生物化学chapter22amines 课件

Chapter22Amines Aminesareorganicderivativesofammoniainthesamewaythatalcoholsandethersareorganicderivativesofwater Theimportantorganicreactionsofamines nucleophiles arewiththecommonelectrophiles alkylhalidesvianucleophilicsubstitution aldehydesorketonesvianucleophilicadditioncarboxylicacidderivatives especiallyacidchloridesoranhydridesvianucleophilicacylsubstitution 22 1Nomenclature Functionalgroupsuffix amineFunctionalgroupprefix aminoThesuffix amineisaddedtothenameofthealkylsubstituent Alternatively thesuffix aminecanbeusedinplaceofthefinal einthenameoftheparentcompound Chenli Chenli PrimaryaminesarenamedintheIUPACsysteminseveralwaysdependingontheirstructure Forsimpleamines thesuffix amineisaddedtothenameofthealkylsubstituent Alternatively thesuffix aminecanbeusedinplaceofthefinal einthenameoftheparentcompound Insecondaryandtertiaryamines thealkylgroupsmaybethesameordifferent Compoundswithfourgroupsattachedtonitrogenarealsoknown butthenitrogenatommustcarryapositivecharge Suchcompoundsarecalledquaternaryammoniumsalts An NH2group whennottheprincipalgroup isnamedbytheprefixamino Symmetricalsecondaryandtertiaryaminesarenamedbyaddingtheprefixdi ortri tothealkylgroup UnsymmetricallysubstitutedsecondaryandtertiaryaminesarenamedasN substitutedprimaryamines Thelargestalkylgroupischosenastheparentname andtheotheralkylgroupareconsideredN substituentsontheparent Nsincethey reattachedtonitrogen 22 2StructureandBonding TheaminefunctionalgroupconsistsofanNatombondedeithertoCorHatomsviasbonds BoththeC NandtheN HbondsarepolarduetotheelectronegativityoftheNatom Thetrigonal 三角形的 pyramidal 金字塔形的 锥体的 arrangementofbondsaroundnitrogenisshallowerinarylaminesvsalkylamines Chenli StructureandBondinginAmine Thebondinginaminesissimilartothebondinginammonia Thenitrogenatomissp3hybridized withthethreesubstituentsoccupyingthreecornersofatetrahedronandthenitrogennonbondinglonepairofelectronsoccupyingtheforthcorner Chenli Chenli CH3NH2Themoreredanareais thehighertheelectrondensityandthemoreblueanareais thelowertheelectrondensity Aminescanreactaseitherbasesornucleophilesatthenitrogen Thereislowelectrondensity blue onHatomofthe NHgroup Removaloftheprotongeneratestheamideion care nottobeconfusedwiththecarboxylicacidderivativeRCONH2 The NHgroupisaverypoorleavinggroupandneedstobeconvertedtoabetterleavinggroupbeforesubstitutioncanoccur Chenli Chenli 陈立 CH3NH3 Themoreredanareais thehighertheelectrondensityandthemoreblueanareais thelowertheelectrondensity TheammoniumNatomisaregionoflowelectrondensity blue duetothepositivecharge Ammoniumionsarenotnucleophilic Thereislowelectrondensity blue onHatomofthe NH3group Removaloftheprotonregeneratestheamine The NH3groupisapotentialleavinggroup Thisisaresultofresonancedelocalisationofthelonepairintothearomaticpsystem suchdelocalisationisalsoresponsibleforthedecreasedbasicityofarylvsalkylamines Chenli Chenli alkylammoniumpKa 10 arylammoniumpKa 5 22 3PhysicalpropertiesofAmines ThepolarnatureoftheN Hbond duetotheelectronegativitydifferenceofthetwoatoms resultsintheformationofhydrogenbondswithotheraminemolecules seebelow orotherH bondingsystems e g water Theimplicationsofthisare highmeltingandboilingpointscomparedtoanalogousalkaneshighsolubilityinaqueousmedia intermolecularH bondinginamines Aminesarehighlypolarandthereforehavehigherboilingpointsthanalkanesofequivalentmolecularweighthave Likealcohols amineswith C5aregenerallywater soluble Primaryandsecondaryaminesformstronghydrogenbondsandarehighlyassociatedintheliquidstate 22 4BasicityofAmines Becauseofthenitrogenlonepairofelectrons aminesarebothbasicandnucleophilic Aminesaremuchmorebasicthanalcohols