第九章第四军医大学药学ppt课件.ppt

Areactionbetweentwoaromaticaldehydescatalyzedbycyanideaniontogivebenzoins hydroxyketones 5 BenzoinCondensation Mechanism Theuniquelysuccessfulroleofcyanideionincatalyzingbenzoinreactionisduetoitsfourqualities i highnucleophilicactivity ii facilitatingtheprotontransfer iii abilitytostabilizenegativechargeinactivealdehydeintermediate iv abilitytodepartfinally Naturehasbeenperformingthistaskefficientlyinacompletelyanalogousmannerusing vitaminB1 thiaminepyrophosphate TPP acoenzymepresentinourbody andotherlivingorganisms BiologicalBenzoinCondensation AdditionofCarbonNucleophilesintheSynthesisofDrugs 3 1 2 AdditionofOxygenNucleophiles 1 AdditionofWater Hydration Aldehydesandketonesreactwithwatertoyield1 1 diols geminaldiols orcarbonylhydrates Hyrdationisreversible Cl3CCHOK 104HCHOK 103CH3CCHOK 1CH3COCH3K 10 2 MechanismofBase CatalyzedHydration MechanismofAcid CatalyzedHydration a Rankinorderofincreasingfavorabilityofhydration Cl3CCHO Cl3CCOCH3 Cl3CCOCCl3 b TreatmentofacetonewithH218Oresultsintheformationoflabeledacetone CH3CO18CH3 Explain 2 AdditionofAlcohol AlcoholsareweaknucleophilesbutacidpromotesadditionHemiacetalsareveryunstableThepositionofequilibriumisfavorableforacetalformationfrommostaldehydesFormostketones thepositionofequilibriumisunfavorable Analdehyde orketone inthepresenceofexcessalcoholandanacidcatalystwillformanacetal FormationoftheacetalproceedsviathecorrespondinghemiacetalAnacetalhastwoalkoxylgroupsbondedtothesamecarbon AcetalsarestablewhenisolatedandpurifiedAcetalformationisreversible Anexcessofwaterinthepresenceofanacidcatalystwillhydrolyzeanacetaltothecorrespondingaldehyde orketone MechanismofAcetalFormation CyclicAcetals AcetalformationfromketonesandsimplealcoholsislessfavorablethanformationfromaldehydesFormationofcyclic5 and6 memberedringacetalsfromketonesismoreeasytoform Dean Starktrap Acetalstoleratebases oxidizingandreducingagents andorganometallicreagents ect butaresensitivetoacidsAnexcessofwaterinthepresenceofanacidcatalystwillhydrolyzeanacetaltothecorrespondingaldehyde orketone UsesofAcetals asProtectiongroups ProtectionofHydroxyGroup CyclichemiacetalsareformedbyintramolecularcyclizationofhydroxyaldehydesCyclicHemiacetalscontainingfive andsix memberedringsarestablecompounds CyclicHemiacetals 6 94 3 1 3 AdditionofSulfurNucleophiles 1 AdditionofSodiumBisulfite Sodiumbisulfiteaddstoaldehydesandunhinderedketones aliphaticmethylketonesand 8 membercyclicketones toformbisulfiteadditionproducts Mechanism Bisulfiteadditionproductsareunstableunderacidicandbasicconditions Uses 1 Identification 2 IsolationandPurification 3 FormationofCyanohydrins 2 AdditionofThiol Inacidicconditions analdehydeorketonewillreactwithtwoequivalentsofathioltoformathioacetal Insteadofaprotoncatalyst aLewisacid suchasBF3orZnCl2 isoftenusedinethersolvent Thioacetalsarestableinaqueousacid amediumthathydrolyzesordinaryacetalsHydrolysisofthioacetalsiscarriedoutbyusingmercuricchlorideinaqueousacetonitrile ThioacetalsaredesulfurizedtothecorrespondinghydrocarbonbytreatmentwithRaneynickel Alkylationof1 3 Dithiane 3 1 4 AdditionofNitrogenNucleophiles 1 AdditionofPrimaryAmines Aldehydesandketonesreactwithprimaryaminestoformimines Hugo Ugo Schiff 1834 1915 wasaGermanChemist HediscoveredSchiffbasesandotherimines Schiffbase HugoSchiff FormationofImines Mechanism ThesereactionsoccurfastestatpH4 5 Why Imineformationoccursinmanybiochemicalreactionsbecauseenzymesoftenusean NH2grouptoreactwithanaldehydeorketone