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OrganometallicChemistryinIndustry
OrganometallicChemistryinIndustry
APracticalApproach
WithaForewordbyRobertH.Grubbs
Editedby
ThomasJ.Colacot
CarinC.C.JohanssonSeechurn
Editors
ThomasJ.Colacot
MilliporeSigma(divisionofMerck KGaA,Darmstadt,Germany) 6000NTeutoniaAvenue Milwaukee,WI53209 USA
CarinC.C.JohanssonSeechurn JohnsonMattheyPlc 28CambridgeSciencePark MiltonRoad,CambridgeCB40FP UnitedKingdom
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Contents
Foreword xiii
Preface xvii
1IndustrialMilestonesinOrganometallicChemistry 1 BenM.Gardner,CarinC.C.JohanssonSeechurn,andThomasJ.Colacot
1.1DefinitionofOrganometallicandMetal–OrganicCompounds 1
1.1.1ApplicationsandKeyReactivity 1
1.1.1.1ElectronicApplications 1
1.1.1.2Polymers 2
1.1.1.3OrganicSynthesis 2
1.2IndustrialProcessConsiderations 7
1.3BriefNotesontheHistoricalDevelopmentofOrganometallic ChemistryforOrganicSynthesisApplicationsPertainingtothe ContentsofthisBook 8
1.3.1SynthesisofStoichiometricOrganometallicReagents 9
1.3.1.1ConventionalBatchSynthesis 9
1.3.1.2OrganometallicsinFlow 10
1.3.2Cross-couplingReactions 10
1.3.2.1C—HBondActivation 12
1.3.2.2Carbonylation 13
1.3.2.3CatalysisinWater–MicellarCatalysis 13
1.3.3HydrogenationReactions 14
1.3.4OlefinFormationReactions 15
1.3.4.1WittigReaction 15
1.3.4.2MetathesisReactions 15
1.3.4.3DehydrativeDecarbonylation 16
1.3.4.4OlefinsasStartingMaterials 16
1.3.5Poly-orOligomerizationProcesses 17
1.3.6PhotoredoxCatalysisforOrganicSynthesis 17
1.4ConclusionandOutlook 17
Biography 18 References 19
2Design,Development,andExecutionofa
Continuous-flow-EnabledAPIManufacturingRoute 23
AlisonC.Brewer,PhilipC.Hoffman,TimothyD.White,YuLu,LauraMcKee, MoussaBoukerche,MichaelE.Kobierski,NessaMullane,MarkPietz,CharlesA. Alt,JimR.Stout,PaulK.Milenbaugh,andJosephR.Martinelli
2.1Continuous-flow-EnabledSyntheticStrategy 25
2.2DesignandScale-upofChan–LamCoupling 28
2.2.1DevelopmentofHomogeneousConditions 31
2.2.2ApplicationofaPlatformTechnologytoAerobicOxidation 32
2.2.3OptimizationofReactionandWorkupParameters 35
2.2.4SafetyConsiderationsforAerobicOxidationonScale 37
2.2.5ContinuousScale-upandManufacturing 38
2.3DesignandScale-upofaBuchwald–HartwigCross-coupling 42
2.3.1InitialScreening 43
2.3.2SynthesisandIsolationofPd(dba)DPEPhosPrecatalyst 45
2.3.3WorkupProcedure,MetalRemoval,andCrystallization 46
2.3.4Scale-upandManufacturing 48
2.4ImpurityControl 48
2.4.1SolubilityandImpuritySpikingStudies 50
2.5Conclusions 54 Biography 54 References 58
3ContinuousManufacturingasanEnablingTechnologyfor Low-TemperatureOrganometallicChemistry 61 AndreasHafnerandJoergSedelmeier
3.1Introduction 61
3.2Organo-LiandMgProcessesinFlowMode 62
3.2.1TechnologicalAdvantagesofFlowTechnologyComparedto TraditionalBatchOperation 62
3.2.2TemperatureProfileofContinuousFlowReactions 64
3.2.3FlashChemistry:FunctionalGroupTolerance 65
3.2.4FlashChemistry:Selectivity 66
3.2.5FlashChemistry:StoichiometryandChemoselectivity 67
3.3ContinuousFlowTechnology 69
3.3.1CloggingasaMajorHurdleinFlowChemistry 71
3.3.2Start-upandShutdownOperation 72
3.3.3MaterialofConstruction 72
3.3.4SafetyConceptandEmergencyStrategies 73
3.4DevelopmentofaFlowProcess 73
3.4.1ScreeningPhase:FeasibilityStudy 74
3.4.2ProcessDevelopmentPhase:ExtendedEvaluationsIncluding TechnicalFeasibility 75
3.5LiteratureExamples:FlowProcessesonMulti100gScale 76
3.5.1ManufactureofVerubecestat(MK-8931) 77
3.5.2ManufactureofEdivoxetine 77
3.5.3Scale-upofHighlyReactiveArylLithiumChemistry 80
3.5.4SynthesisofBromomethyltrifluoroboratesinContinuousFlow Mode 81
3.5.5Two-StepSynthesisTowardBoronicAcids 82
3.5.6ReactionSequenceTowardaHighlySubstitutedBenzoxazoleBuilding Block 84
3.6ConclusionandFutureProspects 86 Biography 86 References 87
4DevelopmentofaNickel-CatalyzedEnantioselective Mizoroki–HeckCoupling 91 Jean-NicolasDesrosiersandChrisH.Senanayake
4.1Introduction 91
4.1.1NonpreciousMetalCatalysisAdvantagesforIndustry 91
4.1.2Mizoroki–HeckCouplingsinIndustrywithPalladium 92
4.1.3EmergenceofNickel-CatalyzedMizoroki–HeckCouplings 93
4.1.4EnantioselectiveNickel-CatalyzedCouplings 94
4.1.5SynthesisofOxindolesviaMizoroki–HeckCyclizations 96
4.2DevelopmentofaNickel-CatalyzedHeckCyclizationtoGenerate OxindoleswithQuaternaryStereogenicCenters 97
4.2.1PrecedentsandChallenges 97
4.2.2OptimizationofReducingAgentandBase 97
4.2.3LigandScreening 98
4.2.4ImpactofArylElectrophileandofStereochemistryofAlkene Moiety 100
4.2.5ExplorationoftheSubstrateScope 102
4.2.6LimitationsoftheMethodology 104
4.2.7MechanisticConsiderations 104
4.3DevelopmentofFirstEnantioselectiveNickel-CatalyzedHeck Coupling 107
4.3.1LigandScreening 107
4.3.2ImpactofAlkeneStereochemistry 107
4.3.3NeutralvsCationicPathways 108
4.3.4NickelPrecatalystComplexSynthesis 109
4.3.5ExplorationoftheSubstrateScope 110
4.3.6MechanisticStudies 110
4.4Conclusions 113 Biography 114 References 115
5DevelopmentofIron-CatalyzedKumadaCross-couplingforthe Large-ScaleProductionofAliskirenIntermediate 121 SrinivasAchanta,DebjitBasu,UdayK.Neelam,RajeevR.Budhdev,Apurba Bhattacharya,andRakeshwarBandichhor
5.1Introduction 121
5.2OptimizationofGradeandEquivalentsofMgMetal 123
5.3OptimizationofEquivalentsof1,2-Dibromoethane 123
5.4EffectofSolventConcentrationonPreparationofGrignardReagent andKumada–CorriuCoupling 124
5.5EffectofAlkylChloride3AdditionTimeontheGrignardReagent Preparation 125
