MicrowaveAssistedOrganic Synthesis(MAOS)

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

GreybarsMAOSpublicaBonsinoneof:J.Org.Chem.,Org.LeG.,Tetrahedron,Tet.LeG.,Synth. Commun.,Synthesis,SynleG. BlackbarsMAOSpublicaBonsreporBngexperimentsperformedindedicatedchemicalsynthesis microwavereactors.

ManyrespectedjournalssuchasACSorganicchemistryjournalswillno longeracceptmanuscriptswhichdescribetheuseofakitchenmicrowave orlackreacBontemperatures.

MicrowaveTheory

ElectromagneBcirradiaBoninthefrequencyrange0.3to300GHz(wavelengths 1mmto1m)allcommercialdomesBcmicrowavesandsynthesismicrowave reactorsoperateat2.45GHztoavoidinterferencewithtelecommunicaBon, wirelessnetworksandmobilephonefrequencies. Theenergyofamicrowavephotonofthisfrequency(0.0016eV)isthereforetoo lowtocleavemolecularbonds(unlikeUVandvisibleradiaBon).

DielectricHeaBng
IndicatestheheaBngofpolarisablematerials.

ElectriccomponentofanelectromagneBceldcausesheaBngby:dipolar polarisaBonand/orionicconducBon. FieldenergyconvertedintokineBcenergyinthealigningmoleculesandthermal energyviamolecularfricBon,andnallyintoheat. BulkmixturephenomenongasescannotbeheatedundermicrowavecondiBons asthedistancesbetweenrotaBngmoleculesistoogreat.

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.

At20oC,HbondingbetweenbiradicalOHandsolventisweakerfor pmethylvalerophonethanvalerophonethiseectismarkedly reducedat80oC.

SuperheaBnginNorrishtypeII reacBon
TestreacBonsperformedindierentsolvents.IrradiaBonat280nmto giveidenBcalphotochemicalcondiBonsforbothcompounds.

ProductdistribuBongreatlychangedbetweenconvenBonalheaBng(CH) andmicrowaveheaBng(MW).GreaterquanBBesofcyclisedproductcould beobtainedviathemicrowavereacBonthanbyconvenBonalheaBng underreuxprobablyduetothelineardependenceofRonTandthe abilitytoachievesuperheatedtemperatures.

SelecBveheaBng
DescribesthephenomenaarisingfromthepreferenBalabsorpBonofmicrowave energybydieringmedia. Cancauselocalsuperheatedhotspotsforinstanceincatalystsprovidingmuch greatertemperaturesatthereacBoninterfacewhilstthebulkreacBonmixture remainsatalowertemperature. Mayalsobeexploitedinsolventdopingforinstancewithionicliquidstoincrease thetemperaturesthatmaybereachedwithpoorlymicrowaveabsorbingsolvents andalsotherateatwhichtheyareachieved. 1

SelecBveheaBngofsolvents
HofmanneliminaBonperformedbyStraussandcoworkersin1995. PreviousaGemptsinwaterat105oCledtopolymerisaBonoftheproduct.

BiphasicsystemallowedthereacBontotakeplaceinwaterwhiletheproduct parBBonsintotheorganicphasewhichiskeptatamuchlowertemperatureeven withinthesamevesselduetothedierencesindielectricproperBesofthetwo solvents.

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.

Studyusing3breopBcthermometersandoneIRtemperaturemonitorshowthe dierencesinreportedreacBontemperatureifagitaBonisinsucientandwillbe dependentontheposiBonofthethermometer

InvesBgaBonofnonthermaleects usingSiCheaBngelements
KappealsodesignedexperimentsusingsiliconcarbideinsertstoinvesBgate nonthermaleectsasafuncBonofpowerin6reacBontypes.

SiCheaBngelementschosenaschemicallyinertmicrowaveenergyabsorbers. WhenusedinconjuncBonwithpoorlyabsorbingsolvent,therequiredamount ofmicrowavepowerneededtoachievegiventemperatureswasreduced signicantly(3070%)

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