Transamination Thechemistryofvision Thevisualcycle 2 AdditionofHydroxylamine HydrazineandSemicarbazide ReactionwithHydroxylamine ReactionwithHydrazine ReactionwithSemicarbazide TheequilibriumconstantsforthesereactionsareusuallymorefavorablethanforreactionswithsimpleaminesThesederivativesareusefulbothasstartingmaterialsforfurtherreactionsandforcharacterizationandidentificationoftheoriginalcarbonylcompoundsOximes semicarbazones andphenylhydrazonesareoftensolidcompoundswithcharacteristicmeltingpoints CondensationsofAmineswithKetonesandAldehydes 3 AdditionofSecondaryAmines Aldehydesandketonesreactwithsecondaryaminestoformenamines EnaminesarestableThesecondaryaminesmostcommonlyusedtoprepareenaminesarecyclicaminessuchaspyrrolidine piperidine andmorpholine Mechanism EnamineformationiscatalyzedbythepresenceofatraceofanacidTheremovalofwaterdrivesthereversiblereactiontocompletion Dean StarkTrap StorkEnamineReactions Enaminesaregoodnucleophiles andcanbeacylated alkylated andusedinMichaeladditions GilbertStork bornDecember31 1921 isaU S organicchemist HeistheEugeneHigginsProfessorofChemistryatColumbiaUniversity TheStorkenaminesynthesisisnamedinhishonor GilbertStork A Acylation B Alkylation 3 2 Reactionsatthe CarbonofCarbonylCompounds Carbon thecarbonnexttocarbonylgroup Hydrogen thehydrogenatomsonthe carbon 3 2 1 Acidityof Hydrogens SimplealdehydesandketoneshavepKa sintherange16 20 whichmakesanC HsimilarinaciditytotheO Hgroupofwaterandmostalcohols Anhydrogenofanesterislessacidicthananhydrogenofanaldehydeorketone AC Hgroupthatistotwocarbonylgroupsismoreacidicthanonethatistoonlyonecarbonyl EnolateAnionandEnol Twofactorsmake hydrogenacidic Electron withdrawinginductiveeffect increasesthepositivecharacterofthehydrogenElectrondelocalization stabilizestheconjugatebase ThecarbonylgroupisstronglyelectronwithdrawingWhenacarbonylcompoundlosesanaproton theanionthatisproduced calledanenolate isstabilizedbydelocalization Theresonance stabilizedenolatecanacceptaprotonineitheroftwoways BothofthesereactionsarereversibleTheketoandenolformsofcarbonylcompoundsareconstitutionalisomers Keto EnolTautomerism Interconvertibleketoandenolformsarecalledtautomers andtheirinterconversioniscalledtautomerization Mostaldehydesandketonesexistprimarilyintheketoform Dicarbonylcompoundsexistprimarilyintheenolform Thegreaterstabilityoftheenolformof dicarbonylcompoundscanbeattributedtoresonancestabilizationoftheconjugateddoublebondsand inacyclicform throughhydrogenbonding MechanismofBase CatalyzedEnolization MechanismofAcid CatalyzedEnolization Keto EnolTautomerism Carbonylcompoundswithhydrogensbondedtotheir carbonsequilibratewiththeircorrespondingenols Thisrapidequilibrationiscalledtautomerism andtheindividualisomersaretautomers Unlikeresonanceforms tautomersareisomers Despitethefactthatverylittleoftheenolisomerispresentatroomtemperature enolsareveryimportantbecausetheyarereactive ThepKa sofmostsimplealdehydesandketonesareabout16 20Boththecarbonylcompoundanditsenolatearepresentwhenanacid baseequilibriumisestablishedwithhydroxideion FormationandStabilityofEnolate Aldehydesandketonescanbeconvertedcompletelytotheirenolatesbyusingverystrongbasessuchaslithiumdiisopropylamide CH3 2CH 2NLi LDA KineticControl Alesscrowdedprotonisremovedfasterthanamorecrowdedonetoformlessstableenolate kineticenolate ThermodynamicControl Amorecrowdedprotonisremovedtoformmorestableenolatewiththemoresubstituteddoublebond thermodynamicenolate EnolateRegiochemistry