinsolutionsatpH=1.Theconditionsarefoundtobepsuedo-rstorderforreactionwithHClO4andHCl,withtherateconstantfoundtobedescribedby Thek1pathwaywasfoundtoundergoaninversekineticisotopeeect,suggestingthattheratelimitingstepforthisprocesscouldinvolveprotonationofanamidenitrogenoranN-Febondintheligand,formingthemorestableN-Hbond.Thek3pathwayisbelievedtoinvolveprotonationsontheperipheralpartsoftheligand.Underweaklyacidicconditions(pH=2-3),thek1pathwaysdominates,whileunderhighlyacidic

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CHAPTER1.INTRODUCTION29conditions,thek3pathwaydominates.Thissuggeststhatthek3pathwayinvolvesprotonationofthetailamideoxygens,whichwouldthenreducethestabilityofligandbindingbyreducingthebasicityoftheamidenitrogens.Amidenitrogenprotonationisnotbelievedtobeoccuringbecauseonlyasingleprotonwouldberequiredtobreakplanarityandcausedemetallationofthecomplex,whiletheratedependenceforthisportionoftheobservedrateisthirdorderinprotonconcentration.Thisisbasedooftheknowledgeoftherelativestabilityofplanarcomplexesascomparedtothosethataredistorted.[23]DFTcalculationsonthediaquacomplexareconsistentwiththesemechanisticconclusions.TheHOMOofthecomplexwasfoundtobediusivelydistributedoverthewholemolecule,butthesecondaryHOMO(sHOMO)wasfoundtobecenteredonlyonthetailnitrogensandoxygens.ThesHOMOwasalsofoundtobeverycloseinenergytotheHOMO,meaningthatsolvent-basedeects(theDFTcalculationswereperformedinthegasphase)couldpotentiallychangetheseenergylevels,renderingthecurrentsHOMOactuallyasthehigherenergyorbital.Thismolecularorbitalpicturedemonstratesthatthemostlikelypointofprotonattackonthemoleculeisatthetailend.[24] Figure1.18:TheHOMO(left)andsHOMO(right)ofTAMLcatalysts,aspredictedfromDFTcalculations.[24]TAMLcatalystswerealsofoundtodegradeinsome(butnotall)Bronstedacidbuersystems.Pyridine(py)andtris(hydroxylmethyl)aminomethane(TRIS)sys-

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CHAPTER1.INTRODUCTION30temsareinactive,butaceticacid,phosphate,andmalonicacidbuersinducedemet-allation.Thepsuedorst-orderrateconstantk1;effappearstodependlinearlyonphosphateconcentration,andtheproleoftherateconstantwithpHissigmoidinshape,withtheinectionpointoccuringat6.5,thepKaofdihydrogenphosphate.ThisimpliesthatH2PO4isthemainspeciescausingthedemetallation.Thisledtoaproposedmechanismforphosphate-induceddemetallationthatinvolvesphosphatebindingfollowedbyprotontransferanddemetallation.[24] Figure1.19:ProposedmechanismforBuer(general-acid)catalyzeddemetallationofFe-TAMLcatalysts.Thebuerinthismechanisticexampleisphosphatebuer.Theproposeddemetallatingspeciesisdihydrogenphosphate.[24]ByanalyzingtheratesfordierentTAMLcatalysts,thetailsubstituentsarefoundtohaveasignicanteectontherateofthereaction,similartowhatisobservedinspecicacidcatalyzeddemetallation.TheabilityofabuertodemetallatedaTAMLcatalystisstronglydependentupontheacidityandstructureofthebuer.Picolinicacidcausesdemetallationevenontypicallystablecatalysts,whilenicotinicandisonicotinicacidareinactive.Thisresultisrationalizedbybuer-induceddemet-allationonlybeingcausedbyintramolecularprotondeliveryfollowingbindingofthebuerspeciestooneoftheaxialpositionsofthecatalyst.Therateisrstorderinpicolinicacidforlessstablecatalysts,butformorestablecatalyststheratewasfoundtobesecondorder.Thiswasfoundtoberationalizedbytheneedforasec-

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CHAPTER1.INTRODUCTION31ondaxialpicolinicacidligandinordertoinducedemetallation.Also,itwasfoundthattheadditionofpyridineornicotinicacidincreasedtherateforpicolinicaciddemetallations.Thiswasrationalizedtomeanthatthedemetallationinmorerobustcatalystsrequiresaligandthathasadonorcapacityonthemetal,butthatiswasnotnecessarytohavethecarboxylicacidonthissecondaxialligand.Thissuggeststhattheroleofthesecondaxialligandistodecreasethelewisacidityofthemetalbyelectrondonationfromanaxialligand,thereforeincreasingtheelectrondensityontheamidatenitrogensandincreasingtheirbasicity.[24] Figure1.20:ProposedequilibriaforFe-TAMLdemetallationbypicolinicacid.Thisschemehighlightsthebindingroleofasecondaxialdonatingligandindemetallationformorerobustcatalysts.[24]1.3.2.6OxidativeDegradationofFe(III)-TAMLsTAMLsmaybedegradedeitherintermolecularlyorintramolecularly.Intermolec-ulardegradationmaybeminimizedbykeepingcatalystconcentrationlow,whileintramoleculardegradationisentirelydependentuponcatalystdesign.Themajorproposedmechanismsforintramolecularoxidativedegradationwereoutlinedearlierinthediscussionabouttheiterativedesignoftheseligandsystems,sothefocushere

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CHAPTER1.INTRODUCTION32willbeontherelationshipbetweencatalyststructureandthekineticnatureofbothactivityandoxidativedegradation.TheoverallmechanisticpictureforTAMLactiv-itycanbeviewedasbelow,includingthetwoacid-catalyzeddemetalationpathwaysandtheintra-andintermolecularoxidativedegradationpathways.[29] Figure1.21:CompletemechanisticpictureforFe(III)-TAMLactivity.[29]TheintramoleculardegradationofTAMLcatalystsmaybeanalyzedbyreactingFe(III)-TAMLcatalystswithSafranineOdyeuntilcompletedeactivationofthecat-alystoccurs.TheideabehindthisisthatFe(III)-TAMLcatalystsareveryslowtoreactwithSafranineO,sotheintermoleculardegradationrateconstantcanbeeasilydeterminedinthissystem.OneinterestingfeaturefoundforTAMLcatalystsisalooseinverselinearfreeenergyrelationshipbetweentherateconstantmeasuringre-activity,kII,andtheintramoleculardegradationrateconstant,ki.WhatwasfoundwasthatTAMLcatalyststhathadelectron-withdrawingsubstituentsontheheadoftheligandwerebothfastercatalystsandalsowerelesssusceptibletooxidativedegradation.Fromthis,aromaticringswithnitrosubstituentswerefoundtobethemoststabletooxidativedegradationandalsosomeofthemostactivecatalysts.[29]

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CHAPTER1.INTRODUCTION33 Figure1.22:LinearfreeenergyrelationshipbetweenthecatalystrateconstantkIIandtheintramolecularoxidativedegradationrateconstantki.ThepointseachrepresentadierentTAMLsystemwithvaryingaromaticheadsubstituents.[29]1.3.3ApplicationsofTAMLSystemsFe(III)-TAMLcatalystshaveabroadrangeofsubstratesthattheyreadilyoxidativelydegrade.WhatisevenmoresignicantisthatFe(III)-TAMLcatalystswilldegrademanysubstratesintomuchmoreinertproductsthanthoseproducedbyotherox-idativedegradationtechniques.Discussedhereareseveralstudiesrelatedtothedegradationofseveraldierentenvironmentalcontaminants,aswellasthepotentialofTAMLcatalystsasdisinfectants.1.3.3.1DegradationofPolychlorinatedPhenolsPolychlorinatedphenolsarecommonlyusedinpesticides,disinfectants,woodpreser-vatives,andpersonalcareproducts,andaresubstantialbyproductsofwoodpulpbleachingbychlorineinthepaperindustry.Growingknowledgeofthetoxicityofthesecompoundshaveleadtoveofthembeinglistedasprioritypollutants.Twoofthesearepentachlorophenol(PCP)and2,4,6-trichlorophenol(TCP),whicharepresentintheenvironmentinlargequantitities.BiologicalmethodsofdegradationofPCPandTCPhavebeentested,butthesemethodsprovetobeslow,ineectiveat

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CHAPTER1.INTRODUCTION34highconcentrationsduetotoxicity,andleadtotheformationofsignicantamountsofdibenzo-p-dioxinsanddibenzofurans,twomoresevereenvironmentalpollutantsusuallyproducedfromthecombustionofhalocarbons.AsystemwasdevelopedbyMeunieretal.thatwasabletodegradePCPandTCP,butledtoverylittleminer-alizationofchlorine,i.e.theformationoforganicchlorideions,adesiredresultforsuchreactions.Fe-TAMLcatalystswerefoundtoworkmuchmoreeectivelyunderambientconditionsinwater,andledtosignicantmineralizationofthecompounds.[30] Figure1.23:Degradationproductsofpentachlorophenol(PCP)and2,4,6-trichlorophenol(TCP)byFe(III)-TAMLcatalysts.Thecompounds(fromtoplefttobottomright)arechloromaleicacid,malonicacid,tartronicacid,chloromalonicacid,3,5-chloro-4-hydroxybenzoicacid,theester7,anddichloromaleicacid.[30]Theconditionsofreactioninvolvedcombininghydrogenperoxide,anFe-TAMLcatalyst,andthesubstrateinpH10water.ThemineralizationofbothTCPandPCPwasdeterminedbyanalyzingtheamountofchlorideionsformandthefromthetotalorganiccarbonpresent.Chlorinewasmineralizedby87%inPCPand83%inTCP.Mineralizationofcarbon(conversionintoCO2andCO)wasmeasuredtobe45%forPCPand35%forTCP.Productsofthedegradationwereanalyzedusingpro-tonNMR,electrosprayionizationmassspectrometry,andgaschromatography-massspectrometry(GC-MS).TCPwasfoundtodegradeintochloromaleicacid,malonic

