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RobDavidsonFuchterGroup
Whyusemicrowavereactors
Rateenhancement:highertemperaturesachievedcangreatly reducereacBonBmes. Improvedpurity:fasterconversionmayleadtoreducedbyproduct formaBonleadingtoeasierpuricaBonandimprovedyields. Greaterreproducibility:homogeneousmicrowaveeldandregular apparatussetupgivesbeGerrepeatperformance. Expandedreac9onspace:reacBonsperformedusingmicrowave irradiaBonthatmaynotbepossibleviaconvenBonalheaBng/ reuxcondiBons.
Background
FirstorganicsynthesisreacBonsperformedin1986byGedyeetal.
FolloweduplaterthatyearbyGiguere/MajeBchmoredetailedsolventstudies& cycloaddiBonreacBons.
Background
MAOStooksolongtobeacceptedasformanyyearsaSerits concepBonitwasdeemedtobeablackboxscience.Thiswasdue to(i)thelackofdedicatedmicrowavereactorskitchenappliances werenotrobustenoughformanyreacBvechemicalspeciesand variedgreatlybetweenmodels,and(ii)lackofunderstandingin usingmicrowaveirradiaBonasanenergysource. ThisledtomanymicrowavereacBonsbeingbothirreproducible anddangerous. MAOSstartedtohavearesurgencein2000whenthe pharmaceuBcalindustryrecognisedthepotenBalofrapidreacBon turnoverforthefacilesynthesisoflargecompoundlibraries.
Background
PublicaBonhistory
MicrowaveTheory
DielectricHeaBng
IndicatestheheaBngofpolarisablematerials.
DielectricproperBes
AbilityofasubstancetoconvertelectromagneBcenergyintoheatisknownas thelosstangent(tan).
tan=/
isthedielectriclossandisdielectricconstant. SolventswithlowerdielectricconstantsmaysBllbeclassiedasbeGer microwaveabsorbersduetotheirhigherlosstangentse.g.Ethanol(at 25oC=24.3)>water(at25oC=80.4) Materialswithoutapermanentdipolemomentmaybeviewedasmicrowave transparent(e.g.CCl4orbenzene) SolventswithlowtanmaysBllbeviableinmicrowavesynthesisifother substancesinthereacBonmixtureincreasethedielectricproperBesorif dopedwithsmallamountsofpolarsolventsorionicliquids.
DielectricproperBes
DielectricproperBesandtemperature
AbsorpBonofmicrowaveradiaBonbyagivenmaterialvariesgreatlyonthe temperature. Forwaterandmostotherorganicsolventsthelosstangentdecreasesatincreased temperatures.(SupercriBcalwaterT>374oCismicrowavetransparent)
Conversely,intheopposingscenario,ifamaterialweretobecomeastronger microwaveabsorberathighertemperaturesthismayleadtothermalrunawayheaBng.
MicrowavevsconvenBonalheaBng
Microwaveeects
Inthemajorityofcases,reacBonsperformedinamicrowavereactordierfrom convenBonalheaBngwithahotplate/oilbathonlybythewaytheheatisapplied tothereacBonmixture.Itisnowwidelyacceptedthatinnearlyallcircumstances, areacBonthatworksunderthelaGercondiBonsmaysuccessfullybecarriedout usingmicrowaveirradiaBon. SincealmostthebeginningofMAOSpublicaBons,therateacceleraBons,altered productdistribuBonsandachievementofreacBvityunobtainableunder convenBonalheaBngcondiBonshasledtospeculaBonabouttheexistenceof microwaveeects. Thetwomaincategoriesofthesemicrowaveeectsare:thermaleectsand,the morecontroversial,nonthermaleects.
Thermaleects
ThermalmicrowaveeectsaremoreeasilyraBonalised, observedandjusBedasreacBvityisderivedsimplyfrom thermal/kineBceects. Thermaleectsinclude: EliminaBonofwalleects SuperheaBngofsolvents SelecBveheaBngofmaterials
Invertedtemperaturegradientvswall eects
Microwave
OilBath
SuperheaBng
TypicallytheoccurrenceofoverheaBngby~1025oCabovethenormal boilingpointofasolvent.NoBcedbyMingos&Baghurstin1992. Closelyrelatedtoinvertedheattransfer,heatlossviaboilingat nucleaBonpointswhichareatthecoolestpartofthegradientin microwaveheaBngasopposedtohoGestinconvenBonalheaBng. ThermaleectnoteasilyreproducedviaconvenBonalheaBng. GivesrisetoshorterreacBonBmes,postulatedtofollowArrheniuslaw:
k=Aexp(Ea/RT)
RoughlyequatestoadoublingofreacBonrateforevery10OCincreasein temperature.
SuperheaBnginNorrishtypeII reacBon
GeneraBonof1,4biradicalswhichreactintramolecularly.
SuperheaBnginNorrishtypeII reacBon
TestreacBonsperformedindierentsolvents.IrradiaBonat280nmto giveidenBcalphotochemicalcondiBonsforbothcompounds.
