中科院上海有机化学研究所-氟化学研究生课程课件

含氟生物活性物质卿凤翎自然界：•有机氟化合物几乎不存在：12•无机氟化合物氟化钙（萤石）：CaF2我国是世界上萤石储量大国，探明储量占世界总储量的三分之一。FabulousFluorineCoverStoryChemical&EngineeringNewsVolume84,Number23:June5,20061771:ScheeleHF1886:MoissanF21892:OrganofluorineChemistry:Swarts;metalfluoride-promotedhalogen-fluorideexchangereactions1930:Organofluorinecompoundsasrefrigerants:MidgleyandHenne1940s:Wartime:Perfluorinatedsubstances1940s:electrochemicalfluorination:SimonsSaturatedfluorocarbons(hydrocarbonanalogous):Lowest:dielectricconstantssurfacetensionsrefractiveindexesGreater:densitiesviscositiescompressibilitiesC6F14C6H14bp(o0C)5769d(g/cm3)1.6720.863nD1.2521.372AcidStrengthAcidpKaCH3SO3H-1.9CF3SO3H-5.1C6H5OH10.0C6F5OH5.5CH3CO2H4.8CF3CO2H-0.2J.FriedJ.Am.Chem.Soc.,1954,76,1455ThebeginningofaneweraoffluorineinbiologicalChemistryOHOAcOOOHF9α-fluoro-hydrocortisoneacetate(activity11timesgreaterthanthatofthecorrespondinghydrocarbon)OHOAcOOOHFThelowerpKaofthe11β-hydroxylgroupanditsincreasedabilitytodonateahydrogenbond,aswellasitsincreasedresistancetometabolicinactivationbyoxidation.FluorinatedcompoundshavebeenapprovedbytheFDAasdrugs:anticancer,antiviral,antibacterial,antidiabetic,antimalarial,antimalarial,antifungal,antidepressant,antipyschotic,antiinflammatory,andanestheticagents.Markedfluorine-containingdrugs:107compoundsCF3N(n-C3H7)2NO2NO2Trifluralin19602001:33%除草剂杀虫剂杀菌剂三氟甲基的芳香化合物和杂环化合物。代血液NCF2CF2CF2CF3CF2CF2CF2CF3CF2CF2CF2CF3FFCF3CF2(CF2)5CF2Br含氟麻醉剂CF3CF3OFCF3CBrClFElectroniceffectsofFluorineF:electronegativityasigma-withdrawingeffect,Iσorthrough-spaceelectrostaticinteraction,afieldeffectFluorinedirectlyattachedtoapisystem:complexFluorinemaybedonatedbacktothepisysteminanIπreplusiveinteractionFluorine-containingmolecules:Electrondistribution;theacidityorbasicityofneighboringgroupdipolemomentsreactivityandstabilityFluorine:1)Stabilizeαcationsbytheinteractionofthevacantporbitalofthecarbocationwiththefilledorbitalsoffluorine2)Fluorinebondeddirectlytoacarbanioniccenter:destabilizingbyIπreplusiveinteractionBut,CF3stabilizing3)asahydrogenbondacceptorbecauseofitsavailableelectrondensity.CFCFStabilisingCFDestabilisingCH3CF3CH2FCHF2α-氟对碳正离子的稳定作用也决定含氟烯烃的亲电加成反应的定位和速率。如：三氟乙酸对-2卤丙烯的加成反应为反应次序：FClBr。并且得到单一的加成产物CFH3CCH3CCH3CH3CF3CO2COCOCF3FCH3H3CH2CCH3CFHF卤代苯亲电取代反应的活性顺序也进一步说明α-氟对碳正离子的稳定作用：从卤素原子的诱导效应来看，卤代苯的亲电取代反应的活性顺序应该是：X=HBrClF。XXEEH+XEH然而，氟苯进行对位氯化和溴化的反应速度是苯的6.3倍。这些结果表明氟原子与反应过渡态之间具有共轭效应。FFHEEH含三氟甲基（氟烷基）的碳正离子是去稳定化的HHOTosOMeOMeCF3HOTosOMeCF3OTosF3C相对水解速度40005.2-2.41HHFStabilisingHHFDestabilisingCCFFFCCFFF+由于氟原子能稳定β-氟碳负离子，一些全氟烷基的叔负离子可以是长时间稳定存在。