Selective fluorination of substituted trichloromethyl benzenes by HF in liquid phase：Preparation of fluorinated building blocks.docx

1、FISFVIF.RContentslistsavailableatScienceDirectJournalofFluorineChemistryjournalhomepage:PreparationoffluorinatedbuildingblocksAlexandrePiou,StephaneCelerier,SylvetteBrunet*lhoraioircdeCatalyseenChiinieOrganiquc.UMRCNRS6503,Universi(e,dePoitiers,FacukczdesSciencesFondainenialcsctApplique'es40.Ave

2、nueduRectcurPineau.86022Poitierscedex,FranceARTICLEINFOABSTRACTamountactivated(heCl/FexchangesandonlyastoichiometricamountofHFwasrequiredwhateverthechlorinatedmolecules.Keywords:Fluorinationl.cwisacidSelectivemonoandditluorinationcouldbeobtainedbyusingbasicsolvents.2010ElsevierB.V.Allrightsreserved.

3、/Xntinwnypen(achk>rideTrichlorotolueneChk>ru-trichk>ru<olucneHF-bascArticlehistory:Received26April2010Receivedinrevisedform14June2010Accepted15June2010Availableonline23June2010TheselectivefluorinationbysuccessiveCl/Fexchangesof3.a.a-lrichlorotolucne.substitutedornotbyachlorineatom,wasstu

4、diedinthepresenceofHFasthefluorinalingagent.Theintlucnccofthepresenceofacatalystorabasicsolvent(suchasdioxane,pyridine,tributylphosphate)inordertocontrolthefluorinationwasalsoinvestigated.Inmildconditions(508Candafter1hofreaction),HFinexcesswasrequiredinordertoobtainedthetrifluoromethylationbyCl/Fex

5、changes.ThepresenceofSbCIsinsmall1242A.Piouetal./JournalofFluorineChemistry131(2010)1241-1246I. IntroductionTheincorporationoffluorine,especiallythe-CFjgroup,intoorganiccompoundresultsinchangesinthephysical,chemicalandbiologicalproperties11-3).Thesechangesmakethemsuitablefordiverseapplicationsinthea

6、reasofmaterialscience,agrochcmistrj'andpharmaceuticals|4-6.Whileawidevarietyofmethodshavebeendevelopedforintroducingtrilluoromcthylgroupsintoorganicmolecules111,thefluorinechlorineexchangeisthemostwidelyusedtechnologyinindustrialscaleespeciallyfor(heselectivesynthesisoffluorinatedbuildingblocks.

7、Thisreactioncanbecarriedoutusingtwodifferentsourcesoffluorine:alkalimetalfluorides,suchaspotassiumfluoride(KF)112|,oranhydroushydrogenfluoride(HF).AlthoughKFismoresafeandcheapiouse,someorganiccompoundsneedmorevigorousconditions(obefluorinatedandinthiscaseHFisrequired.Thereactionbetweenhydrolluoricac

8、idandanorganichalidecanbecarriedouteitherinvapourphaseorinliquidphase.Moreoverinbothcases,theuseofLewisacidascatalystcanimprove(hereaction.Themostcommonlyusedinliquidphasefluorinationreactionsareantimonypeniachloridc(SbCI5)orantimonymixedhalides13.Evenifantimonychloridessufferfromthefactthattheyarcv

9、erycorrosiveandtheycanbereducedfromShvtoSb"TCfl79796633I29995384133100990198141008904964CTCr18768702922100852861210087171281008222962CTCT')71667424221001003%I310084I41584100822296TCMIT310093098,toleadloadeactivationofthecatalyticsystem(Sb111halidesarcinert)14.antimonychloridesareverypowerfu

10、lcatalystsforfluorinationreactions.Thatiswhytheyareusedinindustrialscalereactions15!7|.Thecatalyticprocessesofferalotofadvantagesfromclassicalchemistry.Indeed,thecatalyticfluorinationwithHFasthefluorinatingagentandacatalystsuchasSbCUforthefluorinationofchlorinatedmoleculessuchaschlorinatedhydrocarbo

