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CondensationReactionII
BuildingBridgestoKnowledge
Photo by Michaelle CadetTheprotonsonthemethylgroupoftheacetateportionofethylacetateareweaklyacidic,pKaapproximately24.Therefore,astrongbasesuchassodiumethoxidecanabstractaprotonfromthemethylgroupoftheacetateportionofthemolecule,inamanneranalogoustothatdescribedinthefollowingschema.
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(1)
(2)
(3)
Theconjugateacid,ethanol,isstrongerthantheacid,ethylacetate.Theprotononthemethylgroupofethylacetateisslightlyacetic.Asindicatedabove,theresultingcarbanionisresonancestabilized.Theresonancestabilizedsodiumethylacetate
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makestheanionimportantinorganicsyntheses.Thesodiumenolateanioncanreactwithanothermoleculeofethylacetatetoformsodiumethylacetoacetate.Acidificationofsodiumethylacetoacetateformsethylacetoacetate.ThisreactionisreferredtoastheClaisenCondensation.Thereactionproceedsthroughthecarbanionandthentheenolateanion.Theenolateanionattacksthesp2hybridizedatomicorbitalofthecarbonatomofthecarbonylgroupformingansp3hybridizedatomicorbitalofthecarbonofthesodiumethyl3-ethoxy-3-hydroxybutanoate.Thefinalstepofthesynthesisistheacidificationofsodiumethyl3-ethoxy-3-hydroxybutanoatetoproduceethylacetoacetate.Thesereactionsareillustratedinthefollowingsequenceofchemicalequations.
sodiumsaltofethyl3-ethoxy-3-hydroxybutanoate
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AverystrongbaselikeLDA,lithiumdiisopropylamide,willconvertethylacetateentirelyintotheenolateform.
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LDA
β-ketoestershaveprotonsflankedbytwocarbonylgroups.ThesetypesofcompoundshavepKasequaltoabout11;therefore,theyaremoreacidicthantheacidicprotonsinethylacetate.
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Theresultingcarbanionisconvertedexclusivelytotheenolateanion(theformationoftheenolateionpredominatesbecauseofresonance).
Iftheβ-ketoestercannotformastableenolatethentheClaisencondensationproductislow.Iftheβ-ketoesterformsastableenolatethentheClaisencondensationproductcanbehigh.Forexample,ethylpropanoateformsethyl2-methyl-3-oxopentanoateinthepresenceofsodiumethoxide.Thefollowingequationsillustratetheformationofethylethyl2-methyl-3-oxopentanoatefromethylpropanoate.
sodiumethyl2-methylpropanoate
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ethyl2-methyl-3-oxopentanoate
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Acidificationtoproduceethyl2-methyl-3-oxopentanoate
ethyl2-methyl-3-oxopentanoateIfthestartingmaterialhadbeenethyl2-methylpropanoatewiththeintentofsynthesizingethyl2,2,4-trimethyl-3-oxopentanoate,thenthereactionwouldnothaveoccurred.2,2,4-Trimethyl-3-oxopentanoatecannotreactwithsodiumethoxidesinceitdoesn’tpossessahydrogenatomonthecarbonatomthatisalphatotheestergroup.Aminimumoftwohydrogenatomsmustbeattachedtothe
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carbonatomofthestartingesterfortheClaisenCondensationtobeeffective.Consequently,estersofthetypeRCH2CO2R’canundergotheClaisenCondensation,butestersofthetypeR2CHCO2R’cannotundergotheClaisenCondensation.TheDieckmannReactionTheDieckmannCondensationisanIntramolecularClaisenCondensation,i.e.acyclizationreaction.Thereactionisinitiatedwithestersofdicarboxylicacidsthatcanformfiveorsix-memberrings.Thefollowingsequenceofchemicalequationsillustratesthesynthesisofethyl2-oxocyclopentanecarboxylateviaanintramolecularClaisenCondensationreaction.
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sodiumethyl2-oxocyclopentanecarboxylateAcidificationofthesodiumethyl2-oxocyclopentanecarboxylate
Oncetheethyl2-oxocyclopentanecarboxylatehasbeenformed,itcanbesaponified,solidified,anddecarboxylatedtoproducecyclopentanone.Thefollowingseriesofreactionsrepresenttheformationofcyclopentanone.Saponification
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Acidification
Decarboxylation
Tautomerism
MixedClaisenCondensationThebestresultsforamixedClaisenCondensationiswhenoneoftheesterscannotformanenolate.Suchesterscouldbeformateesters,carbonateesters,oxalateesters,andethylbenzoate.
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EthylacetatecanreactwithethylformateinamixedClaisenCondensation,becauseethylformatedoesn’thaveahydrogenatomattachedtoanalphacarbon,andanalphacarbonatomdoesn’texistinethylformate.Thereactionproceedsasdescribedinthefollowingsetofequations.Theseequationsrepresenttheseriesofelementarystepsthatrationalizetheformationofthedesiredproduct,ethyl3-oxopropanoate.(1)
(2)
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(3)
(4)
OncethesodiumsaltoftheClaisenCondensationisformed,theproductisacidifiedtogivetheester.
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AcylationofKetoneswithEstersinaMixedTypeClaisenCondensationTheacylationofcyclohexanonewithethylformateisanexampleofthistypeofreaction.Thefollowingseriesofstepsdemonstratethepathwaythatresultsintheacylationofcyclohexanonetoproduce2-oxocyclohexylmethanal.(1)
(2)
(3)
(4)
AcidificationoftheClaisenCondensationproductproducestheβ-ketoaldehyde.
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2-oxocyclohexylmethanalReactionofcyclohexanonewithdiethylcarbonatewouldresultintheformationofethyl(2-oxocyclohexyl)-carboxylate.(1)
(2)
(3)
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(4)
Acidificationofthesodiumsaltproducesethyl(2-oxocyclohexyl)carboxylate.
ethyl(2-oxocyclohexyl)carboxylateSynthesisofKetonesviaβ-ketoEstersInitially,β-ketoestersmustbeconvertedintotheβ-ketoacidthroughsaponification.Once,theesterissaponified,thentheresultingβ-ketoacidcanunderdecarboxylationbyheatingtheacidtoformthedesiredketone.Thisconceptcanbeillustratedusingthefollowingfourchemicalequations.
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(1)
(2)
(3)
(4)
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Followingisthemechanismforthedecarboxylationreaction.
Anillustrationofdecarboxylationisthesynthesisschemafor1,3-dicyclohexy-2-propanonefromethylcyclohexylacetate.(1)
CH2 C
O
OCH2CH32
+ NaOCH2CH3CH3CH2OH
CCH2
O
C
C
O OCH2CH3_
Na+
OH
CH3CH2
+ CH3CH2OH
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(2)
(3)
Hydrolysisofthesaltgivestheβ-ketoester.
Acidorbasehydrolysisoftheesterproducesthecarboxylicacid.Ifbasehydrolysisisused,anadditionalacidificationstepleadstothecarboxylicacid.
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Acidificationofthesaltproducestheβ-ketocarboxylicacid.
Theβ-ketocarboxylicacidcanassumeasix-memberintramolecularhydrogenbondingarrangementthatpositionsthemoleculefordecarboxylationwhenitisheated.
Theresultingenolcanundergotautomerismtoformtheketoproduct.
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PreparationofKetonesUsingEthylAcetoacetateEthylacetoacetate,madebytheClaisenCondensation,isanexcellentstartingmaterialforthepreparationofvariousketones.Thepreparationofethylacetoacetatecanbeaccomplishedintwosteps.Thefirststepinvolvestheselfcondensationofethylacetate,andthesecondstepisacidificationofsodiumethylacetoacetate.Intheselfcondensationofethylacetate,theClaisenCondensation,twomolesofethylacetatearetreatedwithsodiumethoxide.Theresultingsodiumethylacetoacetateacidifiedtoproduceethylacetoacetate.Ethylacetoacetateisanexcellentstartingmaterialformakingketones,becausetheα-hydrogenatomoftheβ-ketoesterisacidic(withanapproximatepHequalto4);therefore,theα-hydrogenatomcanbeabstractedwithastrongbaselikesodiumethoxide.Oncethesodiumsaltisformed,itcanreactbywayofasubstitutionnucleophilicbimolecularreactionwithprimaryalkylhalidestoformasubstitutedethylacetoacetate.Theethylacetoacetatecanbesaponified,andtheresultingsaltacidifiedandsubsequentlydecarboxylated.Thefollowingequationsrationalizetheformationofsodiumethylacetoacetate,andtheformationofethylacetoacetatebytheacidificationofsodiumethylacetoacetate.