如氟负离子与全氟异丁烯反应可形成稳定的碳负离子，该碳负离子可通过NMR直接检测到。FF3CF3CFCsFF3CF3CCF3Cs+StericeffectofFluorinevanderWaalsradius:F:1.35;H:1.20Replacementofcarbon-hydrogenbondwithacarbon-fluorinebonddoesnottypicallypresentamajorstericperturbationinamolecule.EffectoffluorinesubstitutiononconformationNFHRHTheelectrostaticattractiveinteractionbetweenC-FandH-Ndipoles:Preferaxialtoequatorialbya96-100:1ratio.EffectsofFluorineonBiologicalReactivity1)thehighcarbon-fluorinebondstrength(108Kcal/mole)rendersthefluorinesubstituentresistanttomanysuchmetabolictransformationsVitaminD3OHOHOHOHOHFOHThrombininhibitor(stroke)NNHNNHNNOONH2HHNNHNNHNNOONH2FFoxidationKi(nM)0.270.042J.Med.Chem.,2003,46,461-4732)Fluorinemayalsobeemployedasaleavinggroupinaddition-eliminationprocesseswhereitssuperiorleavinggroupabilityrelativetohydrogenisimportant.Suchapplicationshaveledtothedevelopmentofveryeffectivemechanism-basedenzymeinhibitors.HFNH2OHHFNHOHflavinHFNHOHflavinNHOHflavinHenzymeMAOenzymeenzymeMAO:monoamineoxidase3)Fluorineonacarbonadjacenttothecarbonylgroupincreasestheelectrophilicityofthecarbonylcarbonandthereforethetendencyofnucleophilestoadd.InhibitionisprobablyduetotheformationofastablehemiketalwiththeactivesiteOCF3OKinM16310,000acetylcholinesteraseONHNHOOONHNHOONHNHOOONHNHOFFKinM560.06Pepsin4)EffectsoffluorinesubstitutiononhydrolyticstabilityOOCO2HOHOOCO2HOHFFTXA210,10-DifluoroTXA210,10-DifluoroTXA2hasfourtofivetimespotentthanTXA2Proc.Natl.Acad.Sci.USA,1989,86,5600.5)FluorinehasbeenemployedasareplacementforbothhydroxylandhydrogenDifluoromethyleneunitshavebeenemployedasisostericreplacementsforoxygenInfact,nootherfunctionalgroupthatcanreplaceoxygenmatchessowellthestericandelectronicdemandofoxygen.NONOOONFFTheCsp3-Fbondof1.40A°isslightlyshorterthantheCsp3-OHbondNNNHOOHOHNNNHOOHFbrevianamideEfluorobrevianamideECompetitiveinhibitorofacylCoA:cholesterolacyltransferaseAngew.Chem.Int.Ed.,2001,40,44616)Fluorinehasbeenidentifiedasimprovingthelipophilicityofamoleculeandhenceitsdistributionwithinanorganism.CF3groupthelipophilicityofsubstituentsXOCH2CO2HXπSCF3+1.58OCF3+1.21CF3+1.07CH3+0.51F+0.13H07)Fluorinehasausefulshort-livedisotope:18Fhalf-lifeof110minutesdecaysbypositronemissionPositronemissiontomography(PET)Introductionof18F-substitutedmaterialsintolivingtissueisanessentialpartofPETOHOHF18CO2HNH218F-labeledfluorodopa,thechemistryandmetabolismofbrain全氟(多氟)烷基卤化物(溴化物和碘化物)的反应CH3CH2BrKICH3CH2IRCF2BrKI++1：亲卤进攻Nuc:+CF3Nuc+CF3CF3HHsolventII+CF2Br2R3PBr+CF2++CF2R3PR3PCF2BrBrCHF2BrCF2R3P+BrCF2CF2BrPhSBr+C