5.6StabilityofGrignardReagentat0–5 ∘ C 125
5.7Iron-CatalyzedCross-couplingReaction 127
5.8OptimizationofEquivalentsofNMPandFe(acac)3 129
5.9OptimizationofEquivalentsofSubstrate 4 andItsRateof Addition 129
5.10ExecutionatPilotScaleandScale-upIssues 129
5.11AgitatedThinFilmEvaporator(ATFE)forPurificationof2 131
5.12Conclusion 132
Acknowledgments 133
Biography 133 References 135
6DevelopmentandScale-UpofaPalladium-Catalyzed IntramolecularDirectArylationintheCommercialSynthesisof Beclabuvir 137 CollinChan,AlbertJ.DelMonte,ChaoHang,YiHsiao,andEricM.Simmons
6.1Introduction 137
6.2KOAc/DMAcProcess 141
6.3TMAOAc/DMFProcess 141
6.4TMAOAc/DMAcProcess 149
6.4.1CyclizationReaction 151
6.4.2MechanisticUnderstandingoftheCyclizationReactionandImpurity Formation 159
6.4.3HydrolysisandWorkup 162
6.4.4CrystallizationandDrying 164
6.5Conclusion 167 Biography 168 References 169
7Ruthenium-CatalyzedC—HActivatedC—C/N/OBond FormationReactionsforthePracticalSynthesisofHeterocycles andPharmaceuticalAgents 171 AnitaMehta,NareshKumar,andBiswajitSaha
7.1Introduction 171
7.2C–HActivationFollowedbyC—CBondFormation 172
7.2.1C–HActivationFollowedbyC—CBondFormation: Biaryl/HeterobiarylSynthesisinOrganicSolvents 172
7.2.2C–HActivationFollowedbyC—CBondFormation: Biaryl/HeterobiarylSynthesisinGreenSolvents 181
7.3Alkyl/Acyl/AlkenylSubstitutiononHeterocycles 185
7.4C–HActivationFollowedbyC—O/NBondFormation:Heterocycle Synthesis 187
7.4.1C–HActivationFollowedbyC—O/NBondFormation:Heterocycle SynthesisinOrganicSolvents 187
7.4.2C–HActivationFollowedbyC—OandC—NBondFormation: HeterocycleSynthesisinGreenSolvents 189
7.5Conclusion 196 Biography 197 References 198
8Cross-couplingsinWater–ABetterWaytoAssembleNew Bonds 203 ThariqueN.Ansari,FabriceGallou,andSachinHanda
8.1Introduction 203
8.2TransitionMetalCatalysisinOrganicSolventsvsMicellar Catalysis 204
8.2.1Micellization 205
8.2.2SurfactantSolution–AHighlyOrganizedReactionMediumto EnhanceReactionRate 206
8.2.3ReactionTemperature 207
8.2.4SizeofMicelles 207
8.2.5NatureofCatalyst 208
8.2.6IncreasingtheEfficiencyinMicellarCatalysis 209
8.2.7OrderofAddition 210
8.2.8ProductPrecipitationorExtraction 211
8.2.9TraceMetalintheProduct 211
8.3HighlyValuableReactionsinWater 212
8.3.1Suzuki–MiyauraCouplings 212
8.3.2HeckCouplings 217
8.3.3NegishiCouplings 219
8.3.4C–HArylations 221
8.3.5Aminations 225
8.3.6Borylation 228
8.3.7ArylationofNitroCompounds 228
8.3.8AdoptionofMicellarTechnologybyPharmaceuticalIndustry 229
8.4Conclusions 234 Biography 234 References 235
9AspectsofHomogeneousHydrogenationfromIndustrial Research 239 StephenRoseblade
9.1HomogeneousHydrogenation:ABriefIntroduction 239
9.2CatalystSelectionbyEffectiveScreeningApproaches 240
9.3ConsiderationsforReactionScale-up 244
x Contents
9.4NotesonAdditiveEffects 247
9.5ANovelApproachtoAliskirenUsingAsymmetricHydrogenationasa KeyStep 249
9.6EfficientChemoselectiveAldehydeHydrogenation 252
9.7ClosingRemarks/Summary 253 Biography 255 References 255
10LatestIndustrialUsesofOlefinMetathesis 259 JohnH.Phillips
10.1Introduction 259
10.2GeneralInformation 260
10.2.1Non-rutheniumCatalysts 260
10.2.2RutheniumCatalysts 261
10.3IndustrialUses 262
10.3.1Ring-closingMetathesis(RCM) 262
10.3.2Cross-metathesis(CM) 264
10.3.3Ring-OpeningMetathesisPolymerization(ROMP) 268
10.4ReactionConsiderations 270
10.4.1CatalystChoice 271
10.4.2CatalystLoading 273
10.4.3Solvent 273
10.4.4ReactionConcentration 273
10.4.5OverallHandling 274
10.4.6ApplicationGuideandAvailability 274
10.5Troubleshooting 275
10.5.1CatalystRemoval 275
10.5.2FunctionalGroupTolerance 276
10.5.3SubstratePurity 276
10.5.4CatalystDecomposition–Isomerization 277
10.6Conclusion 277 Biography 277 References 278
11DehydrativeDecarbonylation 283 AlexJohn
11.1Introduction 283
11.2UseofSacrificialAnhydrideandCatalyticMechanism 285
11.3Rh-,Pd-,andIr-Catalysis 286
11.3.1EarlyStudies 286
11.3.2RecentStudies 289
11.4MilderTemperatures 291
11.4.1PdCl2 /XantPhos/(t Bu)4 biphenolSystem 291
11.4.2Well-DefinedPd-bis(phosphine)Precatalysts 294
11.5NickelandIronCatalysis 295
11.6EsterDecarbonylation 297
11.7SyntheticUtility: α-VinylCarbonylCompounds 299
11.8ConclusionsandFutureProspects 300
Biography 300
References 301
Index 305
Foreword
Inthelate1960sandthroughthe1970s,organometallicchemistryemergedfrom beingasubfieldofinorganicchemistry,wheretheinterestwasinbodingand structure,toafieldinitsownrightwithchemiststrainedininorganicororganic chemistry.Theorganicchemistsbroughtreactivitytothefieldandhelpedto moveorganometallicchemistryintocatalysis.ThepioneeringworkofCollman, Vaska,andHalpernamongothersdefinedthebasicmechanismsofthefieldand providedthebasisfortheapplicationofthisnewfieldinorganictransformations andorganicsynthesis.Now,mostpharmaceuticalsandnaturalproductsyntheses involveone,ifnotmore,catalyticsteps.Thestudyofasymmetrichydrogenation andtheligandsandmechanismsthatcontrolledtheseprocessespavedtheway forthediscoveryofawidearrayofasymmetricprocesses.Thestructuralflexibilityofhomogeneouscatalystsandthewidearrayofligandsnowavailablehave resultedinmostcatalyticprocessesnowbeingcapableofproducingproducts inhighasymmetricpurity.Heterogeneouscatalysts,althoughtheyaregenerallyfavoredforeaseofprocessing,donotprovidetheflexibilityrequiredfor moreprecisetransformations.Theriseofhomogeneouscatalystshasrequired thedevelopmentofprocessesandmethodsthatallowhomogeneouscatalyststo beexploitedinpracticallarge-scaleprocesses.