ethers orwater R NH3 pKa 10 R OH2 pKa 3 Someaminesarestrongerandsomeareweakerinbasestrength NislesselectronegativethanOandthereforeNisabetterelectrondonor alkylandnon aromaticheterocyclicaminesareslightlystrongerbasesthanammoniaarylaminesaremuchweakerbasesthanammonia aresultofthedelocalisationofthelonepairintothepsystemofthering Chenli BasicityofSomeAmines 22 5PreparationofAmines Chenli Chenli ReductionreactionsRearrangementsNucleophilicsubstitutionreactions AminesviaReduction ReductionofnitrocompoundsReductionofnitrilesReductionofamidesReductionofimines enaminesReductiveaminationofaldehydes ketones AminesviaReduction ASummary AminesviaRearrangement Hofmannrearrangement degradation Curtiusrearrangement 22 5 1AlkylationofAmmoniaorAmines Reactiontype NucleophilicSubstitution MechanismofAmmoniaAlkylation Chenli Step1 TheNinammoniafunctionsasthenucleophileandattackstheelectrophilicCofthealkylhalidedisplacingthebromideandcreatingthenewC Nbond Step2 Anacid basereaction Thebase excessammonia deprotonatesthepositiveN ammonium centercreatingthealkylationproduct theprimaryamine Ammoniareactsasanucleophilewithalkylhalidestogiveprimaryaminesinasubstitutionreaction Yieldsareoftenpoorastheproduct aprimaryamine RNH2 isitselfanucleophileandcanreactwithmorealkylhalide Theresultaremixturescontainingprimaryamines secondaryamines tertiaryaminesandquaternaryammoniumsalts Thiscanbeavoidedifalargeexcessofammoniaisused Chenli Summary Thisisaschemeforconvertingalkylhalidestotheircorrespondingprimaryamines Ithastheadvantagethatitdoesnotcreatemorethanonealkylationbutthedisadvantagethatitcannotbeusedforformationofacylamines 22 5 2GabrielSynthesis AlkylationofPhthalimide苯邻二甲酰亚胺 Chenli Chenli MechanismoftheGabrielSynthesis Step1 Anacid basereaction DeprotonationoftheimideN Hprotonbythebase hydroxide ThisprotonismoreacidicthanasimpleamineduetotheresonancestabilisationbythetwoadjacentC Ogroups Thisgeneratesastrongnucleophile the veN Step2 TheNnucleophileattackstheelectrophilicCofthealkylhalidedisplacingthebromideandcreatingthenewC Nbond ThisproductcanbecomparedtoanN alkylamide Step3 Theimidecanbecleavedviaamechanismanalogoustothatofamides Hydrolysiscreatesthedicarboxylicacidandtherequiredamine Summary Theadvantageofthismethodisthatoveralkylationisavoided ReactionofphthalimidewithKOHremovestheN Hprotongivinganimideion agoodnucleophile Nucleophilicsubstitutionbytheimideiononthealkylhalidegeneratesanintermediate N alkylphthalimide 苯邻二甲酰亚胺 Hydrolysisorhydrazinolysis 肼解 liberatesaprimaryalkylamine Arylaminescannotbepreparedviathismethodsincearylhalidesdonotundergosimplenucleophilicsubstitution Chenli Chenli 22 5 3PreparingAminesfromAlcohols 22 5 4ReductionofNitriles AmidesandOximes 肟 22 5 5ReductionofNitriles Reactiontype Oxidation ReductionorNucleophilicAddition Chenli Chenli AminoAlcoholsviaReductionofCyanohydrins Thenitrile RC N isreducedtothe1oaminebyconversionoftheC NtoR CH2 NH2Reagents eitherlithiumaluminumhydride LiAlH4 ethersolventorcatalytichydrogenation e g H2 Pd Alkylnitrilesarepreparedbynucleophilicsubstitution SN2 bycyanideion CN ofprimaryorsecondaryalkylhalides Arylnitrilescanalsobereducedtoarylamines Summary 22 5 6ReductionofNitroCompounds Reactiontype Oxidation Reduction Nitroarenescanbereducedtoprimaryarylamines Typicalreducingagentsinclude Fe H Sn H orcatalytichydrogenation e g H2 Pd Nitroarenesarepreparedbythenitrationofaromatics Thisisprobablythemostimportantmethodforthesynthesisofanilines Ar NH2 and therefore accessingthechemistryofdiazoniumcompounds ReductionofNitroarenes Example Nitroarenescanbereducedtoprimaryarylamines Typicalreducingagentsinclude Fe H Sn H orcatalytichydrogenation e g