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CHAPTER1.INTRODUCTION35acid,tartronicacid,chlormalonicacid,2,6-dichloro-4-hydroxybenzoicacid,theester,andtraceresidualTCP.Thetotalaromaticcontentwaslessthan2.5%.Thema-jorproductsforPCPweredichloromaleicacidandchloromalonicacid.Notracesofdioxinsandbenzofuranswerefoundthatwerenotinitiallypresentwithinthestart-ingmaterial.[30]ThisstudydemonstratedtheeasewithwhichTAMLsareabletodegradepolyhalogenatedaromaticcompounds,agroupofcompoundsusuallyquitediculttoremediate.1.3.3.2DegradationofOrganophosphorousPesticidesOrganophosphoroustriesterpesticidesarethemostwidelyutilizedcropprotectants,andtheirwidespreadusehasbeenlinkedtocholinergictoxicity,delayedneuropathy,andendocrinedisruption.Currentmethodsofremediationareinadequate.Chemicalandenzymehydrolysisarecommonlyused,buttheseoftenleadtotheformationofbyproductsofmoderatetoacutetoxicity.Fentonoxidationshavebeenfoundtobeeective,butoperateathighpHvaluesandwithalargeamountofironsalts.Thesludgeformedfromthisprocesscanleadtosignicanteutrophicationinwaterways.[31] Figure1.24:ThethreepesticidesstudiedfortheirdegradationbyFe(III)-TAMLcatalysts,Fenitrothion,Parathion,andChloropyrifosmethyl.[31]CollinsstudiedtheFe-TAMLcatalyzeddegradationofthreeorganophosphorouspesticides:Fenitrothion,Parathion,andChloropyrophosmethyl.Allpesticideswerefoundtoundergodegradation.WhenthedegradationwasinitiallytestedonFen-itrothionatpH8,themajorityofthethiophosphoestermoeitywascleavedinto

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CHAPTER1.INTRODUCTION363-Methyl-4-Nitrophenol,butasmallamountofFenitrooxonwasformedasaproductofpartialoxidativecleavageofthethiophosphoestermoiety.Thisisnotdesired,asFenitrooxonhasaveryhightoxicity.Phosphoestermoeitiesareknowntobereadilycleavedbybasehydrolysis,sothepHoftheconditionswasraisedto10,alsotheidealizedpHforTAMLligandactivity.TheseconditionsledtonotraceFenitrooxonremaining,mostlikelyduetoperhydrolysis.Thenaloxidationproductswereex-aminedbyavarietyofanalyticaltechniques.Thefourmaindegradationproductswereformic,oxalic,maleic,andmethylmaleicacid,andtheproductsunderwent10%mineralizationofcarbon.Degradationofparathionledtotheformationofmaleicacid,whilechloropyrifosmethylledtotheformationofchloromaleicacid.Formicandoxalicacidwerealsoformedbybothofthesepesticides.Thedegradationproductsofthesepesticideswerefoundtohaveten-foldlessmarinetoxicitythanthestartingpesticides.[31] Figure1.25:DegradationofFenitrothionbyFe(III)-TAMLcatalysts,showcasingtheminorFenitrooxonsynthesispathwayandtheperhydrolyticdegradationrouteofthisintermediate.Finalnonmineralizeddegradationproductsareformicacid,oxalicacid,maleicacid,andmethylmaleicacid.[31]1.3.3.3DegradationofAnthraxSporesWhenanthrax(Bacillusanthracis)sporesareputunderenvironmentalstress,theyenteravegetativestatethatisresistantUVradiation,chemicaldisinfectants,andhigh

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CHAPTER1.INTRODUCTION37temperatures.Thehardinessofthesecoatscomesfromtwochemicallyrobustandstructurallycomplexlayers:theproteinaceouscoatandthepeptidoglycancortex.B.anthracissporesareconsideredamongthemostdicultpotentialbiologicalwarfareagentstodestroy.Achemicaldisinfectionsystemmustquicklydestroytheprotectivecoatingsinordertoirreversiblydamagetheircriticalcomponents. Figure1.26:(Left)a.)DegradationofanthraxsporesbyTBHPeitherwithaTAMLcatalyst(solidline)orwithoutaTAMLcatalyst(dottedline)..b.)Degradationofanthraxsporesoveronehourwithdieringsolutioncomponents.(Right)a.)AnthraxsporebeforeapplicationofFe-TAML/TBHP/CTABsolution.b.)AnthraxsporeonehourafterapplicationofFe-TAML/TBHP/CTABsolution.[32]Thereasonproteincoatsareresistanttodamageisduetotheirproteindisuldelinkages.Fe(III)-TAMLsystemswereshowntoconvertcysteinedisuldeintocysteicacidinonehour.ThissuggestedthatFe(III)-TAMLsystemswouldbeabletopossi-blydestroythebacterialproteincoat,renderingtherestofthecellvulnerabletotheTAMLoxidationchemistry.B.atropheus,anon-infectiousanthraxsurrogate,wasusedinthisstudy,asithasbeeninmanyotherstudiesrelatedtoanthrax.WhentheanthraxsporeswereexposedtoFe(III)-TAMLcatalyst,tert-butylhydroperoxide(TBHP),andcetyltrimethylammoniumbromide(CTAB)atpH10,thesporepopu-

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CHAPTER1.INTRODUCTION38lationwasfoundtodecreasebyafactorof7log10units.ThesporeswerefoundtobedeactivatedmorequicklywithincreasingTBHPconcentration.Inordertoprotectcontaminatedmaterialfromcausticdegradation,atestrunatpH8showeda7log10unitkilloveravehourperiod.ItappearsthedisinfectionworksbecausetheTAMLcatalystsareproducingtert-butylhydroxyradicalsfromthetert-butylhydroperoxide.Thiswasveriedbyndingthepresenceofacetoneinthesupernatant,abyproductofthedecompositionofthetert-butylhydroxyradical.[32]1.3.3.4DestructionofEstrogensEstrogencompoundsimpairlivingorganismsbyaectingendocrinesignalingpath-waysthatinvolvedevelopment.Forexample,sharesensitivetoestrogenconcentra-tionsinwatersatpartspertrillionconcentration.Ithasbeendocumentedhowmaleshbegindevelopingafemale-speciceggprotein(vitellogenin)attheseconcentra-tions.Asignicantamountofestrogensandtheirmetabolitesarereleasedbyanimalexcretaandbyhumanexcretionof17-ethinylestradiol,theactiveingredientinthebirth-controlpill.Thesecompoundsareincompletelyremovedbycurrentmethodsatmunicipalwaste-treatmentcenters,andthisleadstolevelsinsurfacewatersthatarehigherthanthoseshowntoaectvariousorganisms.[33]Fe(III)-TAMLcatalystswerefoundtorobustlyactivatehydrogenperoxideagainstvariousestrogeniccompounds.Thereactionswereanalyzedatvarioustimepointsus-ingLCMS/MS;mostestrogenswerefoundtobedegradedwithinasignicantamountoftime,withatypicalhalf-lifebeingaroundveminutes.Thesolutionsfromthesereactionswerefoundtoactuallyhavedecreasedestrogenicactivity,baseduponscreen-ingusingwhatisknownastheE-Screenassay.Thisassayquantiesestrogenicitybyexaminingtheeectofthecompoundonahumanmammaryepithelialcellline.Othercommontechniquesfordegradingorganiccompoundsinwastewater,suchasozoneandchlorine,werefoundtoproducecompoundsthatweremorehighlytoxic

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CHAPTER1.INTRODUCTION39andactuallyhadincreasedestrogenicityascomparedtotheoriginalestrogens,anex-ampleproductbeingthechlorestrogens.Therefore,Fe(III)-TAMLligandsarefoundtosuccessfullydegradeestrogeniccompoundseectivelyandalsodidnotleadtotheproductionofmoretoxicorestrogenicbyproducts.[33] Figure1.27:EstrogencompoundstobetestedwithFe(III)-TAMLcatalysts.

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CHAPTER1.INTRODUCTION40 Figure1.28:DegradationofestrogensbyFe-TAMLcatalystFe-B.[33]1.4Second-GenerationTAMLLigands Figure1.29:Designofsecond-generationTAMLcatalystsystems.X1mayeither=Hor=NO2.[22]

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CHAPTER1.INTRODUCTION41Collinshaspublishedrecentlyonasetofsecond-generationFe(III)-TAMLcatalysts.Intheoriginalcatalystdesigns,thediuoromalonatespecieswasfoundtobethemoststableandthemostcatalyticallyactive.However,auorinatedspeciesisundesirablefromagreenperspectiveduetothepossibilityofreleasingorganouorinecompoundsuponeventualdegradationofthecatalysts.Therefore,itwasdesiredtoalterthedesignofthecatalysttomimictheelectronegativityeectsoftheuorinesubstituentswithoutactuallyusinguorine.Thiswasdonebyswitchingthecarbonstothemalonamidenitrogenfromsp2tosp2byconvertingthismoeityfromanaminoacidtophenylenediamine.Theoriginalphenylenediaminemoeityisthenconvertedintoanoxalatesystemtomakeitmoreelectronwithdrawing.ThisproducedthemostactiveTAMLcatalystsystemtodateandwasabletobringdowntheoptimalpHforactivityfrom10to9.Thesynthesisofthesecompoundsalsoweremuchsimplerthanthemethodspreviouslyusedtocreatetherst-generationTAMLsystems.[22]1.5GoalsofThesisAscanbeseen,Fe(III)-TAMLcatalystsareverypromisingasapotentialgeneralsystemfortheoxidativetreatmentofmanyhazardouswastechemicals.Itsbroadactivityandusageofthemildandcheapoxidanthydrogenperoxidereallyshowcasesitstruepotential.However,therearestillmanylimitationspresentwiththecurrentcatalystdesignsthatlimittheirpotentialusage.ThepHrangeofactivityforthecat-alystsisverylimitedandstillagooddistancefrompH7,thusrequiringadditionalstepsinvolvingbasicationbeforeandneutralizationaftertreatment.Also,thecata-lystisreadilydemetallatedinacidicmedia,limitingyetagainthepHrandforusageofthecatalyst.Thecatalystseventuallyundergooxidativedegradationaswell,eitherintramolecularlyorintermolecularly.Intramoleculardegradationissomethingthatcanbeaddressedbycatalystdesign,somethingthatwasseenintheiterativedesign