Colacot(MilliporeSigma,abusinessofMerckKGaA)andSeechurn(Johnson Matthey),theeditorsofthisbook,haveaddressedtheseissues.Afterauthoring thefirstchapter,whichprovidesthehistoricalbackgroundforthedevelopmentof homogeneouscatalystsandthebasicmechanisms,theyhavechosenanoutstandinggroupofauthorstoprovidespecificinformationaboutthepracticalaspects oftheconversionoflaboratory-scalereactionsintorealprocesses.Mostofthe processesaredemonstratedbyrealexamples.Themesofthechaptersemphasize newdevelopmentsinthepharmaceuticalindustryprocessessuchasflowand continuousprocessesandthedevelopmentofcatalystsbasedonearth-abundant metals.
Chapters2and3discusstheadvantagesofcontinuousflowprocess.For example,thesafeuseofoxygenwithorganicsolventscanbemitigatedbythe useofflowsystems,andefficientprocessescanbedevelopedforhomogeneous reactionsonscale.ParticularlyinterestingistheuseoftheBuchwald–Hartwig reactioninaflowsystemwiththeefficientremovaloftheresidualpalladium catalysts.Thesecondofthetwochaptersdescribesthemethodsfortheuseof low-temperatureprocessesintheproductionofmaterialsonalargescale,which
involvereactiveandenvironmentallysensitivereagents.Thesetwochapters provideadetailedupdateonflowprocesseswiththegoalofincreasingtheuseof flowprocessesinhomogeneousprocesses.Theseprocessesregainsomeofthe advantagesthatweretraditionalwithheterogeneouscatalystswhilemaintaining theselectivityofhomogeneousprocesses.Inarelatedprocessdevelopment, Chapter8describestheuseofanother“nanoreactor”:micellesinwater.In thischapter,thedevelopmentsoftraditionalhomogeneouscross-coupling reactionssuchasHeckandSuzuki–Miyaurainaqueousenvironmentsusing amicelleenvironmentaredescribed.Carryingoutthereactionsinnanoreactors–micelles–resultsininterestingnewselectivityandreactivity.From aprocesschemist’sperspective,micelle-enabledprocessescanofferbenefits suchasthereplacementoftoxicorganicsolvents,reducedPMIvalue,improved reactionyields,highpurityofAPIwithreducedmetalcontents,andhighcost efficiency.
Asprocessesarescaled,thecostsofthemetalandligandsbecomemoreimportant.Chapters4and5describethedevelopmentofprocessesthataretraditionallycarriedoutusingpreciousmetalsbyratheremployingeithernickelor iron.Thesesuccessfulexampleswillencouragefurtherdevelopmentofefficient selectivecatalystsbasedonearth-abundantmetals.Inspiteofpotentialcosts, palladiumcatalystshavebeenshowntohaveawidearrayofactivitiesandselectivities.Chapter6demonstratesanoutstandingexampleoftheuseofpalladium inthecommercialsynthesisofbeclabuvirutilizingtheselectivityofpalladium catalysts.Although,earth-abundantmetalscantaketheplaceofpalladiumina numberofreactions,orrathercomplementPd,theefficiencyandselectivityof manypalladiumcatalystswillensurethatitcontinuestobeusedinthepharmaceuticalandfinechemicalindustryformanyyearstocome.
Chapters7,9,and10coverspecificreactionsinprocesschemistry.Thechapter onhomogeneoushydrogenationprovidesaguidetotheuseofasymmetrichydrogenationinthesynthesisofcomplexstructuresonacommercialscale.Asymmetrichydrogenationisoneoftheoldestandmostusedasymmetricprocessesin synthesis.Thisup-to-dateguideprovidesthehighlightsofthisfieldandhelpsto simplifythevastliterature.Incontrast,CHactivationincomplexsynthesisisone ofthenewerareasofemphasis.Foranumberofyears,therehasbeentherecognitionofthevalueofbeingabletofunctionalizeC—Hbondsdirectly,although C–Hactivationhasnotrisenuplikethecross-couplingreactionsforindustrial process.Therefore,theeditorswereconscientiousenoughtoaddachapteron thistopic.AsisdemonstratedinChapter7,thispromiseisnowbeingrealizedas demonstratedbytheuseofaCHactivationprocessinthesynthesisofimportant compoundssuchasMerck’sanacetrapib,sartans,etc.Olefinmetathesishasbeen animportanttopicinacademicsynthesisforseveraldecades;Phillipsprovides exampleswherethisbackgroundofreactivityisnowbeingtranslatedintokey structuresforthepharmaceuticalindustry.Heprovidesparticularlygoodcoverageoftheimportanttopicssuchascatalyststabilityandremovalthatarerequired fortheuseofahomogeneouscatalystinalargerprocess.
Thelastchaptertakeshomogeneouscatalystsoutsideoftheapplicationsin thepharmaceuticalindustrytotheconversionofbiomass-derivedmaterialsinto chemicalfeedstocks.Asmanybiomasssourcesaresolids,asolublecatalystis particularlysuitedforsuchapplications.Althoughtheyfocusontheconversion ofcarboxylicacidsintoolefins,thetechniquesandstrategieswouldapplyto manyothersuchprocessesandcanbedevelopedforpotentialapplicationsin industry.
Itisparticularlypleasingtoseetheevolutionoforganometallicchemistryinto catalystsforextremelyusefulorganictransformations.Thebasicprincipleand reactionmechanismsthatweredevelopedintheearlydecadesoftheareaare nowthebasisformajorprocessesthatopentheefficientsynthesisofanamazing arrayofnewchemicalstructuresthathaverevolutionizedhowpresent-day bioactivematerialsaredesignedandprepared.ColacotandSeechurnhaveused theirbroadexperienceinnewcatalystdevelopment,organicsynthesis,and processchemistryinvolvinghomogeneouscatalyststoassembleanoutstanding teamofauthorsfromallovertheworldtohighlighttheimportantdevelopments requiredtofulfillthepromiseofcatalysisinorganicsynthesisforthetwenty-first century.Thisisaverytimelybookforbothacademiaandindustrychemists andengineerstounderstandhowacademicconceptsaretranslatedintoindustrieswithawidevarietyofimportantmoleculesasdepictedinthecoverof thebook.
RobertHowardGrubbs
DivisionofChemistryandChemicalEngineering CaliforniaInstituteofTechnology,Pasadena,CA91125USA (626)3956003,rhg@caltech.edu
Prof.GrubbsBiography
B.A.andM.S.Chemistry,UniversityofFlorida,Gainesville,Florida,1963and 1965.Ph.D.,Chemistry,ColumbiaUniversity,NewYork,1968.NIHPostdoctoralFellow,Chemistry,StanfordUniversity,1968-69.HeistheVictorandElizabethAtkinsProfessorofChemistryattheCaliforniaInstituteofTechnology, Pasadena,California,USA,andafacultymembersince1978.Hewasafaculty memberatMichiganStateUniversityfrom1969to1978.