11、n(toproducehydrofluorocarbon)andchlorinatedaromatics(toproducebuildingblocks)whichinvolvedonlyCl/FexchangesleadtohighdegreeoffluorinatedmoleculesandonlyloHCIastheby-product.Onlyafewexamplesofcatalyticfluorinationreactionshavebeenreportedinlheacademicliterature.Previousworks117|havebeencarriedoutonth

12、efluorinationoftrichloromcthoxy-bcnzcncbyliquidHFwithvariousLewisacidsascatalysts.OnlyLewisacidswithanoxidationstateof+VareeificieniandSbCljis(hemostpowerful.TheefficiencyoftheseLewisacidsisduetothereabilitiestoformnucleophiliccomplexesinthepresenceofHF.Indeed,thepresenceoffewamountofthecatalystfavo

13、uredlheIasiCl/Fexchangetoproducefluoroniethoxy-benzeneonlyinstoichiometricamountofHFandatatemperatureof508C.Moreover,fewworksintheliteraturereportedselectivefluorinationinthepresenceofasolvent(18-22.HF-pyridinciswellknowntobeagoodfluorinatingagent.Thispaperdealswiththeoperatingconditionsforthefluori

14、nationofchlorinatedcompoundsandmoreparticularlyof*Correspondingauthor.TO.：+33549453627;fax:33549453897.E-mailaddivss:sylvette.hrune(univ-poitiers.fr(S.Brunet).irichloromcthyibenzenesubstiluicdornotbyachlorineatom.Indeedthepresenceofchlorineatomwhichisanattractiveatom-1139/$-seefrontmatter2010Elsevie

15、rB.V.Allrightsreserved.doi:10.101,jfluchern.2010.06.013TabicIEffecloflheamounlofHFinthe(ransfontialionofvariimstrkhloromelhylbenzenes<P|=lObar,(inie=Ih.T=508C.subslrute=0.2mol).SubstrateHE'suhstratcinolarratioConversionYield(mol%)hSelectivity*(%)R-CChFR-CCIF：RCFs,Amountofsubstratetransformed.

16、bMolaramountofHuorinatcdproducts(by-producisexcepted).*Amountofnu>no.diandlritliK»rinaiedcompounds.da.a.a-Trichlorotolucnc.R=Ph.'4-Chloro-a.a.a-trichloro(olucnc.R=p-Cl-Ph.r2-Chlon>-a.a.a-trichlorx>toluenc.R-o-CI-Ph.fTrichloromcthoxy-bcnzcnc.(inpositionorthoorpara)inthearomaticringc

17、ouldmodifylhereactivityoflhe-CChgroup.Consequently,theinfluenceoflhesubstitutiononlhearomaticring,theamountofHFusedasfluorinesourceandSbCLusedasthecatalyston(hereactionhasbeenstudied.Selectivefluorinations(monoanddi)werealsostudiedbyusingvariousHF-basesystemswithdioxane,iributylphosphateorpyridineas

18、base.2. ResultsanddiscussionFluorinationoftrichloromcthylbenzenesThefluorinationofdifferentchlorinatedmolecules(a.a.atrichlorotoluene.TCT;4-chloro-a.a.a-trichlorotohicnc.4CTCT;2chloro-a.a.a-lrichlorotolucnc.2CTCT)wascarriedoutfor1hat508Cwithdifferentamounts(from1to4equiv.fromchlorineatoms)ofHF(Table

19、I).Theconversioncorrespondstotheamountofthesubstratewhichistransformedintofluorinatedproductsandtheyieldtothesumofmolarpercentagesofmono,diandtrifluorinatedpnxiucts.Inallreactions,yieldsweregood.WhenIequiv.ofHFwasaddedtothereactionmedium,theconversionofchlorinatedsubstrateswasnottotalandonlytracesof

20、trifluorinatedproductswereobtained.Whateverthetrichlorinatedcompounds,themonofluorinaiedcompoundwasthemajorproduct(66-74%)butthedifluorinatedcompoundwasalsopresent(2433%).WhiletheamountofHFincreasedto2equiv.,theamountofdifluorinationreactionprcxluctincreasedfrom84%to96%andconversionsbecamecomplete.T

