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ReviewChapter19 Thischapterhighlightssolutionstosyntheticproblemswithnewreactions ReductionofC=OtoCH2 Carbonylcompoundscanbeusedtobuild(viacarbonyl,aorbcabon)newcarbon-carbonbonds.Once theframeworkisbuilt,theC=Omaynolongerbeneeded. ThreereactionscanbeusedtoreplaceketoneoraldehydeC=Owith–CH2-.Thechoicedependsonthe toleranceofotherfunctionalgroupsinthemolecule. Wolff-Kishner H 2NNH 2 DMSO, KOH O Clemmensen Zn(Hg) or or aq. HCl O Raney Nickel 1) HS H H SH 2) H 2, Raney Ni TheWolff-Kishnerisunderstronglybasic/nucleophilicconditionsandwouldnottoleratealkylhalides, forexample.TheClemmensenisunderstronglyacidicconditionsandwouldnotworkwellwithalcohols inthemolecule.TheRaney-Nickelreduction,althoughunderneutralconditionswouldhydrogenate alkenesandalkynesaswell. TodrawanWolff-Kishner,ClemmensenorRaney-Nickelproduct: O Simplyerasethe=O! Practice: a. O O b. H 2NNH 2 H DMSO, KOH O Zn(Hg) aq. HCl O c. 1) HS SH O 2) H 2, Raney Ni Protectionofalcohols Alcoholsareacommonorganicfunctionalgroup.Theprevalenceofthisgroupisinnosmallpartdueto its myriad of reaction pathways. Alcohols are weak acids, weak bases, nucleophiles and electrophiles. Sometimesitisnecessarytocoveroverthisreactivitytoreactagroupelsewhereinthemolecule. Simplyconvertingthealcoholstothefarlessreactiveethersmayseemareasonablesolution,butto converttheetherbacktothealcoholrequiresstronglyacidicconditions. Thetextreviewsfivemethodsfortheprotectionofalcoholsasethers.Inclasswehighlightedthetwo mostuseful.Ineachcasethealcoholisconvertedtoanether,butthenatureofthegroupallowsahighly effectiveandselectivereagentforremoval. ProtectionwithMOM-Cl Protection OH Reaction O 1) NaH or NaNH 2 2) O O Deprotection O O Cl + formaldehyde + methanol Protection Reaction OTBDMS TBDMS-Cl imidazole TBDMS = OH dil. H 3O+ ProtectionwithTBDMS-Cl OH H 2O Si Deprotection OTBDMS Bu 4N +F - OH + TBDMS-F Practice: a. ShowtheprotectionofthefollowingalcoholwithMOM,reacttheketonewithPhMgBr,anddeprotectandtoaffordfinalproduct: HO O b. ShowtheprotectionofthefollowingalcoholwithTBDMS-Cl,reactthenitrilewithLiAlH4,anddeprotecttoaffordthefinalproduct: HO C N CatalyticHydrogenation Theconversionofp-bondstos-bondsisahighlyusefulsyntheticprocedurewhereH2isaddedacrossthe p-bond.Althoughthisconversionisexothermic,acatalystisrequiredtodisruptthedi-hydrogenbond. Byincreasinghydrogenpressure,reactiontemperatureandthecatalysttype,virtuallyallp-systemscan bereduced. reduction with 200 atm., 250C H 2 Pt reduction with 160 atm., 135 C H 2 Pt reduction with 75 atm., 80C H 2 Ni reduction with 3 atm. H 2 Rh reduction with 1 atm. H 2 Pt reduces with H 2 Pd/Pt O or O O H C N NH 2 Undertheconditionsspecifiedallgroupswithintheboxwouldbereduced. Catalytichydrogenationisstereospecificandoccurssyn.Inthecaseofchaincompounds,thiswillnot matter.Inthecaseofsubstitutedcycloalkanes,stereochemistrymustberepresentedproperly. Alkynes