TheGrubbsgroupdiscoversnewcatalystsandstudiestheirfundamentalchemistryandapplications.Forexample,afamilyofcatalystsfortheinterconversion ofolefins,theolefinmetathesisreaction,hasbeendiscoveredintheGrubbslaboratory.Inadditiontotheirbroadusageinacademicresearch,thesecatalystsare nowusedcommercially.Otherprojectsinvolvethedesignandsynthesisofmaterialsforuseinmedicalapplications.Hehasalsobeeninvolvedinthetranslation oftechnologythroughthefoundingoffivecompanies.
xvi Foreword
HisawardshaveincludedtheNobelPrizeinChemistry(2005)and10ACS NationalAwards.HewaselectedtotheNationalAcademyofSciences(1989), FellowoftheAmericanAcademyofArtsandSciences(1994),theHonoraryFellowshipoftheRoyalSocietyofChemistry(2006),FellowofNationalAcademyof Inventors,NationalAcademyofEngineering(2015),andForeignMemberofthe ChineseAcademyofSciences(2014)andofGreatBritains’sRoyalSociety(2017). Hehas655+ publicationsand160+patentsbasedonhisresearch.
Preface
Theperceptionthat“thereisprobablynochemicalreactionthatcannotbe influencedcatalytically”wasclearlystatedbyWilhelmOstwaldeveninthe beginningofthepastcentury.Manyclassicindustrialprocesses,suchasthe productionofammoniabyHaberprocessandsulfuricacidornitricacid,require theuseofheterogeneouscatalystssuchasfinallydividedtransitionmetals.
Althoughindustrialprocessesingeneralweredominatedbyheterogeneous catalysis,organometalliccomplexesemergedasanewclassofcompoundswith amajorfunctionashomogeneouscatalystswithmoreprecisionforthesynthesis oforganicchemicals.Theearlierexampleofsuchaprocessisthemanufacture ofaceticacidbyCativaprocess,wheremethanolwassubjectedtocarbonylation withthehelpofanIr-orRh-basedorganometalliccomplex.
Theareaofhomogeneouscatalysisliterallybecameanemergingareaforthe synthesisoffinechemicalsandpharmaceuticalproductsafterthediscoveryof afewimportantcatalystsbyWilkinsonin1950s.Hence,Wilkinsonshouldbe recognizedasthefatherofmodernhomogeneouscatalysis.Wilkinson’swork laterinspiredWilliamKnowlestocomeupwithachiralRh-basedorganometalliccomplexforanewareaofhomogeneouscatalysis,calledasymmetrichydrogenation.In2001,WilliamStandishKnowlesandRyojiNoyorisharedtheNobel Prizefortheirworkonenantioselectivehydrogenationreactions,whiletheother halfwasawardedtoK.BarrySharplessforhisworkonenantioselectiveoxidationreactions.ThechemistrycommunitymayremembertheworkofKagan aswell,althoughhedidnotgettheNobelPrize.Synthesisofnumerouspharmaceuticallyrelevantmoleculesfortreatmentofseveraldiseases,agro-chemical compoundssuchas(S)-metolachlor,andfragrancesinmulti-tonquantitiesare someofthemajorapplicationsofthisarea.Thediscoveryanddevelopmentof theolefinmetathesisreactionsinorganicsynthesisalsoledtothe2005Nobel PrizetoYvesChauvin,RobertH.Grubbs,andRichardR.Schrock.Industries havestartedutilizingthismethodforspecialpolymers,drugsynthesis,aswellas biologicalpesticidessuchaspheromones.Thereisnoareainorganicchemistry thathasbecomeaspopularasthecross-couplingfield,wheretheapplicationslie intheareasofdrugsynthesis,OLED,andrelatedelectronicaswellasagrochemicalapplications.Forthisarea,althoughtheannouncementwasabitdelayed,the 2010NobelPrizeinChemistrywasawardedjointlytoRichardF.Heck,Professor Ei-ichiNegishi,andProfessorAkiraSuzukifortheirworkonpalladium-catalyzed cross-couplinginorganicsynthesis.Someoftheemergingareasinhomogeneous
catalysisareC–Hactivationandphotoredoxreactionswheretheorganometallic complexeshaveabigimpactonselectivityandactivity.However,theseareashave notquitereachedthesamestageasinthecaseofcross-coupling.Althoughaphotocatalystisrequiredtogenerateanorganicradical,asecondarycatalystsuchas aNi-basedorganometalliccompoundisrequiredtodosomeofthechallenging couplingreactionssuchassp2 –sp3 ,sp3 –sp3 ,andC–O/Scoupling.TheC–Hactivatedprocesswasalsocapableoffunctionalizingasp3 carbon.Thesechemistries inconjunctionwithflowprocessesaregettingincreasinglyprominentinindustrialprocessesandapplications.Similarlydoingchemistrywithbetter E -factors isalsobecomingimportantintheindustrialarea.Inspiredbytheorganometallic catalyzedreactions,particularlymetal-catalyzedC–Hactivation,cyclopropanation,transferhydrogenation,andemergingtechnologiessuchas“directedevolution”(2018NobelPrizeinChemistrywhereFrancesArnoldsharedtheprizefor generatinghighlyactiveenzymesbymutation)andelectrocatalysisaregaining momentumaspotentialtechnologiestobetranslatedtoindustry.
Wearefortunateenoughtoassembleagroupofoutstandingprocesschemistry researchersmostlyfromindustry,withtheexceptionofafewfromacademia,to writevariouschaptersrelevanttocurrent-daydevelopmentsinorganicsynthesis.Weaimedtocoverasmanydifferenttopicsaspossiblewiththe11chapters ofthebook.Theintroductionchaptersetsthesceneforthevariousreactivities oforganometalliccomplexesthatfundamentallyenableallchemistriesdiscussed inthesubsequentchapters.Chapters2and3discussthetypesofchemistrythat havebeenfoundtobeadvantageouslyperformedinaflowchemistrysetting. Chapters4and5detailcasestudieswherenon-preciousmetalcatalysiscouldbe applied,withclearcostandsustainabilitybenefitscomparedtousingprecious metalcatalysts.InChapters6and7,C—Hactivationprocessesaredescribed, whichintroduceamoreatom-economicalwayofformingC—C,orC—X,bonds. Inthefirstcase,apalladium-catalyzeddirectarylationreactionisdiscussed,and inthesecondcase,aruthenium-catalyzeddirectedCH-functionalizationchemistryisdetailed.Chapter8outlinesthepotentialusesandadvantagesofcarryingoutconventionalreactionswithmicellarcatalysisinwater,whichisavery attractive,moreenvironmentallyfriendly,option.Chapter9discusseshomogeneoushydrogenation,whichispossiblyoneofthemostfrequentlyseenapplicationsfororganometallicchemistry,orrathercatalysis,thatwasrecognizedby the2001NobelPrize.InChapter10,industrialapplicationsofolefinmetathesis,anotherNobelPrizewinningtechnology,areexemplified.Finally,Chapter 11outlinesareasonablyrecentlineofthoughtwithinthefieldoforganometallic chemistry,convertingbiomassintochemicallyusefulbuildingblocks.Thisparticularchapterfocusesontheconversionofcarboxylicacidsintoolefins.Wethank alltheauthorsfortheirscholarlycontributionstomakethisbookauniqueone. WethankWiley-VCHespecially,Dr.ElkeMaaseforgivingthisopportunity andforworkingwithuspatiently,aswellasProf.Grubbsforgraciouslytaking timetowritetheforeword.Weacknowledgeallthereviewersalthoughwewould liketokeeptheirnamesconfidential.WealsothankMilliporeSigma(abusiness ofMerckKGaA,Darmstadt,Germany)andJohnsonMattheyfortheirsupport onthiscollaborativeprojectinhelpingscienceandtechnologytoimprovethe
Preface xix qualityofthisplanetandlifeingeneralthroughtheutilizationoforganometallic chemistry.Weareconfidentthatthisbookwillhelpchemistsandchemicalengineersinbothacademiaandindustrytoimprovetheirskillsinorganicsynthesis.