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(1)
(2)
(3)
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(4)
AcidificationofSodiumEthylAcetoacetate
Thehydrogenatomsontheα-carbonatomofethylacetoacetateareacidic(pKaofabout11);therefore,ethylacetoacetateismoreaceticthanethanol.EthanolhasapKaofabout16.Consequently,ethylacetoacetatereactswithsodiumethoxideto
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formthesodiumsaltofethylacetoacetate.Theresultingcarbanionisresonancestabilized.
Theethylacetoacetatecarbanionisstabilizedbyresonance.Thiscanberepresentedinthefollowingequation.
Theactualstructuremayberepresentedbythefollowing:
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Theresonancestabilizedsodiumacetoacetatecanreactwithmethylhalide,primaryalkylhalidesandinsomecasessecondaryalkylhalidestoformaβ-ketoalkylsubstitutedethylacetoacetate.ThereactionsoccurbySN2mechanisms.Followingisarepresentationofalkylatingethylacetoacetate,followedbydecarboxylation,followedbyenol-ketotautomerismtoformadesiredalkylsubstitutedacetone.
(1) Resonanceofsodiumethylacetoacetate.
(2)SN2attackofthesodiumenolateonaprimaryalkylhalide(inthiscaseethylbromide)
(3)Thealkylatedethylacetoacetatecanundergosaponificationfollowedbydecarboxylationtoformthedesiredketone(analkylsubstitutedacetone).
CC
COCH2CH3
O O
H
_
CH3
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Acidification,followedbydecarboxylationproducesthedesiredketone.
Acarefulexaminationoftheresultingketoneshowsthatthecompoundisanalkylatedderivativeofacetone(theacetoneresultsfromthede-esterificationofethylacetoacetate,acidificationoftheresultingsalt,anddecarboxylationwithheat).
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Theentitywiththealkylgroupattachedandinscribedinasquareistheresultingportionofthemoleculethatremainsafterthesubstitutedethylacetoacetatewasde-esterified,acidified,anddecarboxylated.Theattachedalkylgroupresultsfromtheesterenolateofethylacetoacetateparticipatingasanucleophileinthenucleophilicsubstitutionbimolecularreactionwithethylbromide.Theethylgroup,outsidethesquare,isthesubstratethatreactedwiththeesterenolateofthecarbanionofethylacetoacetate.
2-pentanoneTheinscribedfragmentintheboxoriginatesfromtheesterenolateofethylacetoacetate.Theethylgroup(inred)isattachedbyanSN2reactionofanethylhalidewiththesodiumsaltofethylacetoacetate.Theresultingethyl2-ethyl-3-oxo-butanoateisde-esterified,acidified,anddecarboxylatedtoproduce2-pentanone(thestructureshownabove).4-Phenyl-2-butanonecanbesynthesizedinananalogousmanner.
C
O
CH3CH
H
CH2CH3
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4-phenyl-2-butanoneFollowingisthisplannedandexecutedsynthesisof4-phenyl-2-butanonefromethylacetoacetate.
C
O
CH3CH
H
CH2
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O
OO
.. - + Br CH2
O
OO
CH2 + Br-
O
OO
CH2+ -OH
CH2
O
OO -
+ CH3CH2OH
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Thefinalstepwouldbethedecarboxylationofthecarboxylicacidbywayofheattoproducethedesiredketone.
Dialkylsubstitutionscanalsobemadeviaethylacetoacetate.Forexample,3-ethyl-5-hexen-2-onecanbesynthesizedbywayofthefollowingreactiononcethegrouptobeattachedhasbeenidentified.Inthiscase,thefragmentwithinthesquarecomesfromethylacetoacetate.