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CHAPTER1.INTRODUCTION42processfortheTAMLligandsystem.Intermoleculardegradationcanbeaddressedwithverylowcatalystconcentrations,butthisissomethingthatmaynotbedesir-ableforquickdegradationofthetargetedsubstrate.Someaspectsofcatalystdesignthatmayimprovestabilityoractivityinoneaspectmayleadtodecreasedactivityinanother.Oneexampleishowincreasedelectrondensityonthecentralironatomcanleadtoincreasedcatalystactivity.However,thisincreasedelectrondensityalsoleadstoincreaseddemetallationandintramoleculardegradation.Therefore,itisnotpossibletoaddressallpotentialwaysofimprovingTAMLcatalysts,andnotallofthesewillbethefocusofthisthesis.Oneproblemthatcanbeaddressedisthepotentialforintermoleculardegradationwiththecatalyst,somethingthatendsuplimitingcatalystconcentration.Areason-ablemethodforallowingincreasedcatalystloadingswithoutsignicantdegradationwouldbetotetherthecatalystsystemtoasolidsupport,renderingthecatalystun-abletomeetanotheractivatedpartner,aswouldhappeninsolution.Theusageofasolid-supportedsystemwouldalsopotentiallyrenderthiscatalystmoredesirableforindustrialapplications,asasolidphasesystemallowsforeasierseparationofcatalystandthepossibilityofusingthecatalystinaowsystem.Thesolidsupportsystemmustbechosencarefully.Theactualsolidsupportsystemmustnotbedegradedundertheconditionsofthereaction,renderingmosttypicalorganicsolidsupportsystems,suchasMerrieldResin,aspotentiallyunde-sirable.Silicaisacheapandreadilyavailablesolidphasematerialthathasbeenusedpreviouslyasasolidsupportformanymetalligands.[34,35]Itisreadilyavailableandeasilymadeinto3-chloropropylsilica,whichallowsforreadyattachmentofanyorganicfragment.Arobustwaytoattachanorganicfragmenttothesolidsupportisusinga1,2,3-triazolelinkage,amoietyeasilymadeusingtherobustcopper-catalyzedazide-alkynecouplingdiscoveredbyK.B.Sharpless.Thisreaction,oftenreferredtoasaformofclickchemistry,usesconditionsthataretolerabletoavastarray

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CHAPTER1.INTRODUCTION43ofsubstratesandissoreliablethatitisaquitepopularmethodincombinatorialchemistryformakinglargelibrariesofcompounds.[36]Anotherinterestingpossibilityisfortheheterocycleformedfromtheclickre-actiontobindaxiallytotheligandsystem.AnaxiallybindingdonorligandwouldmorecloselymimictheactivesitesofCytochromeP450(withanaxialcysteine)andperoxidase/catalase(withanaxialhistidine)enzymes.Thisextradonationaxialtothebindingsiteforhydrogenperoxidewouldpotentiallyincreasetheratefortheformationoftheactivatedcatalyst(therate-limitingstep),astheformationoftheFe(V)-oxospeciesrequiresdonationfromthemetalinordertocleavetheperoxideO-Obond.ItwouldalsostabilizetheFe(V)-oxospeciesformedbystabilizingtheproduct.Some1,2,3-triazoleshavebeenreportedasligandsintheliterature,[37,38]butnotcommonlyenoughthattodetermineeectofthisligandonthekineticsofTAMLcatalystsystemswouldbeinteresting. Figure1.30:Targetstructuresforsynthesisinthisthesis.Leftstructuresarerst-generationTAMLligands,whiletherightstructuresaresecondgenerationTAMLligands.The*indicatesthepointonthetriazoleringexpectedtobindaxiallytotheironintheligand.Therefore,severaldierentliganddesignsareproposed.Boththerst-generation

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CHAPTER1.INTRODUCTION44andsecond-generationTAMLringsystemsbyCollinswillbeused,butwithanat-tachedpropargylmoietyonthemalonateendtoallowformationofthe1,23-triazolelinkerusingthecopper-catalyzedazide-alkynecycloaddition.TheformationofafreeligandwiththetriazolemoietyusingbenzylazidewillbetestedrstwithbothTAMLringsystemstodeterminewhetheritactuallybindstotheiron.Theligandswillthenbeattachedbya1,2,3-triazolelinkagetosilicainordertoformthesolid-supportedcatalyst.

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Chapter2ExperimentalAllofthefollowingreactionsusedchemicalspurchasedfromeitherAcrosorSigmaAldrich.Allchemicalswereusedasreceivedunlessotherwisenoted.Solventsweredriedinthefollowingmanner:dichloromethane,toluene,andtriethylamineweredriedovercalciumhydride,subsequentlydistilled,andstoredover5molecularsieves;tetrahydrofuranwasdriedoversodium/benzophenoneketyl,distilled,andusedim-mediately.ABrukerAC250NMRspectrometerwasusedforallNMRstudies.AnalyticalTLCwasdoneonuorescentaluminum-backedsilicagelTLCplates.Vi-sualizationofTLCplateswasdonebyUVlamp,iodine,orvanillinsolution.Apolyethyleneglycol(PEG)bathwasusedforheatingallreactionsinordertoaccu-ratelymaintainpropertemperature,unlessotherwiseindicated.Commonabbreviationsused:DCM(dichloromethane,methylenechloride);DI(deionized);DMF(dimethylformamide);DMSO(dimethylsulfoxide);Et3N(tri-ethylamine);EtOH(ethanol);NaOEt(sodiumethoxide);pyr(pyridine);rb(round-bottom);rt(roomtemperature);THF(tetrahydrofuran);wt(weight).45

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CHAPTER2.EXPERIMENTAL462.1SynthesisofMalonateFragment2.1.1methylpropargylmalonate,diethylester(2) Figure2.1:Synthesisofmethylpropargylmalonate,diethylester(2).Conditions:(1),NaOEtinEtOH,followedbypropargylbromide.1.57g(68.77mmol)offreshlycutsodiummetal(storedunderhexane)wasaddedinportionsto100mLoffreshabsoluteethanolina500mLrbaskunderN2atroomtemperature.Thesolutionwasstirreduntilallsodiummetalwasconsumed.Anicebathmaybeusedifthereactionbecomestooexothermicduringthesodiumethoxidesynthesis.Uponcompleteconsumptionofsodiummetal,10.77mL(62.5mmol)ofdiethylmethylmalonate(1)wasquicklyadded.Thesolutionwasallowedtostirforonehour,duringwhichsomeprecipitateformationwasnoted.13.92mL(93.75mmol)ofpropargylbromidesolution(80%wtintoluene)wasthenaddeddropwise.Signicantwhiteprecipitateformedwithinveminutes,andthereactionmixturewasallowedtostirovernight.Thereactionwasthenquenchedwith50mLofDIwater,leadingtosolvationofalltheformedsodiumbromideprecipitate.Thesolutionwasslowlyrotaryevaporated(till100mbar)toremoveasmuchethanolaspossiblefromthesolventmixture.30additionalmLofDIwaterwereadded,andtheaqueousphasewasextractedwithdichloromethane(3x50mL).Thecombinedorganicphasesweredriedoveranhydroussodiumsulfate,thedryingagentlteredo,andthesolventremovedbyvacuumtoobtain9.5g(72%yield)ofmethylpropargylmalonate,diethylester(2)asayellow-orangeoil.1H-NMR(CDCl3):4.1ppm(q,2H,OCH2CH3);2.7ppm(d,2H,CH2CCH);2.0ppm(t,1H,CH2CCH);1.4ppm(s,3H,CH3);1.1(t,6H,OCH2CH3).13C-NMR(d6-DMSO):169ppm(C=O);

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CHAPTER2.EXPERIMENTAL4778ppm(CCH);73ppm(CCH);61ppm(OCH2CH3);52ppm(CCH3);25ppm(CH2CCH);19ppm(CCH3);13ppm(OCH2CH3).IR:3287(alkyneC-Hstretch);1730(carbonylstretch);1104(C-Ostretch).Notes:Freshabsoluteethanolisrequiredforthesuccessofthisreaction,asethanolisveryhygroscopicandtracewaterwillconsumethesodiummetal,preventingtheproperamountofsodiumethoxidefrombeingformed.Dichloromethaneiscrucialastheextractionsolventforthisstepinthereaction.Initialextractionswithdiethyletherleadtoapersistentunidentiableimpurityintheuppereldofthe1H-NMRspectrum.Thisimpuritydisappearedafterthefollowingsaponicationstep,butapurespectrumforthiscompoundwasattainablewhendichloromethanewasusedasanextractionsolvent.2.1.2methylpropargylmalonicacid(3) Figure2.2:Synthesisofmethylpropargylmalonicacid(3).Conditions:(2),NaOH,thenHCl.1.06g(5mmol)ofmethylpropargylmalonate,diethylester(2)waswascombinedwith5mLofasaturatedsodiumhydroxidesolution(3.59gin5mLofDIwater)ina25mLrbask.Thestartingmaterialintiallyformsanoilylayerontopofthesodiumhydroxidesolution.Uponstirring,precipitatewouldusuallyforminstantly.ReactioncompletionmaybedeterminedbyTLC(examinationforstartingmaterialusing50%/50%ethylacetate/hexanes).Thereactionmixtureisthenplacedinanicebathandconcentratedhydrochloricacidisaddeddropwiseslowly.Hydrochloric

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CHAPTER2.EXPERIMENTAL48acidisaddeduntilthesolutionispH2.Thesolutionisthenextractedwithethylacetate(3x15mL).Thecombinedorganicphasesweredriedoveranhydroussodiumsulfate,ltered,andthesolventwasremovedunderreducedpressuretoobtain762mg(98%yield)ofmethylpropargylmalonicacid(3)anorange-yellowsolid.1H-NMR(d6-DMSO):9.3ppm(b,2H,COOH);2.9ppm(s,1H,CH2CCH);2.7ppm(s,2H,CH2CCH);1.4ppm(s,3H,CH3).13C-NMR(d6-DMSO):171ppm(C=O);80ppm(CCH);73ppm(CCH);52ppm(CCH3);25ppm(CH2CCH);19ppm(CH3).IR:3295(alkyneC-H);2956(carboxylicO-Hstretch);1696(carbonylstretch).Notes:Rigorousstirringisrequiredinordertogettheimmisciblestartingmaterialtoproperlymixintotheaqueoussodiumhydroxidesolution.Thismaybedonewitharegularmagneticstirrer,asmechanicalstirringisviewedtobeinappropriatefortheusualscalesthisreactionisperformedon.Theratewithwhichthereactionoccuredvariedfromruntorun,goingfrombeinginstantaneoustohavingtobestirredovernight.Ifthereactionappearstobegoingsluggish,theproceduremaybepushedbyeithera.)increasingthespeedofstirringorb.)gentlyheatingthereactionmixtureinawarmwaterbath(40C).Theproductisusuallyisolatedasanorange-yellowsolid.However,sometimesonthenalsolventremoval,aliquidwithadistinctlyacidicsmellwillbeleftintherbask.Thisliquidwasonlynotedonrunswheretoomuchhydrochloricacidwasaddedonthequenchandisbelievedtobeaceticacidformedfromtheacid-catalyzedhydrolysisofethylacetate.Thisliquidmayberemovedbybringingthevacuumontherotaryevaporatordownaslowaspossibleandthenpumpingonthesolidunderhighvacuum.