August9,2019 Milwaukee,USAandCambridge,UK
ThomasJ.Colacot CarinC.C.JohanssonSeechurn
IndustrialMilestonesinOrganometallicChemistry
BenM.Gardner 1 ,CarinC.C.JohanssonSeechurn 2 ,andThomasJ.Colacot 3
1 CambridgeDisplayTechnologyLtd,Unit12CardinalPark,CardinalWay,GodmanchesterPE292XG,UK
2 JohnsonMatthey,28CambridgeSciencePark,MiltonRoad,CambridgeCB40FP,UK
3 MilliporeSigma(ABusinessofMerckKGAaDarmstadt,Germany),6000NTeutoniaAvenue,Milwaukee,WI 53209,USA
1.1DefinitionofOrganometallicandMetal–Organic Compounds
Organometalliccompoundscanbedefinedascompoundsthatcontainatleast onechemicalbondbetweenacarbonatomofanorganicmoietyandametal.The metalcanbealkaline,alkalineearth,transitionmetal,lanthanide,orametalloid suchasboron,silicon,andphosphorus.Therefore,metal–phosphinecomplexes arealsooftenincludedinthiscategory,althoughtheydonotcontainatypical metal–carbonbond–theyaremorecommonlyreferredtoas“metal–organic compounds.”Forthepurposesofthisbook,applicationsofbothorganometallicandmetal–organiccompoundsarediscussedonthebasisof“organometallic chemistry.”
1.1.1ApplicationsandKeyReactivity
Thethreemajortypesofapplicationsoforganometalliccompoundsinindustry areintheareasofelectronics,polymers,andorganicsynthesis.Inorganicsynthesis,theorganometalliccompoundsareusedaseithercatalystsorstoichiometric reagents.
1.1.1.1ElectronicApplications
Forelectronicapplicationstypically,theorganometalliccomplexissubjectedto chemicalvapordeposition(CVD)toformanappropriatethinlayerorsubjected toorganometallicchemicalvapordeposition(OMCVD)wherethedeposition ultimatelyoccursviaachemicalreactionatthesubstratesurfacetoproducea high-qualitymaterial.Theproductionofthinfilmsofsemiconductormaterialsis used,forexample,forLEDapplicationsviametal–organicvapor-phaseepitaxy (MOVPE)wherevolatileorganometallicMe3 E(E = Ga,In,Al,andSb)compoundsareusedasprecursors.Theyreactwithultrapuregaseoushydridesin aspecializedreactortoformthesemiconductingproductasacrystallinewafer [1–23].
OrganometallicChemistryinIndustry:APracticalApproach, FirstEdition. EditedbyThomasJ.ColacotandCarinC.C.JohanssonSeechurn. ©2020Wiley-VCHVerlagGmbH&Co.KGaA.Published2020byWiley-VCHVerlagGmbH&Co.KGaA.
1.1.1.2Polymers
Anothermajorapplicationfororganometalliccomplexesisinthepolymerindustry.Threecommontypesofpolymersproducedviacatalysisareparticularlynoteworthy.Polysiloxanes,alsoknownassilicone,arepolymersmadeupofrepeatingunitsofsiloxane[4].Theyhavewidespreadapplicationinalargenumberof differentfieldsrangingfromcookwaretoconstructionmaterials(e.g.GEsilicone),medicine,andtoys.Pt-basedcatalystsarecommonlyappliedinthesiliconeindustryfortheproductionofavarietyofproducts[5].Amilestonein thehistoryoforganometallicchemistryintheindustrywasthediscoveryofthe Ziegler–Nattacatalystanditsapplicationinpolymerizationreactions[6].Ziegler andNattawereawardedtheNobelPrizefortheirworkinthisfieldin1963[7]. Anotherareathathasbeenrecognizedforitsimportanceisolefinmetathesisfor whichaNobelPrizehasbeenawardedtoGrubbs,Schrock,andChauvin.Thishas beenappliedtosynthesizepolymersviaROMP(ring-openingmetathesispolymerization)[8].
1.1.1.3OrganicSynthesis
Thefocusofthisbook,however,isontheexploitationoforganometalliccompoundsfororganicsynthesis,relevanttoindustryapplications.Oneofthemajor applicationsinorganicsynthesisiscatalysis.
Incaseswheretheorganometalliccompoundisusedasacatalyst,forexample inaprocessinvolvingcrosscoupling,aprecatalystshouldbeabletogetactivated totheactivecatalyticspeciestobindwiththeorganicsubstrate(s),dothetransformation,andreleasetheproductsuchthattheactivecatalyticspeciesreturns toitsoriginalstateinthecatalyticcycle.Duringtheorganictransformation,the concentrationofthecatalystcandecreasewithtimebecauseofpoisoning.The efficacyandefficiencyofthecatalystdependonhowfastandhowlongitcan retainitsoriginalactivity.Theturnovernumbers(TONs)andturnoverfrequencies(TOF)areusuallyusedtodescribetheactivityofacatalyst.Organicchemists havestartedusingorganometalliccompoundsascatalyststodevelopmoreefficientandpracticalprocesses[9–12].
Thereactivityoforganometalliccomplexestowardvariousreagentsisthe reasonbehindthewidespreaduseoforganometalliccompoundsascatalystsfor avarietyoforganictransformations.Themostimportanttypesoforganometallicreactionsareoxidativeaddition,reductiveelimination,carbometalation, hydrometalation, β-hydrideelimination,organometallicsubstitutionreaction, carbon–hydrogenbondactivation,cyclometalation,migratoryinsertion,nucleophilicabstraction,andelectrontransfer.Inthefollowingparagraphs,wewill provideabriefoverviewofthebasictheorywithsomeselectedapplications.