+CH2
O
OO -
H3O+
O
OOH
CH2 + H2O
O
OOH
CH2 CH2
O+ C
O
O
C
O
CH3CH
CH2CH CH2
CH2CH3
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O
O
O
HH
+ Na+ -OCH2CH3
O
O
O
..- Na+
+ CH3CH2OH
O
O
O
..- Na+
+ Br
O
O
O
+ Na+ -Br
O
O
O
+
O
O
O
+
NaOCH2CH3
..- CH3CH2OH
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O
O
O
+..- CH3CH2Br
O
O
OCH3CH2
+ Br-
O
O
OCH3CH2
+ -OH
CH3CH2
O
O
O
-+ CH3CH2OH
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3-ethyl-5-hexen-2-oneAsimilartypeofreactionsequencecanalsobeaccomplishedusingβ-ketoesters.
+CH3CH2
O
O
O
- H3O+
O
OH
OCH3CH2
H2O+
O
OH
OCH3CH2
ΔCH3CH2
O
H+ C
O
O
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TheMalonicEsterSynthesisThestructureofdiethylmalonateis
diethylmalonateIfthediethylmalonateisde-esterfied,acidified,anddecarboxylated,theremainingchemicalentityinscribedinasquarewouldbe
Notethatthisfragmentisacarboxylicacid,andcanbepreparedviadiethylmalonate.Thefragmentwithinthesquareresultsfromthereactionofasubstitutionnucleophilicreactionofthesodiumsaltofdiethylmalonatewithanappropriatealkylhalide,followedbyde-esterification,acidification,anddecarboxylation.Thefollowingsequenceofreactionsisanillustrationofusingdiethylmalonatetosynthesizeacarboxylicacidwithanalkylgrouponthealphacarbonatom.
C
H
H
CCOCH2CH3CH3CH2O
OO
C
O
CH
R
HO
H
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O
O
O
O
H H
+ Na+ -OCH2CH3
O
O
O
O
..-
+ HOCH2CH3
Na+
O
O
O
O
..-
+
Na+
BrCH2CH2
O
O
O
O
CH2CH2
+ Na+ -Br
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O
O
O
O
CH2CH2
+ NaOH2
CH2CH2
O
O
O
O
- -Na+ Na+ + CH3CH2OH2
CH2CH2
O
O
O
O
- -Na+ Na+
+ H3O+
HO
O
OH
O
CH2CH2
2
+ H2O2 + Na+2
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Usingdiethylmalonateasastartingmaterial,suggestsynthesesfor5-heptynoicacidand3-ethylpentanoicacid.Diethylmalonatecanbeusedtosynthesizecycliccarboxylicacids.Followingisanexampleofthesynthesisofacycliccarboxylicacidusingdiethylmalonate.Thesolventforthereactionisethanol.
HO
O
OH
O
CH2CH2 +Δ
CH2CH2 C
O
O
OH
O
C
O
CH
HO
H
CH2CH2
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O
O
O
O
H H
+ Na+ -OCH2CH3
O
O
O
O
..-
+ HOCH2CH3
Na+
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MichaelCondensationwithDiethylMalonateSynthesisofδ-ketocarboxylicacidThesynthesisofhexan-5-onoicacid(5-oxohexanoicacid),aδ-ketocarboxylicacid,isanexampleoftheMichaeltypecondensationwithdiethylmalonate.Thedetailsofthissynthesisisoutlinedbythefollowingsetofchemicalequations.TheproductispreparedbywayofaMichaeltypeofcondensationwithdiethylmalonateinethanol.
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+Na+
O
O
O
O
H H
+ Na+ -OCH2CH3
O
O
O
O
..-
+ HOCH2CH3
Na+
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hexan-5-onoicacidor5-oxohexanoicacid aδ-ketocarboxylicacidReactionofEsterswithLithiumDiispropylamide,LDA
Esterenolatescanalsoaddtoaldehydesandketonestoformβ-hydroxyesters
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ReformatskyReaction(revisited)β-HydroxyesterscanbesynthesizedusingtheReformatskyreaction,namedinhonorofSergeyNikolaevichRefortmatsky(1860-1934).TheReformatskyreactioninvolvesthecondensationofaldehydesorketoneswithanalphahaloesterlikeethylbromoacetatetoformβ-hydroxyesters.FollowingisanexampleofabalancedequationfortheReformatskyreaction.
Thefollowingelementarystepscouldrationalizetheformationoftheβ-hydroxyesters.
