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:20071,:200743(No.20475049)33e2mail:yinxf@zju.edu.cn333(310027)(microfluidics),10,,,,2,,:O62113;O64313:A:10052281X(2008)0120060216ApplicationofMicrofluidicReactorsonSynthesisReactionsMuJinxiaYinXuefeng33(DepartmentofChemistry,ZhejiangUniversity,Hangzhou310027,China)AbstractMicrofluidicsisthetechnologythatprocessesormanipulatessmall(10-9to10-18litres)amountsoffluidsusingchannelswithdimensionsoftenstohundredsofmicrometres.Microfluidicreactorshaveanumberofadvantagesoverconventionalchemicallaboratorybatchmethodologies,suchasshortmoleculardiffusiondistance,largespecificsurfacearea,highmassandheattransfercapacity,whichwillbeexpectedtopromotehighlyeffectivechemicalreactionsinthemicrofluidicreactors.Themainfeaturesofmicrofluidicreactors,themethodtodriveliquidthroughthemicrochannelsandthemethodformixingliquidsinmicrochannelsaresummarizedinthisreview.Subsequently,theeffectsofdownscalingreactionvesselsaswellastheadvantagesofthecontinuousflowmicrofluidicapproachareillustratedbyanumberofexamplesoforganicreactionscarriedoutinmicrofluidicdevices,includingliquid2liquidmisciblefluidreaction,catalyticreaction,phasetransferreactionandstronglyexothermicorendothermicorganicsynthesis.Thedevelopmentofmicrofluidicreactorsisnotonlyofgreatsignificanceforoptimizingmanysyntheticprocedures,butalsohelpfulforimprovingrelatedchemicalindustryprocesses.Keywordsmicrofluidicreactors;organicsynthesis;microfluidicmanipulation1(),:(1),,,,[1]20120081PROGRESSINCHEMISTRYVol.20No.1Jan.,2008(2)500050000m2m-3,,100m2m-3,1000m2m-3[2],,,,[3],,(3),[4],,,,(4),GCGC2MSHPLCNMR,[5],(5),[6](6),,,,[7](7),,,[8](8),,[9](9)[10],,,1997[11]10,[2,1224],[2,8],2[25],100500m,100m,,lPmin,,211,,[26],,,212,(EOF),,[8],Haswell[27]EOF,Nikbin[28]EOF,,EOFEOF(pH)[2931],,;,[8],[32],pHpHEOF,[33]pH[34]213,[8],[35],[36][37][38],(PDMS),161,,,,[8],[39]1,1,2,3,4,5A,B,C,CD,D,4,D,,,1[39]Fig.1Schematicdiagramoftheexperimentsystemofmicrofluidicreactor[39]3,,,m,Re,011100[40],(2)t:t=L2PD(D,L),,,,[41,42],TY,,(2)2[40]Fig.2Mixingoftwomisciblefluidstreamsunderlaminarflowconditions[40],,,,,[43]:,,311,,(ultrasonicallyactuatedmixers)[44](acousticbubblemixers)[45](opticallyactuatedrotators)[46](electrowetting2baseddropletmixers)[47](magneticmicrostirrers)[48](electrokineticinstabilitymicromixers)[49],,,312,,[25],2003,Bessoth[50];Mengeaud[51]Z;Dertiger[52];Stroock[53],2620,Lin[54]710m,,(3),,T,3[54]Fig.3Photographofthemicrofluidicmixer.Aschematicillustrationofthescaledmixingchamberisshownontheright[54]Re,4L,,[5558]4L[55,56]Fig.4Three2dimensionalL2shapedchannelforchaoticmixing[55,56]Jen[59]T[60],(5)Xia[61],,Yang[62][53](6),,,Howell[63](7),5(a)T[60](b)(c)(d)[59]Fig.5Schematicdiagrams(upsidedown)of(a)T2mixer[60],(b)inclinedmixer,(c)obliquemixer,and(d)wavelikemixer[59]6[62]Fig.6Staggered2herringbonegroovesforchaoticmixingatlowReynoldsnumbers[62]7[63]Fig.7Schematicofthechannellayoutforthemixer.Thegroovesonthetopandbottomareoffsetbyonehalfofthespacing[63]Song[64],8,(),pl,,,3618[64]Fig.8Formationofmicrodropletsinmicrochannels[64],,,,[6567]4,,,22411,,,[68,69]Michael[70],20min,100%;24h,20%,Swern[71],Grinard[72],[73]:,,,,,,,10kWm-2K-1[74],,Kawaguehi[71]Swern,-7083%,-20,,19%,-20214s,88%;020,,0101s,89%Skelton[75,76]TWittig,(9),P,,P01575121,2183109Wittig[75,76]Fig.9ThemechanismfortheWittigchemistrywithinamicroreactordevice[75,76]Watts[7781],20min,100%,24hFlÊgel[82]90,Frmeier[83]ESI2MS,,Wensink[84]NMR,BrivioMALDI2MS[85][86](NESI2TOF2MS),Mitchell[5]4620Garcia2Egido[87]LC2MSBaxendale[88],(10),,10[88]Fig.10Synthesisinflowofoxomaritidine[88],,,,Lu[89]T11C18F(11),1111C18F[89]Fig.11Synthesisof11Cor18Flabeledester[89],,,,,,Lu[90]P,(1),,,,,4lPmin40%;10lPmin,21412,,56112Table1Liquid2liquidmisciblefluidreactionreactionmicroreactortypeapplicationref.HantzschT2shapedchannelsynthesisofaseriesof22aminothiazolesfromring2substituted22bromoacetophenonesand12substituted222thioureas91cycloadditionmulti2channelthesynthesisofaseriesofDiels2Alderreactioncycloadductsperformedinglasschipswithpressuredrivenflow92Paal2Knorrmulti2channelsynthesisofpyrrolefrom2,52hexanedioneandprimaryaminesunder65andsolvent2freeconditions93Knorrsingle2channelcoupledwithLC2MSsynthesisoflibrariesofpyrazolesfrom1,32dicarbonylcompoundsandhydrazines,210s,productyield99%87,94peptidesynthesismulti2channelsynthesisofdipeptidefromanFmoc2protectedpentafluorophenylesterof2alanineandthecarboxylicacidprotected2alanineinquantitativeyield77peptidesynthesismulti2channelsynthesisoftripeptidefromN2protecteddipeptideandaminoacid,yield30%78,79peptidesynthesisT2shapedchannelsynthesisofdipeptidefromN2protected2aminoacidandO2protected2aminoacidinquantitativeyieldafter20min80peptidesynthesissingle2channelsynthesisandpurificationofpeptidesfromaminoacids81peptidesynthesissingle2channelpeptidecouplingswithtertbutyloxycarbonyland92fluorenylmethoxycarbonylprotectedaminoacidsin15minat12082aldolreactionfour2channelaldolreactionofasilylenoletherwith42bromobenzaldehydeinthepresenceoftetra2butylammoniumfluoride,quantitativeconversionof2hydroxyketonewasobservedina20minperiod68,69Michaeladdition