OxidativeadditioninvolvesthebreakageofabondbetweentwoatomsX–Y. SplittingofH2 withtheformationoftwonewmetal–Hbondsisanexampleof anoxidativeadditionprocess(Scheme1.1).Reductiveeliminationisthereverse ofthisprocess.Inanoxidativeadditionprocess,theoxidationstateofthemetal isincreasedby2,whereasinreductiveelimination,oxidationstateofthemetalis decreasedby2.Bothstepsarecrucialformetal-catalyzedcross-couplingreactions,asthefirstandthelaststepsofthecatalyticcycle.Severalfactorscan affectthesetwosteps.Thestructureoftheligand(phosphineorothermolecules
1.1DefinitionofOrganometallicandMetal–OrganicCompounds 3 coordinatedwiththemetal),thecoordinationnumberofthemetalinthecomplex,andthewayinwhichthecomplexisactivatedtothecatalyticspeciesin thecatalyticcycle,etc.,canbemodifiedandtailoredtogetthebestoutcome foraparticularreaction[13].TheoxidativeadditionofH2 ontoVaska’scomplex(Scheme1.1)isacrucialstepinmetal-catalyzedhydrogenationreactions. Theapplicationofthismethodologytoindustriallyrelevantmoleculesisfurther discussedinSection1.3.3.
Scheme1.1 Oxidativeadditionandreductiveelimination.
Carbometalationinvolves,asthenamesuggests,thesimultaneousformation ofacarbon–metalandaC—Cbond.Thisismostcommonlyusedtoformastoichiometricmetal-containingreagent,suchasthereactionbetweenethyllithium andbis-phenylacetyleneinthesynthesisofTamoxifenTM ,abreastcancerdrug (Scheme1.2)[14].
Scheme1.2 CarbometalationasakeysteptowardthesynthesisofTamoxifenTM .
Hydrometalationissimilartocarbometalation,where,insteadofaC—C bond,aC—Hbondisformedalongsidethecarbon–metalbond.Onesuch exampleishydroalumination,whereDIBAL(i-Bu2 AlH)isaddedacrossan alkyne(Scheme1.3)[15].This,similartocarbometalation,ismostcommonly astoichiometrictransformationwiththeaimofpreparinganorganometallic reagentthatcanbeusedasareactantforsubsequentdesiredtransformations.
β-Hydrogenelimination,technicallythereverseofhydrometalation,canin somecasesresultintheformationofundesiredsideproducts.Inothercases,it isa“blessing”asthepreferredreactionpathway.InShellhigherolefinprocess (SHOP),fortheoligomerizationtooccur,afinal β-hydrogeneliminationreaction isperformedtoreleasethesubstratefromthecatalyst(Scheme1.4a)[16].In thecross-couplingreactionbetweenanarylhalideandanorganometallic
Hydrometalation
Scheme1.3 Hydroaluminationofalkynes.
Scheme1.4 a) β-hydrideeliminationisexploitedintheShellhigherolefinprocess(SHOP). b)sp2 sp3 cross-couplinginthesynthesisofadiabetesdrug.
reagentcontaining β-hydrogens,thisreactioncanformtheundesiredalkene sideproducts,hencedetrimental.Thisisthereasonwhysp2 –sp3 couplingand sp3 –sp3 couplingbecomeverychallengingeventoday.However,afewsuccess storiesofthesetypesofcross-couplingreactionshavebeenreported,suchas sp2 –sp3 NegishireactionforthesynthesisofLX2761,adiabetesdrugbyLexicon Pharmaceuticals(Scheme1.4b)[17].
Organometallicsubstitutionreactionscanoccureitherviaanassociativeora dissociativesubstitutionmechanism.ThiscanbecomparedtoSN 1andSN 2substitutionmechanismsinorganicchemistry.Theoveralloutcomeineithercaseis anexchangeofaligandontheorganometalliccomplex.Scheme1.5illustratesan associativesubstitutionmechanismtoexchangeClforXonVaska’scomplex.This complexdoesnothaveanysignificantreferencestobeingemployedinindustry asacatalyst,butstudiesofitsreactivityhasbeenvitalinprovidingtheconceptual frameworkforhomogeneouscatalysis[18].
Oneofthereactionsthathasbecomeincreasinglyexploited,particularlyto complementthecross-couplingchemistry,isC–Hactivation.Thisiswherethe
1.1DefinitionofOrganometallicandMetal–OrganicCompounds 5
Organometallic substitution reaction
Scheme1.5 OrganometallicsubstitutionreactionexemplifiedbyVaska’scomplex.Source: Wilkins1991[24].ReproducedwithpermissionofJohnWiley&Sons. metalgetsinsertedintoaC—Hbondofthesubstrate.Therearemanydifferentpathwaysforthistohappen;itcanbepromotedanddirectedtothesiteof choicebyusingadirectinggroup,suchastheamideexemplifiedinScheme1.6. Iridium-catalyzeddirectborylationreactionscanalsobeconsideredasatype ofC–Hfunctionalizationreaction.Thistypeofreactionsisfurtherdiscussedin Section1.3.2.1. Carbon–hydrogen bond
Scheme1.6 Carbon–hydrogenbondactivationexemplifiedbythetotalsynthesisof calothrixinB,whichpossessesvariousbiologicalactivitiessuchasanti-malarialandanti-cance. Source:RamkumarandNagarajan2013[25].ReproducedwithpermissionofAmerican ChemicalSociety.
Incyclometalationreaction,thestrainofcertainmotifsisoftenexploitedto insertthemetalintoC—Cbonds.OneexampleistheRh-catalyzedinsertion intocyclopropanestoformmetallacyclobutanes(Scheme1.7).Thishasbeen appliedinthetotalsynthesisof(±)-β-cuparenone[19].Metallacyclobutanesalso formaverycrucialpartofthemetathesisolefinationmechanism,asdeducedby Chauvin[20].
Cyclometalation
(±)-β-cuparenone
Scheme1.7 CyclometalationexemplifiedbytheoxidativeadditionsofRhintoa cyclopropanemoiety.
Migratory insertion
Scheme1.8 MigratoryinsertionexemplifiedbyastepintheCativaprocess.
Migratoryinsertioniscrucialforanycarbonylationreactionandisillustrated inScheme1.8byastepintheiridium-catalyzedCativaprocess,wheremethanol isconvertedintoaceticacid[21].Themigrationinvolvestheinsertionofoneligand(CO)intothemetal—Cbond(Ir-Me).Thereversereaction,decarbonylation ofaldehydestoformanalkanewiththereleaseofCO,isalsoareactionknown tobecatalyzedbyRhcomplexes[22],suchasWilkinson’scatalyst[23].MigratoryinsertionisnotrestrictedtoCOalonebutcanalsooccurwithSO2 ,CO2 , and,mostimportantly,alkenes.TheinsertionofanalkeneintoanM—Cbondis thekeystepinanyoligo-orpolymerizationreaction,suchastheZiegler–Natta process[26].
Nucleophilicabstractionisaprocesswhenaligandisfullyorpartlyremoved fromthemetalbytheactionofanucleophile.InScheme1.9,theactionof n-BuLi onachromium-coordinatedbenzeneligandresultsinhydrogenabstraction[27]. Basically,thechemicalreactivityoftheligandisalteredwhencoordinatedwitha metal.Thisaltersthereactivityoftheligatedcompoundandmayresultinreactionsthatarenotpossibletocarryoutwiththesamenon-ligatedsubstrate.