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CHAPTER2.EXPERIMENTAL492.1.3methylpropargylmalonyldichloride(4) Figure2.3:Synthesisofmethylpropargylmalonyldichloride(4).Conditions:(3),oxalylchloride,DMF(cat.),DCM.762mg(4.88mmol)ofmethylpropargylmalonicacid(3)wascombinedwith15mLofdrydichloromethaneandadropofdrydimethylformamideina50mLroundbottomask,formingaslurry.Thisslurrywasthencooledwithanicebath,followedbytheadditionof461Lofoxalylchloride.ThereactionmixturewasthenquicklyttedwithanHClgastrap(seegurebelow).Gasevolutionwasnotedinstantlyuponadditionofoxalylchloride.Thereactionmixturewasallowedtostiruntilallsolidhadbeenconsumedandayellowsolutionhadformed.Thissolutionunderwentnofurtherpuricationandwasusedasisinthenextreactionsteps.Ifspectralanalysisisdesired,thereactionmixturemayhavethesolventremovedunderreducedpressuretoobtainmethylpropargylmalonyldichloride(4)asanorangeoil.1H-NMR(CDCl3):3.0ppm(d,2H,CH2CCH);2.1ppm(t,1H,CH2CCH);1.7ppm(s,3H,CH3).13C-NMR(CDCl3):170ppm(C=O);76ppm(CCH);74ppm(CCH3);72ppm(CCH);26ppm(CH2CCH);20ppm(CH3).IR:3299(alkyneC-Hstretch);1774(carbonylstretch).Notes:Threeequivalentsofoxalylchloridewereoriginallyused,butitwasfoundthatonlytwoequivalents(oneequivalentforeachcarboxylicacid)arenecessaryforthisreaction.Additionaloxalylchloridemaybeaddeddropwiseifnotallsolidisconsumedupontheinitialaddition.Theproductappearstodegradeveryreadilyuponcontactwithmoisturefrom

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CHAPTER2.EXPERIMENTAL50theair.Thereactionitselfisnotperformedundernitrogen,buttheproductisquicklyplacedundernitrogenonceithasformed. Figure2.4:HClgastrapsetup2.2Synthesisof2,2'-DiaminooxanilideFragment2.2.12-(carbamate,tert-butylester)aniline(6) Figure2.5:Synthesisof2-(carbamate,tert-butylester)aniline(6).Conditions:(5),ditert-butyldicarbonateEt3N,THF3.6g(33.2mmol)ofo-phenylenediamine(5)and6mLofdistilledtriethylaminewasaddedto30mLofdryTHFina100mLrbaskunderN2.7.9g(36.1mmol)ofneatditert-butyldicarbonate(gentlymeltedtoaidinaddition)wasadded,withgasevolutionbeingnoteduponaddition.Thereactionmixturewaslefttostirovernight,withreactioncompletionbeingnotedbyTLC.Allsolventwasthenremovedtoobtainalightpinksolid.Thissolidwasthensonicatedunderhexaneandlteredtoobtain

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CHAPTER2.EXPERIMENTAL515.44g(79%yield)of2-(carbamate,tert-butylester)aniline(6)asano-whitepowder.1H-NMR(d6-DMSO):8.3ppm(s,1H,ArNHC=O);7.2ppm(d,1H,ArCH);6.85ppm(t,1H,ArCH);6.6ppm(d,1H,ArCH);6.45ppm(t,1H,ArCH);4.8ppm(s,2H,ArNH2);1.4ppm(s,9H,).13C-NMR(d6-DMSO):153ppm(C=O);141ppm(Ar);124.9ppm(Ar);124.5ppm(Ar);123ppm(Ar);116ppm(Ar);115ppm(Ar);78ppm();28ppm(CH3).IR:3373(N-Hstretch);3291(N-Hstretch);1682(carbonylstretch);1153(C-Ostretch).Notes:Ditert-butyldicarbonateisalowmeltingsolid(mp=22-24C).Therefore,thesolidmustbemeltedgentlyinawarmwaterbathbeforebeingdispensedintothereactionmixture.However,theliquidmayfreezeupwhilebeingdispensed.Thus,itiscrucialtousealuerlocksyringefordispensingthistoxiccompoundtopreventanyaccidents.Ditert-butyldicarbonatemayalsobeboughtasasolutioninTHF.Inthefuture,buyingthissolutionorcreatingasolutionofthiscompoundinTHFforstoragemaybethemorepracticaloptionfordispensingthiscompound.Ifthestartingmaterialdoesnotcompletelyconvertintoproduct,anadditionalsmallamountofditert-butyldicarbonatemaybeaddedtothereactiontoguar-anteecompleteconversion.Thisadditionalreagentaddeddoesnotappeartoleadtotheformationofanydi-substitutedspecies.

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CHAPTER2.EXPERIMENTAL522.2.22,2'-(dicarbamate,tert-butylester)oxanilide(7) Figure2.6:Synthesisof2,2'-(dicarbamate,tert-butylester)oxanilide(7).Conditions:(6),oxalylchloride,pyr,THF.1.74g(8.4mmol)of2-(carbamate,tert-butylester)aniline(6)and0.5mLofpyridinewereaddedto20mLofdryTHFina100mLrbaskunderN2.Thereactionaskwascooledonanicebath,afterwhich344L(4mmol)ofoxalylchloridewasadded.Pyridiniumchloridesaltprecipitatedoutinstantlyuponaddition.Themixturewasthenallowedtostirovernight.Thereactionmixturewasthenvacuumltered,andtheltratehadsolventremovedunderreducedpressuretoobtainawhiteprecipitate.Thesolidwassonicatedunderhexaneandlteredtoobtain1.523g(81%yield)of2,2'-(dicarbamate,tert-butylester)oxanilide(7)asano-whitepowder.1H-NMR(d6-DMSO):10.2ppm(s,2H,ArNHC=O);9.0ppm(s,2H,ArNHC=O);7.7ppm(m,2H,ArH);7.4ppm(m,2H,ArH);7.2ppm(m,4H,ArH);1.5ppm(s,18H,C(CH3)3).13C-NMR(d6-DMSO):158ppm(C=O);153ppm(C=O);131ppm(Ar);129ppm(Ar);126ppm(Ar);124.7ppm(Ar);124.6ppm(Ar);79ppm(C(CH3)3);28ppm(CH3).IR:3400(N-Hstretch);1686(carbonylstretch);1154(C-Ostretch).Notes:Ifthereactionstalls,moreoxalylchloridemaybeaddedtothereactionmixturewithouttheriskofformationofamonosubstitutedcarboxylicacidproduct.Thisproductinunstableandreadilydegradesintostartingmaterial,carbonmonoxide,andcarbondioxide.

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CHAPTER2.EXPERIMENTAL532.2.32,2'-diaminooxanilide(8) Figure2.7:Synthesisof2,2'-diaminooxanilide(8).Conditions:(7),3MHClinEtOAc,thensat.sodiumbicarbonate.2.87g(6mmol)of2,2'-(dicarbamate,tert-butylester)oxanilide(7)wasplacedin30mLof3Mhydrogenchlorideinethylacetate(seenotes)ina100mLrbaskoveranicebath.Signicantpinkprecipitateformedwithinthirtyminutes.Thesolidwasltered,dried,andthenaddedportionwiseinto30mLofsaturatedsodiumbicarbonatesolution.Theaqueousphasewasthenextractedwithdichloromethane(3x15mL).Thecombinedorganiclayerswerewashedwithbrineanddriedoveranhydroussodiumsulfate.Thedryingagentwaslteredandthesolventremovedundervacuumtoobtain1.25g(77%)of2,2'-diaminooxanilide(8)asayellow-whitesolid.1H-NMR(d6-DMSO):10.0ppm(s,2H,ArNHC=O);7.4ppm(d,2H,ArH);7.0ppm(t,2H,ArH);6.8ppm(d,2H,ArH);6.6ppm(t,2H,ArH);5.0ppm(s,4H,ArNH2).13C-NMR(d6-DMSO):159ppm(C=O),143(Ar),127(Ar),126(Ar),122(Ar),116.4(Ar),116.3(Ar).IR:3230(N-Hstretch);1670(carbonylstretch).Notes:Aroughly3MsolutionofHClinethylacetate(30mL)canbeeasilyformedbycombining90mmolacetylchlorideand90mmolabsoluteethanolwith30mLdryethylacetateoverice.Formationofthehydrogenchloridesolutioncanbeconsideredinstantaneous.Thissolutionwasfoundmorereasonabletoworkwiththanalcoholichydrogenchloridesolutions.

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CHAPTER2.EXPERIMENTAL54Thestartingmaterialisnotinitiallysolubleinthesolution,butthereisahighlynoticeabledierenceintheamountofsolidinitiallyinthesolutionandtheamountofprecipitateformed.Thereactionappearstoreachcompletionafterthirtyminutes.2.3N,N'-1,2-phenylenebis(2,2-dimethylpropanamide)2.3.12-phthalimidoisobutyricacid(10) Figure2.8:Synthesisof2-phthalimidoisobutyricacid(10).Conditions:(9),phthalicanhydride,heat.2.48gof2-aminoisobutyricacid(9)wasadded(24mmol)and3.91gofphthalicanhydride(26.4mmol)werecombinedina100mLrbaskttedwithastirbarandathermometer.Theroundbottomaskwasthenwrappedinglasswoolandheateddirectlybyaheatingmantle.Whenthereactionmixturereached90C,signicantamountsofphthalicanhydridewouldbegintosublimeinthereactionask.At125C,someofthesolidmaterialintheaskbegantomelt,whichreachedcompletionaround150C.Atthistemperature,thefullyliquidreactionmixturebeganbubblevigorouslyandsignicantcondensationformedonthereactionasked,whichhelpedtowashdownanyofthesublimedphthalicanhydride.Around170C,thereactionmixtureceasedbubbling,becameyellowincolor,andallcondensationintheaskhaddisappeared.Thereactionmixturewasbroughtupto190Cfor10minutes,followingwhich25mLofdrytoluenewasquicklyadded.Withinveminutes,asignicantwhiteslurryformedintheask.Thereactionmixtureistypicallyusedasis,but