21、heproductoftrifluorinationwasisolated(froml%to13%).Thedifferentmoleculestestedhadsimilarreactivitieswith1or2equiv.ofHF.Thepresenceoflhechlorineatomin2or4positiononthearomaticringortheinonofluorinationofthe-CChgroupdidnotchangethereactivityofthesubstrateTable2Efl'ecJof«heamountofHFintheirans

22、formaiionofvarioustrichloromethylbenzenesinthepresenceofSbCh(R=10bar,time=Ih,T=54)8C,$ubs<raie=0.2inol.SbCk=0.004mol:2mol%).SubstrateHF/subsiraiemolarratioConversion,(md%尸Yield<mol%)hSeleciivily*(%)R-CChFR-CCIF：R-CFiTCT1I5440238108287此74773053921004CTCT1602459127983633889310084001002CTCTf15841

23、10127828163488831009200100TCMB«31008600100fbrthelasttwoCl/Fexchanges.ThesesexperimentsconfirmedthatthetwofirstCl/Fexchangeswereveryfast.With3equiv.ofhydrogenfluoride(correspondingtothestoichiometricamountforthetotalCl/Fexchangesforthe-CCI?group),thetrichlorotoluene(TCT)appearedtobethemostreacti

24、veand81%ofirifluorotoluene(TFT)wasisolated.However,forthe2chloro-trichlorotoluene(2CTCT),58%oftrifluorinationproductwasobtainedandonly28%oftheparacompound(4CTCT).Onlysmallamountoftrifluoromethoxy-benzene(2%)wasisolatedfromtrichloromethoxy-benzene(TCMB)underthesesconditions.When4equiv.ofHFwereadded,t

25、hetrifluorinationwasalmosttotalinallcases.TheresultsshowedthatthefirsttwoCl/Fexchangeswereratherfastandthatthelastonewastheslowest.Thisisinaccordancewithoiherstudiesonthefluorinationofaliphaticchlorinatedconipounds23.Infact,thepresenceoftwofluorineatomsoncarbonatommakestheruptureofthelastCClbondmore

26、difficultduetothehighelectronegativityofthefluorineatom.Thetrichloromethoxy-benzene(TCMB)islessreactivethantheotherchlorinatedcompounds.Indeed,thepresenceofthemethoxygroupandmainlythepresenceoftheoxygenmodifiedtheelectronegativityandconsequentlytheCClbondrupture.Inthiscase,thelastCl/Fexchangewasinhi

27、bitedwith3equiv.ofHF(TableI).Thepresenceofchlorineatomonbenzeneringmodifiedthereactivityofthe-CIbondofthe-CCIigroupanddisfavouredalsothethirdCl/Fexchange.Indeed,thepresenceofthechlorineatomonbenzeneringmodifiedtheselectivitytowardsthetrilluoromclhylalionofthe-CCI?group.Morcvovcr.the2chloro-a.a.a-tri

28、chlorotolucncwasmorercaclivcthanthe4chloro-a,a,a-lrichlorololuene.Theseresultsshowthattheparapositionismoredeactivatedthanorthoposition.Theseobservationsareinaccordancewiththeotherworkperformingonacidityofaromaticcompounds24,25.Ithasbeenshownthataciditiesofchlorobenzoicacidandchlorophenolaremoresign

29、ificantwhenthechlorineatomisinparapositionthaninorthoposition.Thereforetheelectronwithdrawingpowerofchlorineisincreasedfortheparaposition.and3equiv.ledtoanincreasetotheconversionwhateverthesubstratewithselectivitytowardsthetrifluoromethylationproductof100%.Nosignificantselectivitywasobsenedbytheincr

30、easeoftheamountofHF.Forallmoleculesstudied,thecatalystenabled(heselectiveformationoftrifluoroniethylatedcompoundevenifasubstoichiomeiricamountofHFwasused.Withonly2%ofSbCkandastoichiometricamountofHEa.a.a-trichlorotolueneandtrichloromethoxy-benzenehadthesamereactivity.Theconversionwascompleteforbothm

