206推进了在环氧化物的有机化学赠送品-03A位的电子&Conformational作用- Nucl

Chemistry206AdvancedOrganicChemistryHandout–03ASteric,Electronic,&ConformationalEffectsinEpoxide–NucleophileReactionsD.A.EvansMondaySeptember27,1999MickDartEvansGroupSeminar,December,199303A-00-Coverpage1/20/0012:54PMEpoxidesasElectrophilesD.A.Evans,M.DartChem115Parker,R.E.;Isaacs,N.C.Chem.Rev.1959,59,737-799.Rosowsky,A.InTheChemistryofHeterocyclicCompounds;Weissberger,A.,Ed.;Interscience:NewYork,1964:Vol19,Part1,p1.Buchanon,J.G.;Sable,H.Z.InSelectiveOrganicTransformations;Thyagarajan,B.S.,Ed.;Wiley:NewYork,1972:Vol.2,p1.Berti,G.InTopicsinStereochemistry;Allinger,N.L.;Eliel,E.L.,Eds.;IntersciencePublishers:NewYork,973:Vol.7,p93.Rao,A.S.;Paknikar,S.K.;Kirtane,J.G.Tetrahedron1983,39,2323.Sharpless,B.K.;Behrens,C.H.;Katsuki,T.;Lee,A.W.M.;Martin,V.S.;Takatani,M.;Viti,S.M.;Walker,F.J.;Woodward,S.S.PureAppl.Chem.1983,55,589-604.Behrens,C.H.;Sharpless,B.K.AldrichimicaActa1983,16,67-80.GorzynskiSmith,J.;Synthesis1984,629-656.Lewars,E.G.InComprehensiveHeterocyclicChemistry;Katritzky,A.R.,Ed.;PergamonPress:NewYork,1984:Vol.7,p100.Weissberger,A.;Taylor,E.C.InTheChemistryofHeterocyclicCompounds;HassnerA.,Ed.;Wiley:NewYork,1985:Vol.42,Part3,p1.Rossiter,B.E.InAssymetricSynthesis;Morrison,J.D.,Ed.;Academic:NewYork,1985;Vol.5,Chapter7.Hanson,R.M.ChemRev.1991,91,437-475.Alsosee:Larock,R.C.ComprehensiveOrganicTransformations,p505-526.STERIC,ELECTRONIC,ANDCONFORMATIONALEFFECTSINEPOXIDE/NUCLEOPHILEREACTIONSReviewsParker,R.E.;Isaacs,N.C.Chem.Rev.1959,59,737-799.R=variousalkyl,aryl,orvinylsubstituentsSN2Transition-StateDuetoringstrain,bondbreakingismoreadvancedthanbondmakinginthetransition-staterelativetoanormalSN2reaction.Inaddition,thecarbonatomatwhichdisplacementtakesplacewillbearapartialpositivechargeinthetransition-state.NormalSN2behaviorisobservedunderneutralorbasicconditionstoprovidenucleophilicattackattheleastsubstitutedcarbonwithinversion.R'isalkyloragrouphavingnomarkedinductiveorconjugativeeffects.Exceptions:HydrogenationinthepresenceofRaney-nickelproceedswithoppositeregioselection.δ−δ−δ+H-N3-RO-RS-RNH2R2NHNH3R-Nu=NuREGIOSELECTIVITYOFEPOXIDERINGOPENINGNEUTRALORBASICCONDITIONS:SN2‡OR'HNuHHOR'R'NuOH03A-01-epoxideintro1/20/0010:49AMMoreabnormalisformedinH2OthaninEt2Owhichisexpectedsincethereactionproceedsthroughapolartransirtionstate.TheelectrondonatinginductiveeffectofanextramethylsubstituentslightlyoverridestheadditionalstericeffecttherebyenhancingC_αattack.HI,whoseanionismostnucleophilicintheseriesofacids,providesthehighestproportionofnormalproductasexpected.74HCl,Et2O,∆2618HI8271HBr2944HClHX56REGIOSELECTIVITYOFEPOXIDERINGOPENINGACIDICCONDITIONS:BORDERLINESN2TOSN1AbnormalProdNormalProdHX,H2O70-85°CHCl,H2O4555αβαβBuchanon,J.G.;Sable,H.Z.InSelectiveOrganicTransformations;Thyagarajan,B.S.,Ed.;Wiley:NewYork,1972:Vol.2,p1.Stewart,C.A.;VanderWerf,C.A.J.Am.Chem.Soc.1954,76,1259.Swain,C.G.;Scott,C.B.J.Am.Chem.Soc.1953,75,141.REGIOSELECTIVITYOFEPOXIDERINGOPENINGNucleophilicattackoccursontheconjugateacidoftheepoxide.ThetransitonstateismorepolarandC_ObondcleavageismoreadvancedthaninSN2reactions.EpoxideswhichexhibitnormalSN2behaviorunderbasicorneutralconditionsgivemixturesunderacidicconditions.StericfactorsareimportantalthoughlesssothanobservedinSN2reactions.Thepositivechargebuildupisstabilizedbyelectronreleasinggroups.IntheborderlineSN2mechanisms:NormalProductAbnormalProductBABORDERLINESN2βαδ+δ−++++δ−δ+δ+δ+ACIDICCONDITIONS:BORDERLINESN2TOSN1βαSN1SN1++FavoredelectronicallyDisfavoredstericallyDisfavoredelectronicallyFavoredstericallyR=alkylMajorproductusuallyEpoxidesasElectrophilesD.A.Evans,M.DartChem115HHNuHRHOROHROHOHRNuROHOHHRHNuROOHNuRNuROHMeOOHXMeXMeOHOMeMeMeClMeOHMeOHMeCl03A-02-epoxides1/20/0010:49AMParker,R.E.;Isaacs,N.C.Chem.Rev.1959,59,737-799.Lemieux,R.U.;Kullnig,R.K.;Moir,R.Y.J.Am.Chem.Soc.1958,80,2237.Stericeffectsdominateregioselectivity,especiallyinacyclicsystemsinwhichconformationalconsiderations(Fürst-Plattnerrule)maynotbeasimportant.However,inmanysystemsstericsoneachsideoftheepoxidemaybesimilarandsubstituentelectroniceffectsemergeastheimportantfactorsindeterminingregioselection.EtOH,H2SO4aqiPrNH2aqiPrNH2NaOMeNaOMeNH3orNH3(NH2)δ+δ−δ−EWG=ElectronWithdrawingGroupAttackatC-αisdiscouragedduetodestabilizationofthetransitionstatebyjuxtapositionofpositivecharge.αβEFFECTOFELECTRONEGATIVE,NONCONJUGATINGSUBSTITUENTSConformationaleffectsareguidingtheregioselectivityofreaction3.1.2.3.δ−δ+‡Chem115D.A.Evans,M.DartEpoxidesasElectrophilesEPOXIDESADJACENTTOCARBONYLSOthernucleophilessuchasamines,varioushydrides,andmalonateanionsshowthesameregioselectivity.REGIOSELECTIVITYOFEPOXIDERINGOPENINGSLiwschitz,Y.;Rabinsohn,Y.;Perera,D.J.Chem.Soc.1962,1116.R=HorBnRNH2NH3TheoppositeselectivityobservedinthiscaseisduetostabilizationofthedevelopingpositivechargeatC-2bythecarboxylateanion.Thereactionproceedswithinversionofstereochemistryatthiscenter.Parker,R.E.;Isaacs,N.C.Chem.Rev.1959,59,737-799.23MeOHOOOF3COEtOOOHONHROHMeOOEtMeMeOEtOOOONH2ONH2HOOEtF3CMeOEtNH2OHOMeH2NOHOOEtNH2OH2NOHOR'R'HNuOHOMeOOMeOMeOOMeOHOMeOMeOHOMeOMeOMeNH2OArONHiPrNHiPrMeF3C