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CHAPTER2.EXPERIMENTAL55asampleoftheslurrymaybelteredandthesolidrinsedwithhexanestoobtain2-phthalimidoisobutyricacid(10)asawhitepowderforNMRanalysis.1H-NMR:9.3ppm(b,1H,COOH);7.9ppm(s,4H,ArH);1.7ppm(s,6H,CH3).13C-NMR:174(COOH),168(C=O),136(Ar),135(Ar),131(Ar),123(Ar),60(C(CH3)2),24(CH3).IR:2992(COOHstretch);1704(carbonylstretch).Notes:Itiscrucialforthereactiontobeperformedusingasolvent-freemethod,eventhoughthispresentsissuesduetothetendencyofphthalicanhydridetosub-limetothesidesoftheaskandnotgetwashedbackdownintothereactionmixture.Attemptsatthisreactionusingtolueneorxylenesasasolventleadtonoreaction,demonstratinghowcrucialitistoreachtemperatureshigherthantheboilingpointsofthesetwosolventsystems.Duetothepresentofsomeun-reactedphthalicanhydrideonthesidesoftheaskafterreactioncompletion,aslightexcessofphthalicanhyrideisused.Itisalsocrucialforthereactionasktobewellwrappedinglasswoolinorderforproperevaporationofallwatercondensationfromthereactionmixture.Anytracesofwaterleftinthemixturewilldestroythionylchloridereagentinthenextstep.Aluminumfoilmayalsobeadditionallywrappedaroundtheglasswoolforadditionalheatinsulation.Despitetheproblemsassociatedwithusingheatingmantles,itwasfoundtobethemosteectiveheatingmethodforthehightemperaturesusedinthisreaction.

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Chapter3ResultsandDiscussion3.1RetrosyntheticAnalysisandPreviousSyntheses Figure3.1:Retrosyntheticanalysisofsecond-generationliganddesign.Thetwopossibleamidedisconnections,aandb,areshown.Therststepbeforeembarkingonanytarget-orientedsynthesisofamoleculeinvolvesretrosyntheticallyanalyzingpotentialdisconnectionsinthemoleculetodeterminepotentialstartingmaterialstouseinthesynthesis.Therstreasonabledisconnectionforanyofourligandsinvolvesthe1,2,3-triazolewithinthemolecule,whichleadstoanazideandanalkyneasprecursors.Disconnectingthisfunctionalityrstisdesirable,mainlybecausethisconnectionshouldcomelastbecauseitwillbewhat56

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CHAPTER3.RESULTSANDDISCUSSION57attachestheligandtoitssolidsupportsystem.ThisleavestheTAMLligandsystemwithanalkynemoeity.Thenextsetoflogicaldisconnectionsinvolveoneofthepairsofamidelinkageswithinthemolecule.However,thisleadstothedecisionofwhichamidelinkagestodisconnectrst.Itisbesttoproducedisconnectionsinanysynthesisthatwouldleadtothehighestlevelofconvergence.Themalonatefragmentofthismoleculeisnotcommerciallyavailableandthusrequiressynthesis,sodisconnectionattheseamidelinkages(disconnectionb)providesforthemostconvergentsynthesis.Anydisconnectionisasidealizedportrait,however,andasyntheticpathwayalwaysneedstestinginlab.Therefore,thedisconnectionoftheoxalateamidelinkages(disconnectiona)couldalsoleadtoapotentiallyviableroutetothisligand.Onepointofanalysisbeforegoingforwardwithanysynthesisisdeterminingwhatpreviousprecedencethereisforthebelievedsyntheticpathway.Themoreconvergentrouteleadsustotwofragments:amalonatefragmentand2,2'-diaminooxanilide.Themalonatefragmenthasneverbeenpreviouslysynthesized,butitssynthesisonlyin-volvesstandardenolatechemistry.Propargylbromideisanexcellentalkylatingagent,anddiethylmethylmalonateischeapandcommerciallyavailable.Therefore,develop-mentofproceduresforthiscompound'ssynthesiswererelativelystraightforward.The2,2'-diaminooxanilidefragmenthasbeenpreviouslyreported.[39]SynthesisofthiscompoundwasattemptedbyDanKaplan,apreviousthesisstudentinDr.Scudder'slab,andI.[40]Theoriginalrouteattemptedforthiscompoundinvolvedreactionofoxalylchloridewith2-nitroanilineandsubsequentreductionofthenitrogrouptotheamine.Usingthenitrogroupaspseudo-protectinggrouporanamineequivalentisgoodbecauseitproducesmuchbetteratomeconomythananactualprotectinggroup,usesacatalyticmethodforconversion,andproducesonlywaterasabyproduct.

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CHAPTER3.RESULTSANDDISCUSSION58 Figure3.2:Previousrouteto2,2'-diaminooxanilide.Therststepinvolvesreactionofoxalylchlorideand2-nitroanilineinthepresenceofbase.Thesecondstepinvolvesaromaticnitroreduction.However,thisroutepresentedsignicantdicultyforbothDanKaplanandI.Theintermediate2,2'-dinitrooxanilidewasfoundtobeinsolubleinmostsolvents,despitewhatwasreportedintheliteratureprocedurethatwasbeingusedforitssynthesis.Theoriginalpreparationinvolveddissolvingthecompoundinabsoluteethanolforthesubsequentnitroreduction.[39]TheonlysolventfoundtoreadilydissolvethecompoundwasboilingDMSO.Itisbelievedthattheoriginalauthorsproducedasampleofthematerialthathadwasimpureenoughastocauseapoorcrystallat-tice,enablingincreasedsolubilityofthematerial.Thisprovesdicultbecausemosttypicalproceduresforreductionofanaromaticnitrocompoundinvolveheterogenouscatalysis.Thetypicalprocedure,involvingpalladiumoncarboncatalytichydrogena-tion,usesaninsolublesolidstatecatalyst.Therefore,thereactantmustbesolubleforittoevereasilyreachtheactivatedpalladiumsurfaceinordertoreact.Othermethods,suchasRaneynickelreduction,iron/hydrochloricacidreduction,etc.,allinvolveheterogenouscatalysis.Therefore,thesolubilityissuedirectlyhindersanyfurtherreactionatthisstep.DanKaplanwasabletogetanimpuresampleofthematerialtodissolveandreact,reinforcingthebeliefthatthisissuewasduetocrystallatticeformationduringsynthesis.Someconversionwasabletooccurfortheinsol-ublecompoundwithPd/Cinethanoloveraweek,butthistimescaleistoolongtobereasonableforanysynthesis.Therefore,despiteitbeingundesirableintermsofmakingagreensynthesisofthiscompound,arouteusingaprotectedamineinsteadofanitrowasexplored.In2010,TerryCollinspublishedhisroutetothesecond-generationTAMLcatalystswhich

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CHAPTER3.RESULTSANDDISCUSSION59containedtheringstructurebothDanKaplanandIhadbeenpreviouslyattemptingtosynthesize.[41]Therouteinvolvedsynthesisofamalonilidefragmentrstfollowedbyringclosureusingoxalylchloride.ThereasonCollinsdecidedtobuildthemoleculefromthemalonateendrstisunknown,butCollinshadnoconcernsaboutconver-genceinhissynthesisbecausehismalonatefragment(dimethylmalonyldichloride)ischeapandcommerciallyavailable.Collins'preparationusesat-butoxycarbamate(BOC)protectinggrouponphenylenediamineinsteadof2-nitroaniline,andthisroutewasfoundtosuccessfullyproducesolublespeciesthatwereabletoreactinsubsequentsteps.3.2SynthesisofMalonateFragment Figure3.3:Synthesisofmethylpropargylmalonyldichloride.Conditions:a.)NaOEt/EtOHb.)NaOH,thenHClc.)oxalylchloride,DMF(cat.)3.2.1methylpropargylmalonate,diethylester(2) Figure3.4:Synthesisofmethylpropargylmalonate,diethylester(2).Conditions:(1),NaOEtinEtOH,followedbypropargylbromide.Synthesisofthiscompoundinvolvesstandardenolatealkylationchemistry.Sev-eraldierentapproacheswereattemptedforthesynthesisofthediethylesterofthe

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CHAPTER3.RESULTSANDDISCUSSION60methylpropargylmalonatefragmentbaseduponsearcheswithintheliterature.Ini-tialattemptsbasedonaliteraturesearchbeganwiththepropargylationofdiethylmalonate,followedbyasecondalkylationusingamethylatingagentsuchasmethyliodide.[42]Thisroute,however,undergoessignicantissueswithchemoselectivityformonoalkylationintherststep.Theproductalsohasan-hydrogenthatisacidicandthatmaybedeprotonatedbytheprecursorenolate,leadingtopotentialdoublealkylationoftheproductanddeactivationofthestartingenolate.Thus,withoutsignicantcontrol,apotentialmixtureofproductswouldbeobtained.Inattemptsofthissynthesis,thiswasfoundtobethecase,theproductmixturebeingcomposedofmono-,di-,andunsubstituteddiethylmalonate.ATLCoftheproductmixturerevealedthatthemono-anddisubstitutedproductshadanRfdierencelessthan0.1,demonstratingthattheywouldbeverydiculttoseparatebycolumnchromatog-raphy.Therefore,thismethodwasabandonedbyforcingamonopropargylationbyusingmethyldiethylmalonate,astillcomparativelycheapprecursor. Figure3.5:Selectivityissueswithrespecttomalonatealkylation.PathwayAdemon-stratestheissueofdialkylationwhenbeginningwithdiethylmalonateonly.PathwayBdemonstratesthatbeginningwithreadilycommerciallyavailablemethyldiethylmalonateleadstocleanformationofthedesiredproduct.Next,severaldierentmethodswereattemptedfortheformationofthemethylmalonateenolate.InitialattemptsusingsodiumhydrideinTHFwereabandonedduetothedicultyremovingthemineraloilpresentincommercialsodiumhydridereagentfromthenalproduct.[42]Amethodusingfreshlymadesodiumethoxideinethanolwaslaterfoundtobepreferable.Initialattemptsatthereactionuseddiethyl

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CHAPTER3.RESULTSANDDISCUSSION61etherastheextractionsolvent,butthiswasconsistentlyfoundtoproduceaproductwithasignicantamountofupeldimpurityinthe1H-NMR.Thisimpuritywasfoundtodisappearfromthespectruminthefollowingsaponicationstep.However,aserendipitoususageofdichloromethaneastheextractionsolvent(duetoalackofdiethylether)ledtothediscoverythatthisextractionsolventledtoapureproductspectrum.Therefore,dichloromethaneisrecommendedasthesolventofchoiceforthisextractionstep.ProductformationcanbeveriedbycomparisonoftheNMRspectraofthiscompoundtothepredictedspectra(gureA.4)producedbytheChemNMRsoftwarepackage.The1H-NMR(gure3.6;gureA.1)and13C-NMRshifts(gureA.2)arecomparable,andtheintegrationveriestheproperratioofthetwospecies,e.g.theethylCH2'sat4.1ppmintegratewiththepropargylCH2at2.7ppminexactlya2:1ratio.Themethylgrouppresentat1.4ppmisasinglet,signifyingthatitisattachedtoaquaternarycenter.Also,noevidenceisseenforthemalonate-hydrogen,againsignifyingtheformationofaquaternarycenter.