under excess hydrogen and catalyst hydrogenate twice to give alkane. If a Lindlar catalyst is used,hydrogenationisstoppedattheadditionofoneequivalentofH2;acis-alkeneresults.Ifatransalkene is desired, a non-catalytic addition of hydrogen can be used where the alkyne is treated with Na0/NH3(l). Todrawtheproductofcatalytichydrogenation H O OH H O H H2 meso Lindlar OH H Na NH 3 O NH 2 NH 2 H H + enantiomer N NH 2 Foralkenes,alkynes,carbonyls Forcycloalkenes,addH2inasyn andnitrilessimplyerasepmannerinplaceofp-bond bondsandreplacewith hydrogens For alkynes with Lindlar, replace triple bond with cisdouble bond. With Na0/NH3 replacewithtrans-doublebond. Practice: a. H2 Pt/C b. H2 Pt/C c. O O 3 atm H 2 Rh d. CN e. 75 atm H 2 Ni, 80 oC O H 2N 160 atm H 2 Pt, 135 oC f. H2 Pt, 25 oC g. H2 Pt, 25 oC h. H2 Lindlar i. Na NH 3, -33 oC OxidationofAlcoholstoCarbonylCompounds Theoxidationofalcoholstocarbonylcompoundsisthereverseofnucleophilicaddition(below).Most oxidantsacceptthealcoholoxygenasanucleophilefollowedbylossoftheacidichydrogen.Theprocess iscompletedbyanE2-likeeliminationofhydrogenfromtheproto-carbonylcarboninconcertwith formationoftheC=Op-bondandreductivelossoftheleavinggroup. B General B H Mechanism H H H O H O Ox H Ox -H + O O Ox Ox ChromicAcid B O Cr O O H O H H O O Cr O H O H+ xfer H OH O Cr O O B H O OH Cr O O ScopeandLimitations 1. Asahydrogenatomisneededfortheeliminationstep,3oalcoholsdonotoxidizetocarbonyl compounds. 2. Normally1oalcoholsareconvertedtoaldehydesand2oalcoholstoketones. 3. However,inthepresenceofwater,aldehydesformhydratesthatundergomorerapidoxidation thanthestarting1oalcohols.ThuswithCrO3/H2SO4,Na2CrO7,K2CrO7,H2CrO4,1oalcoholsare convertedtocarboxylicacids. B R H O H 2O H R HO O H O Cr O O H R HO O O Cr O H O H+ xfer B H H R HO OH O Cr O O R O HO OH Cr O O 4. Thisover-oxidationisavoidedwiththeuseofPCC. 5. Aldehydes treated with with CrO3/H2SO4, Na2CrO7, K2CrO7, H2CrO4 are converted to carboxylic acids. Practice: a. OH CrO 3 H 2SO 4, H 2O b. Na 2Cr2O7 HO H 2SO 4, H 2O c. OH HO H 2CrO4 H 2O d. OH H 2CrO4 H 2O e. OH PCC CH2Cl2 f. OH H Na 2Cr2O7 H 2SO 4, H 2O O g. OH H O PCC CH2Cl2 KEY: ReductionofC=OtoCH2 a. O O H 2NNH 2 H b. O DMSO, KOH O Zn(Hg) aq. HCl O c. 1) HS SH O 2) H 2, Raney Ni Protectionofalcohols a. HO O 1) NaH or NaNH 2 2) O Cl MOMO O 1) PhMgBr 2) H 3O+ MOMO OH H 2O Ph dil. H 3O+ HO OH Ph b. HO C N TBDMS-Cl imidazole TBDMSO NH 2 1) LiAlH 4 C N 2) H 3O+ Bu 4N +F - TBDMSO HO NH 2 CatalyticHydrogenation a. H2 Pt/C b. H2 Pt/C c. O O OH 3 atm H 2 Rh O d. CN e. 75 atm H 2 Ni, 80 oC NH 2 O H 2N O H 2N 160 atm H 2 Pt, 135 oC f. H H H2 Pt, 25 oC g. H H2 Pt, 25 oC H h. H2 Lindlar i. Na NH 3, -33 oC OxidationofAlcoholstoCarbonylCompounds a. OH O CrO 3 H 2SO 4, H 2O b. HO Na 2Cr2O7 HO H 2SO 4, H 2O O c. OH HO O H 2CrO4 H 2O HO d. OH O H 2CrO4 H 2O OH e. OH O PCC CH2Cl2 H f. OH H Na 2Cr2O7 H 2SO 4, H 2O O O HO O g. OH H O PCC CH2Cl2 O H O