H2 Pd Nitroarenesarepreparedbythenitrationofaromatics Thisisprobablythemostimportantmethodforthesynthesisofanilines Ar NH2 and therefore accessingthechemistryofdiazoniumcompounds Summary 22 5 7ReductionofAmides ReactionsusuallyinEt2OorTHFfollowedbyH3O work ups Reactiontype NucleophilicAcylSubstitutionthenNucleophilicAddition R R orR maybeeitheralkylorarylsubstituents ReactionOfLiAlH4WithAnAmide Step1 ThenucleophilicHfromthehydridereagentaddstotheelectrophilicCinthepolarcarbonylgroupoftheester ElectronsfromtheC OmovetotheelectronegativeOcreatinganintermediatemetalalkoxidecomplex Step2 ThetetrahedralintermediatecollapsesanddisplacestheOaspartofametalalkoxideleavinggroup thisproducesahighlyreactiveiminiumionanintermediate Step3 RapidreductionbythenucleophilicHfromthehydridereagentasitaddstotheelectrophilicCintheiminiumsystem pelectronsfromtheC NmovetothecationicNneutralisingthechargecreatingtheamineproduct SynthesisofAminesfromAmides 22 5 8ReductiveAminationofKetonesandAldehydes Reactiontype NucleophilicAdditionthenOxidation Reduction KeytoSuccessfulReductiveAmination ReductiveAmination AVersatileStrategy ReductiveAmination PrimarytoSecondaryAmines StepwiseReductiveAminationisPossible ReductiveAmination SecondarytoTertiaryAmines IminiumIonsandEnamines PossibleIntermediatesinReductiveAmination Summary Aldehydesandketonesreactwithammoniatogive1oamines 1oaminestogivesubstitutediminesand2oaminestogiveenamines 烯胺 TheseNspeciescanthenbereducedtoamines Themethodprovidesaccessto1o 2o or3oamines Typicalreagents mostcommonlycatalytichydrogenation e g H2 Pd R R andR maybeeitherhydrogen alkyl oraryl Chenli LeukartReaction Thisisausefulreactiontoconvertaketoneoraldehydeintoanamine References1 R Leuckart Ber 18 2341 1885 2 Moore ML OrganicReactionsvol V p301 1949 TheLeuckartreactionisakeystepinthesynthesisofamphetamines 苯丙胺 RecentexamplesoftheLeuckartReactionincludethefollowing Reference LoupyA MonteuxD PetitA MerienneC AizpuruaJM PalomoC JournalofChemicalResearch S 4 187 187A Comments TherateofthisreactioncanbeincreasedusingMicrowaves Italsoproducesseveralstereoisomers Eschweiler ClarkeReaction ThereactionsareusuallycarriedoutinanacidicbuffertoactivatetheC Oandfacilitatedehydrationbutwithoutinhibitingthenucleophile TheMechanism 22 5 9PreparationofAminesfromCarboxylicAcidsandTheirDerivatives HofmannRearrangementCurtiusRearrangementSchmidtRearrangement HofmannRearrangement Anunsubstituedamideistreatedwithsodiumhypobromate i e sodiumhydroxideandbromine togiveaprimaryaminethathasonecarbonfewerthanthestartingamide Chenli Chenli RecentExamplesZhang L h Kauffman G S Pesti J A Yin J J Org Chem 1997 62 6918 6920 CurtiusReaction Rearrangement Thestepwiseconversionofacarboxylicacidtoanaminehavingonefewercarbonunit viatheazideandisocyanate isreferredtoastheCurtiusreaction ItinvolvestheCurtiusrearrangement whichistheformationofisocyanatesbythermaldecompositionofacylazides Thisisaverygeneralreactionandcanbeappliedtoalmostanycarboxylicacid aliphatic aromatic alicyclic heterocyclic unsaturated andcontainingmanyfunctionalgroups Reference Journal Radwan ShabanM Bakhite EtifyA MOCMB7 Monatsh Chem EN 130 9 1999 1117 1128 22 6ReactionsofAmines Chenli Chenli AminesareBr nsteadBasesandNucleophiles ReactionsInvolvingAmines SeveralreactionsinvolvingaminesarealreadybeenpresentedBasicityReactionwithaldehydesandketonesReactionwithacylchlorides anhydrides andesters Theimportantorganicreactionsofamines nucleophiles arewiththecommonelectrophiles alkylhalidesvianucleophilicsubstitutionaldehydesorketonesvianucleophilicadditioncarboxylicacidderivatives especiallyacidchloridesoranhydrides vianucleophilicacylsubstitution