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CHAPTER3.RESULTSANDDISCUSSION62 Figure3.6:1H-NMRspectrumofmethylpropargylmalonate,diethylester(CDCl3).CH2Cl2ispresentat5.2ppm.(LargerversionavailableingureA.1)3.2.2methylpropargylmalonicacid(3) Figure3.7:Synthesisofmethylpropargylmalonicacid(3).Conditions:(2),NaOH,thenHCl.Thesynthesisofthiscompoundinvolvesaclassicsaponicationreaction.However,substitutedmalonicacidsareinfamouslyunstable,especiallyunderacidicconditions.Malonatesarecommonlyusedasstableenolateequivalentsofcarboxylicacids,with

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CHAPTER3.RESULTSANDDISCUSSION63thesecondcarboxylategroupbeinglostascarbondioxideunderacidicconditionswithheat.Whiledecarboxylationisdesirableinsomeapplications,herethemalonicacidisthedesiredproduct,andthereforecaremustbetakentonotaccidentlycausedecarboxylationintheworkup.Toaccomplishthis,acidicationofthesodiumcar-boxylatesaltformeduponsaponicationoftheesterderivativemustbedoneoveranicebathwithconcentratedhydrochloricacidbeingaddeddropwise.Thesecondi-tionswerefoundtoavoiddecarboxylation,asevidencedbythelackofan-hydrogenappearinginthe1H-NMR.Theaqueoussaponicationconditionsrequirevigorousstirringinordertoallowproperreactionbetweentheimmisciblestartingmaterialandtheaqueoussodiumhydroxidesolution.Reactiontimesarefoundtovary,withdisodiummalonatesaltsometimesforminginstantlywhileatothertimesonlyformingthemalonatesaltovernight.ThereactioncaneasilybefollowedbyTLCbecausetheesterstartingmaterialtravelsontheplatewhilethesodiumcarboxylateproductdoesnot;botharemadevisibleusingiodine.Itappearsthereactioncanbelightlyforcedbyplacingtheaskinwarmwater(35C).Anyresidualwatershouldberemovedbypumpingonthesamplewithhighvacuumbeforeusingitinthenextreactionstep.Thereisnotedlossoftheethylpeaks,presentat4.1and1.1ppminthe1H-NMRspectrum(gure3.6;gureA.1)andat13and52ppminthe13C-NMRspectrum(gureA.2)ofthestartingmaterial.Abroadpeakaround9.4ppminthe1H-NMR(gure3.8;gureA.5),typicalforcarboxylicacids,alsoappearsinproduct.ThecarboxylicacidOHpeakinthe1H-NMRspectrumcanbeeasilylostduetoexchangewithanytraceresidualwaterwiththesample.ThisalsomeansthatifthecarboxylicacidpeakisthereandwaterisalsopresentintheNMRsample,theshiftforthecarboxylicacidmaybealtereddependingonwaterconcentration.Again,nodecarboxylationwasnotedduetothelackofevidenceforitwithinthe1H-NMRspectrum.Ascanbeseeninthepredictedspectrum(gure3.9),

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CHAPTER3.RESULTSANDDISCUSSION64thedecarboxylatedproductwouldwouldhaveasextetpeakinthespectrum,pro-ducedbythe-hydrogen.Decarboxylationwouldalsoproduceachiralcenter,sothepropargylichydrogenswouldbecomediastereotopicandwouldsplit,ascanbeseenbythepredictedpeaksat2.38and2.13ppm.Theobtainedspectrum(gure3.8)looksnowherenearlyascomplicatedandresemblesmorecloselythespectrumforthestartingmaterialwithouttheethylsubstituents,asisexpected. Figure3.8:1H-NMRspectrumofmethylpropargylmalonicacid(d6-DMSO).Waterispresentat3.4ppm(broad).(LargerversionavailableinA.5).

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CHAPTER3.RESULTSANDDISCUSSION65 Figure3.9:Predicted1H-NMRspectrumforpotentialdecarboxylationproduct.3.2.3methylpropargylmalonyldichloride(4) Figure3.10:Synthesisofmethylpropargylmalonyldichloride(4).Conditions:(3),oxalylchloride,DMF(cat.),DCM.Thepreparationofthiscompoundwasbaseduponaliteraturesearchforgeneralmethodsfortheformationofsubstitutedmalonyldichlorides.[43,44]Mostmethodsfortheformationofanyacylchlorideleadtotheproductionofhydrogenchloridegasintheprocessandrequireheatinginordertogettheprocesstoproperlygo.OnewaytogetaroundthisistoaddacatalyticamountofN,N-dimethylformamidetothereactionmixture,whichthenallowstheprocesstogoatroomtemperature.Thisprocesscanbedonewitheitherthionylchlorideoroxalylchloride,butoxalylchlorideisusuallyconsideredtobethemilderreagentandwasinthissituation

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CHAPTER3.RESULTSANDDISCUSSION66foundtobethemosteectiveatallowingconversiontothemalonyldichloride.Theactualchlorinatingagentinthereactionisnottheoxalylchloride,butadimethyliminochloridespeciesthatisformeduponreactionofN,N-dimethylformamidewithoxalylchloride(seegure3.8).Thisspeciesismuchmorereactiveandisabletoconvertcarboxylicacidstoacylchloridesatroomtemperature.Thisprocedurewaspreferableinordertopreventpotentialdecarboxylationofthestartingmaterial.Thisprocedurewasfoundtoeectivelyconvertthemalonicacidprecursorsuccessfullyintothemalonyldichloridewithoutdecompositionofthestartingmaterial.Theproductisusuallyusedwithoutfurtherpurication,duetoeasydegradationoftheproductuponexposuretomoistureinair.Becauseofthis,itisnecessarytouseonlyanequivalentofoxalylchloridetopreventpossiblesideproducts;oneequivalentofoxalylchloridejustaseectivelycausedconversiontothemalonyldichlorideasthethree-foldexcessusedintheliteraturepreparationtheprocedureismodeledupon.[43,44] Figure3.11:GeneralschemeforDMF-catalyzedacylchlorideformationusingoxalylchloride.Evidencefortheformationofthedichloridespeciesisapparentbythelossofthecarboxlicacid-OHpeakwithinthe1H-NMRspectrum(abroadpeakaround10ppm;gure3.12andgureA.9)andIRspectrum(averydistinctbroadabsorptionbandaround3000cm1;gureA.11).AshiftinthecarbonylIRabsoptionbandfrom1696cm1to1774cm1isalsopresent,adrasticshifttohigherfrequencyexpectedforgoingfromacarboxylicacidtoanacylchloride.

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CHAPTER3.RESULTSANDDISCUSSION67 Figure3.12:1H-NMRspectrumofmethylpropargylmalonyldichloride(d6-DMSO).Somestartingmaterialimpurityformedpotentiallybyhydrolysisisseeninthisspec-trum.(LargerversionavailableingureA.9).3.3Synthesisof2,2'-DiaminooxanilideFragment Figure3.13:Synthesisof2,2'-diaminooxanilide.Conditions:a.)ditert-butyldicar-bonate,Et3Nb.)oxalylchloride,pyridinec.)HClinethylacetate

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CHAPTER3.RESULTSANDDISCUSSION68Thisrouteleadstothesynthesisofthediaminecompoundusedinthesecond-generationTAMLcatalystsystems.Allcompoundshavebeenfullycharacterized,withappropriatespectraavailablewithintheappendix.3.3.12-(carbamate,tert-butylester)aniline Figure3.14:Synthesisof2-(carbamate,tert-butylester)aniline(6).Conditions:(5),ditert-butyldicarbonateEt3N,THFThiscompoundwassynthesizedbyaprocedurebaseduponthe2010preparationbyCollins.[41]Theoriginalpreparationusedtheditert-butyldicarbonateasthelimitingreagentinthereaction,possiblybasedupontheassumptionthattherepotentiallywasariskfordiprotectioninsteadofthedesiredmonoprotection.OriginalattemptsattheCollinsprocedurethatusedditert-butyldicarbonateasthelimitingreagentproducedamixtureofstartingmaterialandproduct,asexpected.TLCanalysisofthemixture(50%ethylacetate:50%hexanes)showedthetwocompoundsbeingverycloseinRfvalue,demonstratingthatthesetwocompoundswouldnotbeeasilyresolvedbycolumnchromatography.Additionalliteraturesearchesforthesynthesisofthiscompoundshowedthatthemonosubstitutedproductcouldbeeasilyformedbyusinganexcessoftheditert-butyldicarbonate.[45]Thiswasfoundtobetrueuponexperimentation,with1.1equivalentseasilyleadingtocleanformationof2-(carbamate,tert-butylester)aniline.Evidenceforformationoftheprotectedspeciesisapparentinthe1H-NMRspec-trum(gure3.15;gureA.13)bytheappearanceofanamideNHgroupinthespec-trumat8.3ppm.Thisgroupintegratesforonehydrogen,ascomparedtotheamine

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CHAPTER3.RESULTSANDDISCUSSION69NHpeakat4.9ppm,whichintegratesfortwohydrogens.Also,thearomatichydro-genpeakshavethedistinctivedoublet-triplet-doublet-tripletsplittingpatterntypicalofahetero-ortho-substitutedbenzenering.ThecarbonylcarbonforthecarbamateintheBOCprotectinggroupispresentwithinthe13C-NMR(gureA.14)at153ppm.Thiscompoundhasbeenpreviouslysynthesized,andthe1H-NMRspectrumwasfoundtomatchthatreportedintheliterature.[6] Figure3.15:1H-NMRspectrumof2-(carbamate,tert-butylester)aniline(d6-DMSO).Waterispresentat3.4ppm.(LargerversionavailableingureA.13).