31、olecules.Trifluorotolueneandtrifluoromethoxy-benzenewereisolatedwithgoodselectivity(100%).Moreover,thepresenceofthecatalystinhibitedeffectsofsubstitution.Whateverthesubstituentpositiononthearomaticring,allmoleculestestedshowedthesamereactivitytothetrifluorinationreaction.Thetrifluoromethylatedproduc

32、twasalwaysthemajorproduct.WithSbCls,astoichiometricamountofHFwasenoughtoobtainaselectivityof100%oftrifluorinatedproductswithgoodtoexcellentyields(7792%).Foreachsubstrate,nosecondaryproductcorrespondingtotheFriedelCraftproductswasobserved.Moreover,therewasnoproductofsubstitutionofthechlorineatomonaro

33、maticringbyafluorineatom.Onlychlorineatomsonthemethylgroupwereexchangedbyfluorineatom,evenifSbCUwasused.TheseresultsconfirmthatSbChiseffectivetoactivatethelastCl/Fexchange.Thisisinaccordancewithotherworksperformedontluorinationoftrichloromethoxy-benzene(19orothersubstratesf28-32).Theactivityofantimo

34、nypentachlorideisrelatedtoitsabilitytoformmixedhalidesandtoitsstrongLewisacidity.InthepresenceofHF,SbCI,canformspeciessuchasSbCkExwhichcouldgiveprotonsandveryreactivenucleophilicspecies(Scheme1).ASN>concertedmechanismcanbeproposedIF$GDT)l_ehcS(mtoexplainthelastCl/Fexchangeasreportedforfluorinatio

35、nofaliphaticchlorinatedmolecules26-30.2.3.FluorinationbyHF-basesystem2.1. EffectofthepresenceofSbChTheeffectofthepresenceofantimonypeniachloridcascatalyst(2mol%)wasstudiedinthesamecondilions(Table2).Whatever(hechlorinatedcompounds,thereactionof(rifluorinationwasalmostcomplete.Allyieldsweregoods(77-9

36、2%)withthreeequivalents.WithIequiv.ofHF.lheconversionwasnottotalinallcases(54-60%).Theproductobtainedwastheproductoftrifluoronicthylation(78-82%).Smallamountofmonoordifluorinalcdproductwerealsoisolated.TheincreaseoftheamountofHFto2*Amountofsubstrale(ransfonned.*Molaranx>un(offluorinaiedproducts(b

37、y-productscxccptcd).cAmountofmono,diandtrifluorinatedcompounds.da.a.a-Trichloro<olucnc.R=Ph.c4-Chloro-a.a.a-(richlurotoluene.R=p-Cl-Ph.'2-Chlon>-a,a.a-trichlorotoluene.R=o-Cl-Ph.'Trkhloromethoxy-benzenc.R=Ph-O.Itcouldbepossibletoproduceselectively(hemonoordifluorinalcdcompoundsinlhepre

38、senceofHFandabasicsolventsuchasdioxane,tribuiylphosphate(TBP)orpyridine.Asreportedinlheliterature,pyridinewasmorebasicthandioxaneandtribuiylphosphate31.Thepresenceofabasicsolventinlhereaction,allowedtheselectivefluorinationoflhedifferentsubstratesandlheproductionwithgoodselectivityofthemonoordilluor

39、inatedproducts.Allreactionswerecarriedou(inlhesameconditionsasdescribedbefore(508C.Ih.P=10barofN2).Thechangeoflheconversion,theyieldinHuorinalcdproductsandthesclectivilytowardsmonoanddilluorinationarcrcspcclivclyreportedinTable3withtheintroductionofdioxane,inTable4withpyridine,andinTable5withtribuiy

40、lphosphate.Theiniroduclionofdioxaneallowsthecontroloflhefluorinationwhateverlhechlorinalcdstartingmaterials.WhatevertheamountofHFused,nomoreirifluorinaledproductswereproduced.WithaHF/dioxaneratioof3.5,theconversionofa.a.a-trichlorotoluenewasaround57%andthenionolluorinatcdproductswasisolatedwithasele