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(1)
(2)
Acidhydrolysisofthezincsaltwouldyieldtheβ-hydroxyesters
Thereactionworksbetterinazinc-coppercoupleandwithRiekezinc(aninsitupreparationofzincformedbyreducingzinchalideswithpotassium).
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ProblemsCondensationReactionsII
1. Suggestnamesforeachofthefollowing.
(a)
(b)
(c)
(d)
2. SuggestIUPACnamesforthefollowingstructures.
(a) ethylcyclobutanecarboxylate(b) n-propyl3-methylbutyrate(c) 3-ethyl-2-pentanone(d) methyl4-oxo-2-methylpentanoate(e) isopropyl4-hydroxyoentanoate
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3. Suggestsynthesesfor
(a)
(b)
4. Suggestamechanismforthefollowingreaction.
5. Suggestamechanismforthefollowingobservation.
6. Suggestasynthesisfor2-methylcyclopentanonefromadipicacidandanyothernecessaryorganicorinorganicmaterials.
7. Suggestasynthesisfor2-methyl-4-pentenoicacidfromdiethylmalonateandanynecessaryorganicandinorganicmaterials.
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8. AcompoundwiththemolecularformulaofC12H14O3,exhibitsthefollowing1HNMRand13CNMRspectra.
TheinfraredspectrumofC12H14O3exhibitsprominenttransmittancesignalsat1724cm-1;1751cm-1;1250cm-1;and1051cm1.C12H14O3isinsolubleinwater,diluteacid,ordilutebase,anddoesnotreactwithacetylchloride,butitdoesreactwith2,4-dinitrophenylhydrazine.Also,C12H14O3reactswithhotsodiumhydroxide,followedbyacidhydrolysis,andheattoproduceacolorlessgas,andC9H10O.C9H10O,aneutralcompound,isapaleyellowliquidthatisinsolubleinwater,andgivesanegativeiodoformtest,butreactswith2,4-dinitrophenylhydrazine.C9H10OreactswithlithiumaluminumhydridefollowedbyhydrolysistoproduceC9H12O.C9H12OreactswithacetylchloridetogiveC11H14O2.FollowingaretheNMRspectrumandpartialmassspectrumofC9H10O.
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Prominentsignalsatm/eequalto105and57arenotshowninthemassspectrumofC9H10O.C9H12OExhibitsastronginfraredtransmittancesignalat3333cm-1,anditdoesnotproduceayellowprecipitatewhentreatedwithsodiumhydroxideiniodine.
(a) SuggeststructuralformulasforC12H14O3,C9H10O,C9H12O,andC11H14O2,
(b) Writeamechanismtoaccountfortheformationofthecolorlessgas.
(c) GiverationalreasonsforthesolubilityobservationsforC12H14O3
(d) WriteanequationforthereactionofC12H14O3with2,4-dinitrophenylhydrazine.
(e) WriteareactionbetweenC9H12Oandacetylchloride.
(f) WhatistheIUPACnameforC12H14O3?
(g) SuggestasynthesisforC12H14O3
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9. Suggeststructuresconsistentwiththedataprovidedinthefollowingreactions,andsuggestmechanismstoaccountfortheirformations.
(a)
(b)
WhatistheIUPACnameforC5H6O4?
10. C8H12O4,canbesynthesizedfromethylacetoacetateviathefollowingsteps. Step1 Ethylacetoacetate+sodiumethoxide/ethanol Step2 Theproductofstep1reactswithmethylbromidetoform C7H12O3 Step3: Theproductofstep2reactswithsodiumethoxide/ethanol
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Step4 Theproductofstep3reactswithmethylbromidetoproduce C8H14O3 Step5 Theproductofstep4reactswithzincandbromoaceticacid followedbyhydroylsisinanacidicmediumtoformC12H22O5.
TreatingC12H22O5withexcesshydrochloricacidandheat producedC8H12O4.SuggestastructuralformulaforC8H12O4.
11. Therearemanyexamplesofdecarboxylationinbiologicsystems.Forexample,innature,isopentenylpyrophosphate,abiologicalprecursortosqualeneandcholesterol,isformedfrom3-phosphate-5-pyrophosphatemevalonicacidviathefollowingchemicalequation.