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CHAPTER3.RESULTSANDDISCUSSION703.3.22,2'-(dicarbamate,tert-butylester)oxanilide Figure3.16:Synthesisof2,2'-(dicarbamate,tert-butylester)oxanilide(7).Condi-tions:(6),oxalylchloride,pyr,THF.SynthesisofthiscompoundwasadaptedfromthepreparationprovidedbyCollinsforsynthesisofhismalonilidefragment,[41]insteadreplacingdimethylmalonylchloridewithoxalylchloride.Thereactionrequiresvigorouslydryconditions,asoxalylchlo-ridewillveryeasilyreactwithatmosphericmoistureandreadilydegradeintocarbondioxide,carbonmonoxide,andhydrogenchloridegas.Oneinitialconcernwiththisreactionwasthebeliefthatmoisturewithinthereactionmixturewouldleadtomono-insteadofdisubstitutedoxanilidederivatives.Afteroneamidebondformation,ifwa-terwastoreactwiththeacylchlorideend,itwasbelievedacarboxylicacidproductwouldalsobeisolated.Thereactionfailedtoinitiallygotocompletioninsomerunsofthereactionbelievedtohavebeenexposedtomoisture,butnocarboxylicacidmoi-etywasfoundpresentwithintheproductmixture.Instead,onlystartingmaterialandproductwasfound.Fromthisapotentialserendipitousmechanismisproposedforhowmoisturemaynotleadtoformationofaproductwithacarboxylicacidmoi-ety.Aswaspreviouslystated,oxalylchloridereadilydegradesintocarbondioxideandcarbonmonoxideuponreactionwithwater.Themonosubstitutedproductwouldalsoreadilydegradeintothosetwobyproductsuponattackbywater,leavingbehindanilinestartingmaterial.Therefore,iftheprogressofthereactionappearstostarttostall,additionaloxalylchloridemaybeadded,leadingtosuccessfulfullconversiontothedesiredprotectedoxanilideproduct.

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CHAPTER3.RESULTSANDDISCUSSION71TheformationofthiscompoundcanbeveriedbythelossoftheamineNHpeak,at4.8ppminthe1H-NMR(gure3.18;gureA.16)ofthestartingmaterial,andtheappearanceofasecondamideNHpeakinthe1H-NMRspectrumat10.2ppm.Also,thearomaticshiftsmovemoredowneldduetotheincreasedshieldingcausedbytheadditionalamidecarbonylmoeitynexttothearomaticring.Anadditionalcarbonylpeak,at158ppm,appearsinthe13C-NMRspectrum(gureA.17). Figure3.17:Proposedreactionofwaterwithmonosubstitutedoxanilideleadingtodecomposition Figure3.18:1H-NMRspectrumof2,2'-(dicarbamate,tert-butylester)oxanilide(d6-DMSO).Waterispresentat3.4ppm.(LargerversionisavailableingureA.16).

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CHAPTER3.RESULTSANDDISCUSSION723.3.32,2'-diaminooxanilide Figure3.19:Synthesisof2,2'-diaminooxanilide(8).Conditions:(7),3MHClinEtOAc,thensat.sodiumbicarbonate.SynthesisofthiscompoundinvolvesremovaloftheBOCprotectinggroupsfrom2,2'-(dicarbamate,tert-butylester)oxanilide.TheinitialprocedureoutlinedbyCollinsinvolvesdissolvingthereagentinethylacetateandthenaddingalargevolumeofconcentratedhydrochloricaciddropwise.ThissolutionisthendilutedwithbasicsolutionandsignicantportionsofsolidsodiumhydroxideisaddeduntilthislargevolumereachespH11.[41]Thisprocedurewasfoundtobeundesirableduetothelargevolumeofsolventusedforsuchasmallreactionscaleandalsoduetotherelativelyineectivenessofusingabiphasicreactionsystem.ClassicmethodsforremovalofBOCprotectinggroupsinvolvereactionoftheprotectedaminewithhydrogenchloridegasdissolvedinorganicsolvents.[46]Theproductformedistheammoniumchloridesalt,whichwillcrashoutoftheorganicsolvent.Thissolidmaythenbeplacedinaqueousbasicsolutionandextractedwithorganicsolventtoretrievethedesiredamineproduct.ThismethodwasfoundtobeprocedurallymuchsimplerthanthemethodoutlinedbyCollins.A3MHClsolutioninethylacetate(madefromacetylchlorideandethanolinethylacetate)wasfoundtobethepreferredacidicsolventsystemtobeused.Evidencefortheformationofthisspeciesispresentwithinthe1H-NMRspectrum(gure3.20;gureA.20)bytheappearanceofanamineNHpeakat5.0ppminte-gratingfortwohydrogens,alongwiththelossofthetert-butoxycarbamatemethyl

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CHAPTER3.RESULTSANDDISCUSSION73hydrogens,at1.4ppminthestartingmaterial,fromthespectrum.Also,thearo-maticsplittingagainfollowsthedoublet-triplet-doublet-tripletpatternexpectedforahetero-ortho-substitutedaromaticring.Thisspectrumalsomatchesspectraprevi-ouslyreportedbyDanKaplanandintheliterature.Also,thecarbamatecarbonylpeak,at153ppminthestartingmaterial,islostwithinthe13C-NMRspectrum(gureA.21)forthecompound. Figure3.20:1H-NMRspectrumof2,2'-diaminooxanilide(d6-DMSO).Waterispresentat3.4ppm.(LargerversionisavailableingureA.20).

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CHAPTER3.RESULTSANDDISCUSSION743.4N,N'-1,2-phenylenebis(2-aminoisobutyramide) Figure3.21:RoutetothesynthesisofN,N'-1,2-phenylenebis(2-aminoisobutyramide).Conditions:a.)phthalicanhydride,heatb.)thionylchloride,toluenec.)phenylene-diamine,THFd.)hydrazineThiscompoundisthediamineusedinthesynthesisoftherstgenerationTAMLcat-alystsystem.Thissynthesishadbeenperformedpreviouslyuptostep(c)previouslyusingtheprocedurebyCollinsthatdidnotattempttoisolateintermediates.Whatwillbediscussedbelowarethemorerecentattemptstosynthesizethesecompoundsinordertoaordpropercharacterization.3.4.12-phthalimidoisobutyricacid Figure3.22:Synthesisof2-phthalimidoisobutyricacid(10).Conditions:(9),ph-thalicanhydride,heat.

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CHAPTER3.RESULTSANDDISCUSSION75SynthesisofthisfragmentisfromapatentpreparationfromtheCollinsgroupandrepresentsthemostrecentsyntheticroutetotherst-generationTAMLsystem.[47]Thisstepinvolvesprotectionoftheaminoendof2-aminoisobutyricacidwithaph-thalimideprotectinggroup.Theconditionsbasicallyinvolveacondensationbetweentheanhydrideportionofphthalicanhydridewiththeaminogroupwithreleaseofwaterandisdoneundersolventfreeconditionsintheoriginalpreparation.Oneissuethatoccuredwithoriginalattemptsatthisprocedureinvolvedthetendencyforph-thalicanhydridetosublimeuponheating.Thisusuallyoccursaround70Candleadstothisreagentcoatingthesidesoftheaskandnotreachingbeinginthevicinityoftheotherreagentuponmelting.Theinitialattemptsatthisprocedureoftenleadtoincompleteprotection,requiringaslightexcessofphthalicanhydridetobeused.Attemptsatrunningthereactioninsolventssuchastolueneorxylenestopreventthesublimationleadtonoreactionoccuring,demonstratingthatthereuxtemperaturesreachedwiththesesolventsarenothighenoughforthereactiontooccur.Thereac-tionisusuallybroughtupto190Cwhendonesolventfree,buttolueneandxylenesonlyreach110.6Cand138.5Catreux,respectively.Therefore,thebestwaytoguaranteeallphthalicanhydrideisusedthroughoutthecourseofthereactionistohavetheroundbottomaskusedthoroughlywrappedinglasswoolandaluminumfoiltoguaranteethattheentireasksurfaceishot.Also,anyphthalicanhydridethatsublimesduringthereactionmaybepushedbackdownintothereactionmixtureusingastirringrod.Otherwise,thispreparationisconsideredtobesuccessful,andthematerialformedisusuallyusedinthenextstep.Evidenceforformationofthiscompoundispresentwithinthe1H-NMRspectrum(gure3.22;gureA.23),wherearomatichydrogensonthephthalimidegroupandthedimethylsubstituentsintegrateinaratioof4:6,aswouldbepresentwithintheproduct.

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CHAPTER3.RESULTSANDDISCUSSION76 Figure3.23:1H-NMRspectrumof2-phthalimidoisobutyricacid(d6-DMSO).Acetoneispresent2.2ppm,whileanunknownimpurityispresentat1.2ppm.(LargerversionisavailableingureA.23).3.5MacrocyclizationReactions Figure3.24:MacrocyclizationReaction.Conditions:Et3N,THF,CH2Cl2.Themacrocyclizationrepresentsoneofthetrickieststepsinthesynthesisoftheseligands.Signicantcontrolofreagentconcentrationandadditionisrequiredto

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CHAPTER3.RESULTSANDDISCUSSION77preventpossiblesideproductsthatwouldresultfrompolymerizationofthetworeagents.Also,themalonyldichloridederivativemustbemadedirectlybeforehandandusedrightawayinordertopreventdegradation,whichwouldresultinmono-substitutedproductorcarboxylicstartingmaterialintheproduct.Severalattemptsweremadeatsynthesizingthedesiredsecond-generationligandmacrocycle.Typicalconditionsinvolvedproducingadilutesolutionofthemalonyldichloridefragmentindichloromethane(1mmolin50mL)andadilutesolutionof2,2'-diaminooxanilideinTHF(1mmolin50mL).Thesetwowouldbeaddeddropwise(1dropeveryveseconds)totwoequivalentsoftriethylamineinTHF(2mmolin50mL).Precipitatewouldbenotedtoforminstantlyuponaddition,andusuallyuponcompletionthereactionwouldbeallowedtostirovernight.TypicalworkupconditionswerebaseduponthepreparationbyCollinsandinvolvewashingwithdiluteacid(0.1Msodiumhydrogensulfate)anddilutebase(0.1Msodiumbicarbonate),followedbyremovaloforganicsolventtogainproduct.1H-NMRspectrafortheproductsgainedtypicallyweresignicantlycomplexandimpure,suggestingapotentialmixtureofpolymeriza-tionproductsinthereaction.