41、ctivityof94%,For(he4-chloro-a.a.a-(richlorotolucncandthe4-chloro-a.a,a-trichlorotoluene.theinonotluorinatedproductcouldbeisolatedwithaselectivityof82%and94%withrespectivelyanHF/dioxaneratioof4or6(Table3).IncreasingtheHF/dioxancratioto5forthea.a.a-trichlorotokiencand6forihc4-chloro-a.a.a-trichlorotol

42、uene,theconversionofthesubstrateincreasedrespectivelyto95%SbCI5.HF*SbClxF5.xand97%.Moreoverthedifluorinatedproductwasisolatedwithaselectivityof84%forihca.a.a-y已ASbCISMSbCIfjTable3EffectoftheaniounlofHF/dioxaneinihc(runsformationofvariouslrichlon>HK(h)lbenzenes(P,=lOtxtr.time=Ih.T=508C.substrate=0

43、.2mol).SubstrateHF/dioxHF/substratcConversion(mol%)aYield(mol%)11Selectivity(%)R-CCkFf%)RCCIF>(%)RB(%)TCTf-410089-4963.565751946-599587128444CTCT-41008222%47565082186119776187842CTCT'-41008222%6II6235946-Amountofsubstrateinmsfbrmed.hMolaramountoffluorinatedproducts(by-priMiuctsexcepted).Amoui

44、nofmono*diand(rifluorinatedcompounds,da.a.a-Trichloru(oluenc.R=Ph.c4-Giloro-a»a»aur>chloro(oluene.R=p.Cl-Ph.r2-Chlofo-a,a,a-irichloriMoluenc.R-o-Cl-Ph.Table4Effectof(heamountofHF/pyridineintheflm>rinationofvarioustrichlaromeihyllienzenesinthepresenceofSbCIsfP,lObar,time：Ih,T50SC,subs

45、trate0.2mol).SubstrateHI'VpyridincHF/subslratcConversion(mol%),1YieldSelectivity4(%)R-CChF(%)R-CC1F：(%)RB(%)TCT*-4KX)89-49651043338020-2CTCTf-41008222967141010100-7149783137894CTCr410082229671441358812Amountofsubstratetransformed.bMolararnounloffluorinatedproducts(by-pruducUcxcepled).cAmountofmo

46、no,diandtrifluorinatedcompounds.>ia.a.a-Trichlormolucnc,R=Ph.c4-Chloro-a.a.a-trichlorotolucnc.R=p-Cl-Ph.t2-Chloro-a,a-trichloro(oluene.R=o-Cl-Ph.Table5EffecloftheamountofHFlribulylphcsplutte(TBP)in(hetransfomuitiimofvariousirichlorunielhylbenzenes(Pi=lObar.(imc=Ih.T=508C.substrale=0.2mol).Substra

47、teHF.'TBPHF/subsiratcConversion(moi%fYield(mol%)hSelectivity%)R-CCI>F(%)RCCIF-(%)R-CF»(%)TCT'-310099-19815358519010-754752174924CTCP310087i712863.583747723-2CTCT*3100841415863.55141991,Amountofsubstratetransformed.bMolaramountoffluorinatedproducts(by-productsexcepted).1Atnounlofnumo.

48、diandtrifluorinaicdcompounds.da.a.a-Trichlorotolucnc.R=Ph.e4-Chloro-a.a.a-(richlorocoluene,R-p-Cl-Ph.'2-Chl<wo-a.a.a-irichlonxoluene,R=o-Cl-Ph.withouttributylphosphateandwith3equiv.ofHhwithrespectofthesubstrate,(heconversionwas100%and(hemajorproductwas(heirifluorinaiedcompound(81%ofseleciivii