Thekineticenolateisfavoredby Astrongnonnucleophilicbase LDAisastrong stericallyhinderedbasePolaraproticsolvent THFisbothpolarandaproticLowtemperature 78 Thethermodynamicenolateisfavoredby Astrongbase Na OCH2CH3 K OC CH3 3 orotheralkoxidesarecommonProticsolvent CH3CH2OHorotheralcohols Roomtemperature 25 Enolatesisanambidentnucleophile ReactionsofEnolsandEnolates Enols Enolates 3 2 2 TheAldolCondensation Inthepresenceofacidorbase twoaldehydes orketones reacteachothertoforma hydroxyaldehyde or hydroxyketone aldolfromaldehydeandalcohol AldoladditionorAldolreaction Underacidicconditions thereactiongenerallyleadsdirectlytothedehydrationproduct MechanismofBase CatalyzedAldolCondensation hydroxyaldehyde unsaturatedaldehyde Theproductsofaldoladditionundergodehydrationonheating toyield unsaturatedaldehydes MechanismofAcid CatalyzedAldolCondensation Thisreactiongenerallyleadsdirectlytothedehydrationproduct unsaturatedaldehyde SyntheticApplications CrossedAldolReactions Crossedaldolreactions aldolreactionsinvolvingtwodifferentaldehydes areoflittleusewhentheyleadtoamixtureofproducts PracticalCrossedAldolReactions Crossedaldolreactionsgiveonepredictableproductwhenoneofthereactionpartnershasno hydrogen CyclizationviaAldolCondensation Intramolecularreactionofdicarbonylcompoundsproceedstoformfive andsix memberedringspreferentially WhyMeatfromYoungerAnimalsIsSofter Oneofthemostabundantproteinsfoundinmammalsiscalledcollagen Individualmoleculesofcollagencanbeisolatedfromyounganimals butnotfromolderanimals becausewithage collagenmoleculescross linkwitheachotherviaanaldolcondensationreaction First aminogroupslocatedonsidechainsofcollagenareconvertedtoaldehydegroupsviaaprocesscalledoxidativedeamination Then theresultingaldehydegroupscanundergoanaldolcondensation Thisprocessresultsinthecross linkingoftwocollagenmolecules Asananimalages thenumberofcross linkedproteinsincreasesattheexpenseoftheindividualcollagenmolecules ABiologicalAldolCondensation 3 2 3 Halogenationatthe Carbon Carbonylcompoundsbearinganahydrogencanbehalogenatedattheacarboninthepresenceofacidorbase Acid catalyzedhalogenation Acid catalyzedhalogenationproceedsviatheenolAcidgeneratedbythereactioncatalyzesfurtherreaction autocatalytic Acid catalyzedhalogenationcanhalogenateonlyoneortwo H sHalogenationslowsdownenolization Base PromotedHalogenation Base promotedhalogenationoccursviaanenolateBaseisconsumedThe haloketoneproducedismorereactivethanketoneEnolateionstabilizedbye withdrawinghalogen MultipleHalogenation 3 2 4 HaloformReaction Amethylketoneistreatedwithexcessbaseandexcesshalogentoaffordacarboxylicacidafteracidicworkup Mechanism UsesofHaloformReaction 1 Convertingmethylketonestocarboxylicacids Chlorineandbrominearemostcommonlyusedasthehalogencomponentforthepurpose 2 Theiodoformclassificationtest Theiodoformreactionisusedintheclassificationtestformethylketonesandmethylsecondaryalcohols ChloroforminTapWater Whenwaterischlorinatedtopurifyitforpublicconsumption chloroformisproducedfromorganicimpuritiesinthewaterviathehaloformreaction Manyoftheseorganicimpuritiesarenaturallyoccurring suchashumicsubstances Thepresenceofchloroforminpublicwaterisofconcernforwatertreatmentplantsandenvironmentalofficers becausechloroformiscarcinogenic Thus thetechnologythatsolvesoneproblemcreatesanother Itisworthrecalling however thatbeforechlorinationofwaterwasintroduced thousandsofpeoplediedinepidemicsofdiseasessuchascholeraanddysentery 3 2 5 MannichReaction Condensationofaprimaryorsecondaryam