SelecBveheaBng
DescribesthephenomenaarisingfromthepreferenBalabsorpBonofmicrowave energybydieringmedia. Cancauselocalsuperheatedhotspotsforinstanceincatalystsprovidingmuch greatertemperaturesatthereacBoninterfacewhilstthebulkreacBonmixture remainsatalowertemperature. Mayalsobeexploitedinsolventdopingforinstancewithionicliquidstoincrease thetemperaturesthatmaybereachedwithpoorlymicrowaveabsorbingsolvents andalsotherateatwhichtheyareachieved. 1
SelecBveheaBngofsolvents
HofmanneliminaBonperformedbyStraussandcoworkersin1995. PreviousaGemptsinwaterat105oCledtopolymerisaBonoftheproduct.
Nonthermaleects
NonthermalmicrowaveeectsareacceleraBonsof chemicaltransformaBonsinamicrowaveeldthat cannotberaBonalisedbythermal/kineBceects. ProposeddirectinteracBonofthemicrowaveeldand thereacBonmedia. SBllhighlycontroversialandthesubjectofmuch debate. RaBonalesfornonthermaleectsinclude:
PreorientaBonofreacBngmoleculesintheelectriceld. LoweringofpolartransiBonstateenergiesthrough microwaveeldstabilisaBon.
TesBngmicrowaveeects
DipolarorientaBonreacBonenhancementisconsideredunlikelyduetothe disorientaBoncausedbythermalandmechanicalagitaBon. StabilisaBonofpolartransiBonstatesmoreplausible(cf.SolventstabilisaBonof transiBonstates) Loupyetal.publishedsomestudiesinirreversibleDielsAldercycloaddiBonsto comparepolarandnonpolarmechanisms.Showedenhancedconversionin microwaveforthetransformaBonwithapolartransiBonstate.
TesBngmicrowaveeects
Synchronous,isopolar mechanism
Asynchronous,polar mechanism
TesBngmicrowaveeects
ReinvesBgaBonsbyKappegroupshowedthatwithcarefulmonitoringand regulaBonofthereacBontemperature,nodierenceswereseenbetweenoilbath andmicrowaveexperiments.
Temperaturemonitoring
Problemscausedwithimpropermeasuringoftemperaturesasshowninprevious example.
InvesBgaBonofnonthermaleects usingSiCheaBngelements
KappealsodesignedexperimentsusingsiliconcarbideinsertstoinvesBgate nonthermaleectsasafuncBonofpowerin6reacBontypes.
InvesBgaBonofnonthermaleects usingSiCheaBngelements
6examplereacBonswere:Claisenrearrangement,DielsAldercycloaddiBon,benzoic acidestericaBon,aromaBsaBonofdihydropyridine,HeckarylaBon&thiourea crosscouplingwithphenylboronicacid.
Noeectonconversionatconstanttemperaturewithdierentpowerlendsweight tothegrowingbeliefthatobservedmicrowaveeectsarethermalinnature.
UsefulapplicaBonsofMAOS
Highthroughputchemistry(combinatorialand parallelsynthesis) PreparaBonofisotopicallylabelleddrugswith shorthalflives(11C,t1/2=20min;122I,t1/2=3.6 min;18F,t1/2=100min) CatalysisshorterreacBonBmescanhelpto preservecatalystandpreventdegradaBon
DesignandopBmisaBonofmicrowave synthesis
Bookp174table5.2+surroundingpages
NoreacBonorincompleteconversion Result Op9ons IncreasereacBontemperature ExtendreacBonBme Changesolvent,catalyst,reagents,etc. ChangemolarraBos IncreaseconcentraBon IncreaseiniBalpower Decreasetemperature ShortenreacBonBme Changetoamoretemperaturestable reagent DecreaseconcentraBon DecreaseiniBalpower ReduceBmeunBltheconversionissBll completetomaximiserentenhancement
DecomposiBonofreagents/products
ReacBoncomplete
FutureofMAOS
MustnotviewmicrowavereacBonsasalastresortbutasafurther availableopBontoalabbasedchemist.Methodsofapplyingheathave evolvedthroughouthistory. ThiswillbemadeeasierasmicrowaveheaBngbecomesmoreprevalent anddedicatedmicrowavesynthesisequipmentbecomescheaper.
References
C.O.Kappe,D.Dallinger,S.S.Murphree,PracBcalMicrowaveSynthesisforOrganicChemists,1sted.,Wiley,Ch1,2&5 A.delaHoz,A.DazOrBz,A.Moreno,Chem.Soc.Rev.,2005,34,164178 R.Gedye,F.Smith,K.Westaway,H.Ali,L.Baldisera,L.Laberge,J.Rousell,Tet.LeG.,1986,27,279282 R.J.Giguere,T.L.Bray,S.M.Duncan,G.MajeBch,Tet.LeG.,1986,27,49454948 M.A.Herrero,J.M.Kremsner,C.O.Kappe,J.Org.Chem.,2008,73,3647 V.Polshezwar,M.N.Nadagouda,R.S.Varma,Aust.J.Chem.,2009,62,1626 T.Razzaq,J.M.Kremsner,C.O.Kappe,J.Org.Chem.,2008,73,63216329 D.Dallinger,M.Irfan,A.Suljanovic,C.O.Kappe,J.Org.Chem.,2010,75,52785288 P.Kln,J.Literk,S.Relich,J.Photochem.Photobiol.,A,2001,143,49 K.D.Raner,C.R.Strauss,R.W.Trainor,J.Org.Chem.,1995,60,2456 C.R.Strauss,R.W.Trainor,Aust.J.Chem.,1995,48,1665 L.Perreaux,A.Loupy,Tetrahedron,2001,57,91999223