Writeamechanismfortheconversionof3-phosphate-5-pyrophosphatemevalonicacidtoisopentenylpyrophosphate,andidentifytheotherproductsproducedinthetransformation.
12. Suggestasynthesisfor6-methyl-5-hepten-2-onefromethyl4-oxopentanoateandanyothernecessaryorganicorinorganicreagents.
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13. Thecarbon-13magneticresonancespectrumandtheprotonmagneticresonancespectrumofanunknowncompoundwiththemolecularformulaofC9H14O6areindicatedbelow.
SuggestastructureforC9H14O6.
14. Suggestasynthesisforyouranswertoproblem13fromanyorganicandinorganicmaterials.
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15. Suggestamechanismtoexplainthefollowingconversion.
16. YotesandAndersonreportedthefollowingtransformationintheJournaloftheAmericanChemicalSociety.
Suggestaseriesofelementarystepsthatcouldaccountforthistransformation.Inyoursuggestedmechanism,usearrowstoshowhowelectronsareflowing.
17.Aperplexedundergraduatesummerresearchstudentwasgivenanassignmentbyhisprofessortomakeethyl3-hydroxy-3-methylbutanoate.Hedecidestotreatmethylmagnesiumiodidewithethylacetoacetateinanefforttoobtainethyl3-hydroxy-3-methylbutanoate.Everythingappearedtohavegonewell.Thereactionmixturebubbled,andheproceededwithcareandgreatskill.Heisolatedanexcellentyield,butuponspectralanalyseshedeterminedthatethylacetoacetate(thestartingmaterial)wastheonlyproduct.Heimmediatelydiscardedtheproduct,and,intears,rantohisprofessor’soffice.(a)Writeanequationtodemonstratewhatwentwrongwiththisstudent’s
research(don’tforgetthegenerationofbubbles).(b)Suggestamoreacceptablepathwaythatcouldleadtoformationofthe
desiredproduct,ethyl3-hydroxy-3-methylbutanoate.
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17. Suggestlaboratorysynthesesforthefollowingcompounds:
(a)
andanyotherorganicandinorganicreagents (b)
Fromdiethylphthalateanddiethylmalonateandanyotherinorganicmaterials.
(c)
fromadipicacidandanyothernecessaryorganicorinorganicmaterials.
19.(a)Suggestasynthesisfor2,7-octanedionefrom1,2-dimethylcyclohexene
andanyothernecessaryorganicandinorganiccompounds(b)When2,7-octanedioneistreatedwithsodiumethoxideandthenacidified,
compoundAisisolated.
CompoundA,methyl(2-methylcyclopentenyl)ketone
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Suggestamechanismthatwouldaccountfortheconversionof2,7-octanedioneintocompoundA.
20.α-Onocerin(I)hasbeensynthesizedinseverallaboratories.Approximatelyfive
decadesago,Storket.alpublishedatwenty-onestepsynthesisforα-onocerin.Fourdecadeslater,E.J.Coreyet.alatHarvardUniversitypublishedafourstepsynthesisforα-onocerinstartingwithatriterpenederivative.
I
Storketal.decidedtouse6-methoxytetrahydroteralone(3,4-dihydro-6-methoxy-1(2H)-naphthalenone),compoundII,astheprecursorforthesynthesisofcompoundI.
II
ThefirstfewstepsintheirlongsynthesisaredesignedtopreparecompoundIII.
III
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Thefollowingreagents(notnecessarilyinreactionsequence)aswellasotherreagents(notmentioned)canbeusedtopreparecompoundIII:(a) 3-buten-2-one(b) B2H6(c) aGrignardreagentSuggestasynthesisofcompoundIIIfromcompoundIIusingthesethreereagentsandanyothernecessaryreagents.OncecompoundIIIisprepared,potassiumtertiary-butoxideandmethyliodidecanbeusedtoconvertcompoundIIItocompoundIV.
IV
SuggestamechanismtoexplainthetransformationofcompoundIIIintocompoundIVinthepresenceofpotassiumt-butoxideandmethyliodide.
21.Suggestasynthesisforp-methoxybenzoicacidfromcyclohexaneandanyother
necessaryorganicandinorganicmaterials.
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