Anotherimportantorganometallicreactiontobediscussediselectron transfer.Theabilityofcertainorganometalliccomplexestoinitiateelectron transferreactionsincombinationwithavisiblelightsourcehasmadesome transformationspossiblethatcannotbeachievedusingconventionalchemistry. ThisisillustratedinScheme1.10withonestepinthephotocatalyticPschorr reactionusingRu(bpy)32+ asthephotoredoxcatalyst[28,29].Thephenanthrene formedcanbefurtherusedforvariouspurposes,suchasinthemanufacture ofdyes,pharmaceuticals,etc.[30].Thepotentialofmetal-catalyzedelectron transferreactionsformsthebasisforanewareainorganicsynthesiswithlotof potentials[31].
Exploitationofthewidevarietyof“organometallicreactivity”hasmadethefield oforganometallicsoneofthemostappliedareasinprocesschemistrywithparticularimportancetothepharmaceutical,agrochemical,polymer,andfinechemical industries.
Scheme1.10 ElectrontransferillustratedbyonestepinthephotocatalyticPschorrreactionto formphenanthrene.
1.2IndustrialProcessConsiderations
Organometalliccompoundsareroutinelypreparedandusedasstoichiometric reagentsorcatalystsforarangeofsyntheticprocessesonamultikilogramscale orevenatonscale.
Inordertooperateacommerciallyviableindustrialchemicalprocess,areliablechemicalsynthesisrouteisneededaswellasanunderstandingofhowa processwillbehaveduringthescaleupbytakingintoconsiderationfactorssuch asheatandmasstransfer,mixing,particlesize,andfilterability,etc.Air,moisture,andthermalsensitivityofsomeoftheorganometalliccomplexesortheir intermediatesneedstobeaddressedwithproperhandlingtechniquesincluding inertconditionstoachievethemaximumprocessefficiencyandprocesssafety. Inaddition,incorporationofenvironmentalimpactoftheprocessisalsovery important,whereexposureofchemicalsandsolventsandwastegenerationneed tobeminimized.
Itisimportanttohaveascalablechemicalprocess,usuallyoptimizedona benchscaletoproducemilligramtogramandthentransferredtothepilotplant, typicallytoakilogramscale.Duringthistransfer,typically,oneneedstoreadjusttherateofreagentadditiontomanagetheexotherm,rateofagitation,rateof heating,degassingcycles,reactiontime,etc.Identifyingtheoptimalcatalystwith theminimalloadingespeciallywhenoneuses platinumgroupmetals (PGMs) inconjunctionwithexpensiveligandsisalsoimportant.Evenforawell-known organictransformationsuchasaPd-catalyzedcross-coupling,theprocesswill notbeeconomicalifthereactionispoorlyoptimized,consideringmetalloss, purificationoftheproducts,andwastedisposal.Aproperunderstandingofthe thermodynamicsandkineticsisalsoimportant.
ExperienceinusingDOEcoupledwitha“knowledge-based”processapproach canacceleratetheprocessdevelopment.Itisimportanttoinvolvebothchemists andchemicalengineersduringthescale-upandprocessoptimization,consideringtheequipmentdesign,safety,rawmaterialselection,etc.Eveniftheprecatalystisnotsensitivetoair,onehastoconductthereactionsunderinertconditions asthe“activecatalyticspecies”inthecyclemightbesensitivetoair.Thiscannot onlyminimizetheby-productformationbutalsoincreasethelifecycleofthe catalystandhencetheTONsandTOFs.
Thekineticcontrolofanorganometallicprocesscanbeanotherimportantfactor.Oneexampleislow-temperaturereactionsinvolvingorganolithiumreagents, whereitisessentialtoavoidsignificantdecompositionofthermallysensitive species,thermalpromotionofundesiredsidereactions,andcontrolthereactivity ofexothermicprocesses.
Treatmentofwastestreamsfromorganometallicprocessesmustbeconsideredcarefullyastheymaycontainpreciousmetalorevenothertransitionmetal residuesoriginatingfromthedecompositionoftheorganometalliccompounds. Apartfromthewell-documentedenvironmentalimpactofPGMcompounds, finelydividedPGMparticles,ifallowedtodryout,poseasignificantfire hazard.Becauseofthesignificantenvironmentalhazardsassociatedwithheavy metalresidues,predominantlyarisingfromtheirpersistenceinthebiosphere viabioaccumulation,generationofthistypeofwastestreamonproduction scaleshouldbeavoidedwhereverpossible,withenvironmentalregulations strictlycontrollingthelevelofanyemissions.Somecommoncatalystprecursor complexesreleaseharmfulsideproductswhenactivatedorsubstituted.For instance,[Pd(COD)(Cl)2 ]releases1,5-cyclooctadiene(COD)inthepresence ofphosphines,which,amongitsotherchemicalhazards,hasapungentodor eveninlowconcentrations.Therefore,extremecaremustbetakenwhendealing withprocesswastethatcontainsit.Similarly,manyofthemetalcarbonyl compoundscangenerateCOgas,whichneedstobeproperlyvented.Someof thesecarbonyl-basedcompoundsundergosublimationaswell.
1.3BriefNotesontheHistoricalDevelopment ofOrganometallicChemistryforOrganicSynthesis ApplicationsPertainingtotheContentsofthisBook
Mostorganometallicprocesseshaveevolvedanddevelopedfromseminaldiscoveriesinthelate1800sorearly1900s.Insomecases,itiseasiertopinpointthe exactseminalreports,whereasinothercases,thistaskisnotsoeasy.Sabatier’s reportofnickel-catalyzedhydrogenationcaneasilybeidentifiedasthediscoveryofmetal-catalyzedhydrogenationreactions[32],forwhichhegottheNobel PrizeinChemistryin1912.Forthecross-couplingarea,itsoriginisslightlymore difficulttodeducepreciselyalthoughour2012reviewarticlesandbookprovidea muchbetterunderstandingofthearea[9,10,13,33,34].Onecouldarguethatit datesbackto1912NobellaureateVictorGrignard’sdiscoveryofRMgXreagents, whereGrignardsharedtheNobelPrizewithSabatier.Althoughbothtechnologies(Grignardin1912andcross-couplingin2010)gotNobelPrizes,theformeris consideredtobea“breakthroughinnovation,”whereasthelatteriscalled“incrementalinnovation.”Theimpactofcross-couplinginchemicalprocessesshowsits significancebybeingawardedtheNobelPrize,incomparisontomanycompeting technologies.
Inthissection,wewillbrieflygothroughtheoriginsofafewprominentareas withinorganometallicchemistryandhowtheyrelatetothecurrentindustrial applicationswithrespecttothetopicscoveredbythechaptersinthisbook.
1.3.1SynthesisofStoichiometricOrganometallicReagents
1.3.1.1ConventionalBatchSynthesis
Arguably,themostimportantstoichiometricorganometallicreagentsare organolithiumcompounds,RLi.Thestudiesofthesereagentswerepioneered byKarlZiegler,GeorgWittig,andHenryGilman[35].Theirrelativelystraightforwardpreparation,highbasicity,andwidearrayoffunctionalityprovide convenientaccesstousefulsyntheticroutessuchasmetalation,deprotonation,carbolithiation,andtransferorexchangeofthenucleophilicorganic fragmentR .
In1899,bysubstitutingMgforZninalkylationreactions,PhilippeBarbier’s studentVictorGrignard(Figure1.1)developedtheRMgXalkylatingagentsthat bearhisnametothisday.Beingalesssensitivebutmorepotentsourceofalkyl anionsthantheirZn-basedcounterparts,Grignardshowedhowtheycanefficientlyalkylatecarbonylcompounds,adiscoverythatprovedtohavehugeimpact insyntheticchemistryandearnedhimaNobelPrizein1912[36].