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CHAPTER3.RESULTSANDDISCUSSION78gfh Figure3.25:Typical1H-NMRspectrumoftheisolatedproductforamacrocyclizationreaction.Onepossibleexplanationfortheinabilitytoisolateanypurecomplexisapossibletendencyforthe2,2'-diaminooxanilidestartingmaterialtopreferaconformationthatdoesnotallowforringclosure.Onepossiblereasonisduetoahydrogenbondinginteractionbetweenaromaticaminogroupandtheoxalatecarbonyl,aninteractionthatwouldmakethereactiveaminefunctionalitylessconformationallyavailable.Also,theoxalategroupwouldpreferablyhaveit'scarbonylgroupsalignedsothattheirdipolemomentscanceleachother.Acombinationofthesetwopotentialfactorswouldalignthemoleculeinsuchawaythatthetwoaminogroupsarealignedasfarfromeachotheraspossible.Thiswouldpreventquickclosureofthemoleculeonbothendsofthemalonatefragmentbeforethemalonylchloridendsanotheraminogrouponanothermolecule.Thesefactorsareentirelyspeculative,however,

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CHAPTER3.RESULTSANDDISCUSSION79andcomputationalstudiesshouldbeperformedon2,2'-diaminooxanilidetopossiblypredictthemoststableconformationofthemolecule.However,thereisevidenceapparentinCollins'synthesis.WiththesecondgenerationTAML,hebuildsthecompoundfromthemalonateend,whileinhisrstgenerationTAMLhegoesinthedirectionperformedhere.EventhoughCollinsgivesnodirectreasonforswitchingtheendofthemoleculehestartedfrom,itmaygiveclueastowhatmayactuallyworkwithinthelab.Duetothesefactors,thesynthesisofthismoleculefromthemalonateendwillbeexploredinthefuture,despitethedecreasedconvergenceofthesyntheticscheme.

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Chapter4ConclusionAroutetowardtheproposedsynthesisofasolid-supportedTAMLligandhasbeenex-plored,withmanyproblemsfacedinprevioussynthesisattemptsbybothDanKaplanandIresolved.Anovelmalonate,methylpropargylmalonate,hasbeensynthesizedandcharacterizedinitsdiethylester,acid,anddichlorideforms.Previousattemptsatthesynthesisofthe2,2'-diaminooxanilide,involvingusageof2,2'-dinitrooxanilideasanintermediate,werereplacedbyarouteinvolvingBOCprotectionofphenylenediamine,subsequentreactionwithoxalylchloride,andsubsequentdeprotection.Thisroutewasfoundtosuccessfullyleadto2,2'-diaminooxanilidewithoutthesolubilityproblemsfacedwith2,2'-dinitrooxanilide.Coupingbetweenmethylpropargylmal-onyldichlorideand2,2'-diaminooxanilidewasattemptedtoproducethemacrocyclicligandprecursor.Acomplexmixtureofproductswasformed,suggestingpotentialpolymerizationofthecompounds,theundesiredproductofthereaction.80

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CHAPTER4.CONCLUSION81 Proposedrouteforsynthesisofligandbeginningfromthemalonateend.Potentialconditions:a.)Et3N,THFb.)HClinethylacetatec.)Et3N,THF.Collinsinsteadproducedsimilarligandsbystartingfromthemalonateend,sug-gestingthatthisroutemaypotentiallybemoreviable.Therefore,futureworkwillfocusondevelopingaviableroutebeginningconstructionofthemoleculefromthemalonateend.Asuggestedpotentialsyntheticschemegoingfromthisendisdetailedabove.ThepreviouslysynthesizedmalonyldichloridederivativeisreactedwiththeBOC-protectedphenylenediamine(a).Thisspeciesisthendeprotected,presumablyusingconditionssimilartothatusedfortheBOC-protectedoxanilidederivative(b).Adilutesolutionofthediamineproductisthencombinedwithadilutesolutionofoxalylchloride,hopefullyleadingtosynthesisofthedesiredmacrocyclestructure(c).Thebeginningofthisrouteiscurrentlybeingexplored.

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AppendixASpectra82

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APPENDIXA.SPECTRA83 FigureA.1:1H-NMRspectrumofmethylpropargylmalonate,diethylester(2)(CDCl3).CH2Cl2at5.2ppm.

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APPENDIXA.SPECTRA84 FigureA.2:13C-NMRspectrumofmethylpropargylmalonate,diethylester(2)(d6-DMSO).CH2Cl2at54.4ppm.

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APPENDIXA.SPECTRA85 FigureA.3:IRspectrumofmethylpropargylmalonate,diethylester(2).

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APPENDIXA.SPECTRA86 FigureA.4:Predicted1H-NMRand13C-NMRspectraformethylpropargylmalonate,diethylester(2).

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APPENDIXA.SPECTRA87 FigureA.5:1H-NMRspectrumofmethylpropargylmalonicacid(3)(d6-DMSO).Waterat3.4ppm(broad).

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APPENDIXA.SPECTRA88 FigureA.6:13C-NMRspectrumofmethylpropargylmalonicacid(3)(d6-DMSO).

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APPENDIXA.SPECTRA89 FigureA.7:IRspectrumofmethylpropargylmalonicacid(3).

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APPENDIXA.SPECTRA90 FigureA.8:Predicted1H-NMRand13C-NMRspectraofmethylpropargylmalonicacid(3).

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APPENDIXA.SPECTRA91 FigureA.9:1H-NMRspectrumofmethylpropargylmalonyldichloride(4)(CDCl3).Somedegradationbacktotheprecursor(2)isnoted.

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APPENDIXA.SPECTRA92 FigureA.10:13C-NMRspectrumofmethylpropargylmalonyldichloride(4)(CDCl3).

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APPENDIXA.SPECTRA93 FigureA.11:IRspectrumofmethylpropargylmalonyldichloride(4).

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APPENDIXA.SPECTRA94 FigureA.12:Predicted1H-NMRand13C-NMRspectraformethylpropargylmalonyldichloride(4).

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APPENDIXA.SPECTRA95 FigureA.13:1H-NMRspectrumfor2-(carbamate,tert-butylester)aniline(6)(d6-DMSO).Waterat3.4ppm.

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APPENDIXA.SPECTRA96 FigureA.14:13C-NMRspectrumfor2-(carbamate,tert-butylester)aniline(6)(d6-DMSO).

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APPENDIXA.SPECTRA97 FigureA.15:IRspectrumfor2-(carbamate,tert-butylester)aniline(6).

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APPENDIXA.SPECTRA98 FigureA.16:1H-NMRspectrumfor2,2'-(dicarbamate,tert-butylester)oxanilide(7)(d6-DMSO).Waterat3.4ppm(broad).

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APPENDIXA.SPECTRA99 FigureA.17:13C-NMRspectrumfor2,2'-(dicarbamate,tert-butylester)oxanilide(7)(d6-DMSO)

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APPENDIXA.SPECTRA100 FigureA.18:IRspectrumfor2,2'-(dicarbamate,tert-butylester)oxanilide(7).

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APPENDIXA.SPECTRA101 FigureA.19:Predicted1H-NMRand13C-NMRspectrafor2,2'-(dicarbamate,tert-butylester)oxanilide(7).

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APPENDIXA.SPECTRA102 FigureA.20:1H-NMRspectrumfor2,2'-diaminooxanilide(8)(d6-DMSO).Waterat3.4ppm(broad).

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APPENDIXA.SPECTRA103 FigureA.21:13C-NMRspectrumfor2,2'-diaminooxanlide(8)(d6-DMSO)

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APPENDIXA.SPECTRA104 FigureA.26:Predicted1H-NMRand13C-NMRspectrafor2-phthalimidoisobutyricacid(10).

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APPENDIXA.SPECTRA105 FigureA.22:IRspectrumfor2,2'-diaminooxanilide(8).

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APPENDIXA.SPECTRA106 FigureA.23:1H-NMRspectrumof2-phthalimidoisobutyricacid(10)(d6-DMSO).Acetoneat2.1ppm.Unknownimpurityat1.2ppm.

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APPENDIXA.SPECTRA107 FigureA.24:13C-NMRspectrumof2-phthalimidoisobutyricacid(10)(d6-DMSO).Acetoneat30.7ppm.Unknownimpurityat28ppm.

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APPENDIXA.SPECTRA108 FigureA.25:IRspectrumof2-phthalimidoisobutyricacid(10).

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BIBLIOGRAPHY111[19]Collins,T.J.DesigningLigandsforOxidizingComplexes.AccountsofChemicalResearch.1994,27,279-285[20]Collins,T.J.TAMLOxidantActivators:ANewApproachtotheActivationofHydrogenPeroxideforEnvironmentallySignicantProblems.AccountsofChemicalResearch.2002,35,782-790[21]Ryabov,A.D;Collins,T.J.MechanisticconsiderationsonthereactivityofFe(III)-TAMLactivatorsofperoxides.AdvancesinInorganicChemistry.2009,61,471-521[22]Ellis,W.C;Tran,C.T;Denardo,M.A;Fischer,A;Ryabov,A.D;Collins,T.J.DesignofmorepowerfulIron-TAMLPeroxidaseEnzymeMimics.JournaloftheAmericanChemicalSociety.2009,131,18052-18053[23]Ghosh,A;Ryabov,A.D;Mayer,S.M;Horner,D.C;Prasuhn,D.E;Gupta,S.S;Vuocolo,L;Culver,C;Hendrich,M.P;Rickard,C.E.F;Norman,R.E;Horwitz,C.P;Collins,T.J.UnderstandingthemechanismofH+-induceddemetallationasadesignstrategyforrobustIron(III)Peroxide-activatingcatalysts.JournaloftheAmericanChemicalSociety.2003,125,12378-12379[24]Polshin,V;Popescu,D.-L;Fischer,A;Chanda,A;Horner,D.C;Beach,E.S;Henry,J;Qian,Y.-L;Horwitz,C.P;Lente,G;Fabian,I;Munck,E;Bominaar,E.L;Ryabov,A.D;Collins,T.J.AttainingControlbyDesignovertheHydrolyticStabilityofFe-TAMLOxidationCatalysts.JournaloftheAmericanChemicalSociety.2008,130,4497-4506[25]Ghosh,A;deOliveira,F.T;Yano,T;Nishioka,T;Beach,E.S;Kinoshita,I;Munck,E;Ryabov,A.D;Horwitz,C.P;Collins,T.J.Catalyticallyactive-oxodiiron(IV)oxidantsfromiron(III)anddioxygen.JournaloftheAmericanChemicalSociety.2005,127,2505-2513

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