Chenli 22 6 1Acylation Chenli Chenli Primaryandsecondary butnottertiary aminescanbeacylatedbyreactionwithacidchloridesoracidanhydridestoyieldamides Reactiontype NucleophilicAcylSubstitution Primaryamines R NH2andsecondaryamines R2 NHundergonucleophilicacylsubstitutionwithcarboxylicacidderivativestogiveamides Themostcommonexamplesarethereactionsofacidchloridesandanhydrides thoughestersdoreactwithamines Summary 22 6 2HinsbergReaction Ifasulfonylchloride RSO2Cl isusedastheacylatingagent asulfonamideisproduced HinsbergTest 22 6 3QuaternaryAmmoniumCompounds Quaternaryammoniumsalt Quaternaryammoniumhydroxide Phase TransferCatalysis AsubstancethattransfersionsfromanaqueousphasetoanorganicphaseAneffectivephase transfercatalystmusthavesufficienthydrophiliccharactertodissolveinwaterandformanionpairwiththeiontobetransportedhydrophobiccharactertodissolveintheorganicphaseandtransporttheionintoitThefollowingsaltisaneffectivephase transfercatalystsforthetransportofanions Phase TransferCatalysis Phase transfercatalyst 22 6 4HofmannElimination Reactiontype Elimination PrimaryReferencesHofmann A W Ann 1851 78 253 Hofmann A W Ann 1851 79 2203 Hofmann A W Ber 1881 14 659 Cope A C Trumbull E R Org React 1960 11 317 DePuy C H King R W Chem Rev 1960 60 431 1 QuaternaryammoniumsaltsundergoanE2eliminationwhenheatedwithsilveroxide Ag2O inwater 2 Aminescanreadilybeconvertedintoquaternaryammoniumiodidesbytreatingthemwithexcessmethyliodide 3 AgO H2Oreactsgivingthequaternaryammoniumhydroxide silveriodideprecipitates Whenheatedthehydroxideinducesabasepromoted1 2 orb eliminationgivinganamineandalkene TheregioselectivityisoppositetothatpredictedbyZaitsevsruleinthatitleadstothelesshighlysubstitutedalkene ThelesshighlysubstitutedalkenemaybereferredtoastheHofmannproduct Theoutcomeisdictatedbystericeffectsofthelargeleavinggroupandthealkylchain NH2 andNR2 areverypoorleavinggroups bothanionic butNR3ismuchbetter neutral Comparethiswithwith OHandH2Ointhedehydrationofalcohols 22 6 5SelectivityoftheHofmannElimination IngeneralE2reactionsoccurmostrapidlywhentheH CbondandC LGbondsat180owithrespecttoeachother Thisisdescribedasanantiperiplanar periplanar全平面的 conformation Thisconformationpositionsthesbondsthatarebeingbrokeninthecorrectalignmenttobecomethepbond Chenli Chenli Thestaggered 错列的 antiperiplanaralignmentispreferredbecauseitalignsthetwosbondsthatbecomethepbond HofmannElimination Whilequaternaryammoniumhalidesarerelativelystablesalts thecorrespondinghydroxidesundergoE2eliminationwhenheated Hydroxideionisabase bromideisnot HofmannElimination Quaternaryammoniumhydroxidesarerelativelyunstableandwhenpyrolyzed undergoeliminationtoformatertiaryamineandanalkene ThisprocessiscalledtheHofmannelimination PreparationofQuaternaryAmmoniumHydroxides arepreparedfromtrialkylammoniumhalidesthroughionexchangewithsilver I oxide PreparationofQuaternaryAmmoniumHydroxides HofmannElimination HofmannElimination Mechanism Hofmann srule eliminationoccursinthedirectionthatgivestheless substituteddoublebond HofmannElimination Regioselectivity Stericfactorsseemtocontroltheregioselectivity Thetransitionstatethatleadsto1 buteneislesscrowdedthantheoneleadingtocisortrans 2 butene HofmannElimination Regioselectivity ConformationalAnalysisofsec ButyltrimethylammoniumHydroxide E Lowestenergyconformer Highestenergyconformer HofmannElimination Regioselectivity Inthistransitionstate thelargetrimethylammoniumgroupisgauchetotwoC Hbonds HofmannElimination Regioselectivity ThistransitionstateishigherinenergybecausethetrimethylammoniumgroupisgauchetoaC CH3bond HofmannElimination Regioselectivity Thistransitionstateishigherinenergybecausethetrimethylammoniu