Today,VictorGrignardisrememberedasthefatheroforganometallicchemistry.Organomagnesiumcompoundsrepresentveryusefulalternativestotheir lithiumcounterparts,exemplifiedbythewidespreaduseofGrignardreagents, RMgX,forefficientalkylationsandarylations.Thesereagentsarenowproduced inmultitonquantities.Organocalciumcompoundsaremorereactivealkyl sourcesthanGrignardreagents,buttheirapplicationsarelimitedbecauseof theincreaseddifficultyoftheirpreparationandthethermalinstabilitythey exhibit.Organocalciumcompoundshavealsoshownpromiseashydroamination catalysts.Incomparisontoorganolithiumandorganomagnesium,organoaluminumcompounds,R3 Alreagents,aregenerallyfarlesseffectivestoichiometric reagentsbutdoaddtoalkenesandalkyneswithhighregio-andstereoselectivity viacarboalumination.Importantly,however,theyhavefoundparticularuseasa vitalcomponentoftheheterogeneousZiegler–Nattapolymerizationprocessfor theindustrial-scaleproductionofpolyethyleneandpolypropylene.Aluminum
Figure1.1 VictorGrignard.Source:https://commons .wikimedia.org/w/index.php?curid=545837.Licensed underCCBY3.0.
alkylsarealsowidelyutilizedforgroupIII–Vchemistryfortheproductionof electronicmaterialsviaCVD.
1.3.1.2OrganometallicsinFlow
Industrial-scaleorganicsynthesisforfinechemicalapplications,suchasnatural productsoractivepharmaceuticalingredients(APIs),andorganometallicsyntheseshavetraditionallybeenconductedinbatchusinglarge-volume(>100l) reactors.Incontinuousflowprocesses,smallamountsofreagentsolutionsare continuouslypumpedalongaflowingstreamtomixataspecificjunctionwith resonancetimetoreactthemtogethertoyieldtheproduct,whichisbeingpurifiedundertheflowconditionsandcollected.Insomecases,acascadeapproach hasbeenconsideredwheremultiplereagentshavebeenmixedsequentially ratherthanperformingreactionsindifferentbatchreactors.Industrieshave beenusingthistechniqueforthemanufactureofpetrochemicalsandbulk chemicalsasthisapproachhasproventobenotonlymosteconomicalbut alsoproducegood-qualityproductsconsistently.Therecentinterestinflow chemistryinacademiaforthesynthesisofmorecomplexorganiccompounds hasincreasedeffortstoapplythisrapidlyburgeoningtechnologybothinfine chemicalandpharmaceuticalindustries.Theadvantagesthatflowprocessescan bringinacommercialcontextrelativetobatchproductionareshorterreaction times,greatertemperaturecontrol,rapidoptimization,shorterpathlengthfor photochemicalreactions,andimprovedprocesssafety.Chapter2,authored byJosephMartinelliofEliLilly,presentsthedesign,development,andimplementationofanAPImanufacturingrouteundercontinuousflowconditions toshowcasetheapplicationofthistechnologyinorganicsynthesis.Chapter3 detailsthelithiationandborylationchemistryunderflow,asdevelopedbyJoerg SedelmeierandAndreasHafneratNovartis.Thischapterprovidesasnapshot ofhowthistechnologycanalsobeappliedforthesynthesisoforganometallic reagents.
1.3.2Cross-couplingReactions
SeveralyearsafterGrignard’sdiscoveryofRMgXreagents,in1941,Kharaschundertookthefirstsystematicinvestigationoftransition-metal-catalyzed sp2 –sp2 carboncoupling,detailingtheobservationofhomocouplingofGrignard reagents[37,38].Subsequentresearchfromhisgroupledtotheearliestreport ofacross-couplingreaction,whereacobalt-basedcatalystwasusedtocouple vinylbromidewithanarylGrignardreagent[39].Thismadehimtobethefather ofcross-couplingreactions.
Themetalcatalystsinquestionarealsoorganometalliccomplexesthatmediatethecouplingoftwodifferenthydrocarbonfragmentsfororganicsynthesis purposesinthefinechemical,agrochemical,andpharmaceuticalindustries.A simplifiedcatalyticcycleisshowninScheme1.11.Manyofthekeyreactivity stepsthatarecharacteristicfororganometalliccomplexesareaprerequisitefor thesereactionstotakeplace.Initialoxidativeadditionisfollowedbytransmetalation(organometallicsubstitution)andfinallyreductiveeliminationtoformthe
Reductive elimination
Transmetalation
Oxidative addition
Negishi Suzuki–Miyaura Stille Kumada, etc.
insertion
Heck–Mizoroki
Scheme1.11 Simplifiedcatalyticcyclesforcross-couplingreactions.
desiredproductandregeneratethecatalyst.Eachofthesestepshasbeenthesubjectofanumberofstudiestotryandunderstandtheexactnatureoftheirmechanism.ForSuzuki–Miyaurareactions,thetransmetalationstephasbeenthefocus ofattentionofseveralresearchgroups.TheDenmark,Lloyd-Jones,andHartwig groupshaveindependentlystudiedthisstepofthecatalyticcycleforthesetypes ofcross-couplingreactions[40–42].InSonogashirareactions(sp–sp2 bondformation),aCucocatalystiscommonlyemployed[43].Inmanyrecentrefinements ofthisreaction,however,theneedforacocatalysthasbeencircumventedby, forexample,acarefulchoiceofPdcatalystandreactionconditions[44–46].The mechanismoftheHeckreactiondiffersfromtheothernamedcross-coupling reactionsinthata β-hydrogeneliminationiscrucialfortheformationofthefinal product.
Manypioneershaveplayedaroleinthedevelopmentofthisareaandlenttheir namestothereactionstheyhavediscovered.Theimportanceofcross-coupling tothefieldofchemistrywasultimatelyrecognizedin2010byawardingthe NobelPrizetoRichardF.Heck,Ei-ichiNegishi,andAkiraSuzukifortheir researcheffortsinpalladium-catalyzedcross-couplingsinorganicsynthesis [9,10,13,35,36].Cross-couplingisanexamplewhereincrementalinnovationis ofequalimportancetothebreakthroughdiscovery,significantenoughevenfor theawardoftheNobelPrize.
FollowingfromanearlierworkbyFujiwara,in1969,RichardHeckpublished thefirstexamplesofcross-couplingusingstoichiometricpalladium(II).Building onaseparateworkbyMizoroki,heproposedthefirstPd(0)-mediatedcatalytic cycleforthecross-couplingofiodobenzeneandstyrene,openingthedoorfor anexplosionofdiscoveriesinPd-catalyzedcross-couplingchemistry.ThetraditionalMizoroki–Heckreactionformsasubstitutedalkeneviacross-coupling ofanunsaturatedhalideorpseudo-halidewithanalkeneunderPdcatalysis andisfrequentlyemployedforC–Ccouplinginindustrialsettings.TheHeck mechanismcanalsobeaccessedusingnickeltomediatethecatalysis.Under