49、y).Theintroductionof(ributylphospate(HF/tributylphosphate=5)ledtoadecreaseoftheconversionio58%andundertheseconditionsthemonofluorinatedproductwasformedwithaselectivityof90%.Theselectivityofthedifluorinatedproductincreasedto52%when(heratioHF/iribuiylphosphaieraisedto7.InthecaseofaA.Piouclal./Journalo

50、fFluorineChemisiry131(2010)124112461245Table6EflcctofthepresenceofSbC)5inthetransfomationofa.a.a-trichlorcxolucnc(TCT)(R=10bar.time=Ih.T=5O8C.subsiratc=0.2mol,SbCh=0.004mol:2mol%).SolventCatalystHF)TCT*Conversion,(mol%)1'Yield(mol%)cSclcctivityd(%)R-CChF(%)R-CCIF：(%)R-CF.)Dioxane(HF/diox=2)-3.55

51、510000SbCIs3.5443390100Pyridine(HF/py=4)823209910SbCI58341777176TBP,<HF7TBP=7)-492754752<1SbCh4977915823trichlorotolueneand78%forthe4-chloro-a,a,a-trichlorotoluene.For(he2-chloro-a.a.a-trichlorotoluene,nodifluorinatedproduclcouldbeisolatedwithgoodselectivityevenincreasingtheamountofHF.Aswithdi

52、oxane,thepresenceofpyridinesloweddownthereactionandnotrifluorinatedprcxiuctwasformedwhatevertheamountofHFintroduced(Tabic4).Forthea,a,a-trichlorotoluene,anincreaseoftheamountofHF,fromaHF/pyridincratiofrom5to7.ledtoanincreaseoftheconversionfrom43%to97%.TheselectivitydependsontheamountofHFused.WithHF/

53、pyridine=5.nionofluorinatcdwasformedwithaselectivityof80%.TheincreaseoftheHF/pyridincratioto7allowedtheformationofthedifluorinatcdproductwith78%ofselectivity.Inthecaseof(he4-chloro-a,a,a-trichloroioluene,theconversionwas41%withaHF/pyridincratioof7andonlythenionofluorinatcdproductcouldbeisolatedwitha

54、goodselectivity(88%).The"a.a.a-Trichlonxoluene.R=Pii.hAriK>umofsubsiraietransformed.、Molaramountoffluorinatedproducts(by-pr<xiuctsexcepted).11Amountofmono,diandtrinuorinatedcompounds.11Tributylphosphatc.2-chloro-a.a.a-trichlorotolucncwasthelessreactivesubstrateandinthesameconditionsasfort

55、he4-chloro-a.a.a-trichlorotolucnc.theconversionwasonly10%.Theintroductionofiributylphosphate(TBP)duringthereactionwaslessselectivethandioxaneorpyridine(Table5).Forthea.a.atrichlorotolucnc.substitutedmolecules(4-chloro-a.a,a-trichlorotolueneand2-chloro-a,a.a-trichlorotolucnc).theintroductionoftributy

56、lphosphatc(HF/tributylphosphatc=6)inthereactionmediumledtotheformationofthenionofluorinatcdproductswithaselectivityof77%for(he4-chloro-a,a,a-trichlorotolueneand99%fbrthe2-chloro-a,a,a-trichloroioluene.Theseresultsshowthattheintroductionofabasicsolventslowsdownthereactionofhalogenexchangewhichallowst

57、heselectiveformationofmonoordifluorinatcdproducts.Ontheotherhand,asreportedpreviously,thepresenceofachlorineatom,onthearomaticring,deactivatedtheCl/Fexchanges.AhigheramountofHFwasrequiredtoobtaingoodconversionsofsubstrates.Moreover,itiswellknownthatHFmoleculesformpolymersanddecreasethenucleophilicit

58、yinanhydrousconditions32.Thebasicsolventcouldcomplexapartofthispolymeranddecreasestheacidityofthemediumandthenucleophilicofthefluorideatomasreportedintheliteratureforpyridine20.Twosourcesofnucleophilicfluoridecouldbepresent,onefromfreeHFandtheotherfromthecomplexHF-base.Theformationofthemonoanddifluorinatedproductsdependsontheamountofthesetwo