chapter 10 · chapter 10 the chemistry of alcohols and thiols organic chemistry, 5th ed. marc...

Chapter10TheChemistryofAlcoholsandThiols

Organic Chemistry, 5th ed. Marc Loudon

Eric J. Kantorowski California Polytechnic State University San Luis Obispo, CA

Chapter10Overview

•  10.1Dehydra,onofAlcohols•  10.2Reac,onsofAlcoholswithHydrogenHalides•  10.3SulfonateandInorganicEsterDeriva,vesofAlcohols•  10.4ConversionofAlcoholsintoAlkylHalides:Summary•  10.5Oxida,onandReduc,oninOrganicChemistry

•  10.6Oxida,onofAlcohols•  10.7BiologicalOxida,onofEthanol•  10.8ChemicalandStereochemicalGroupRela,onships

•  10.9Oxida,onofThiols•  10.10SynthesisofAlcohols•  10.11DesignofOrganicSynthesis

2

Dehydra2onofAlcohols

•  Strongacids(e.g.,H2SO4,H3PO4)catalyzeaβ‐elimina,onreac,oninwhichwaterislost

•  HeatandLewisacids(e.g.Al2O3)canalsobeusedtoeffectdehydra,on

310.1Dehydra8onofAlcohols

MechanismofDehydra2on

•  Dehydra,ondoesnotfollowtheE2reac,onobservedforalkylhalides

•  Hydroxideisapoorleavinggroup•  TheO‐HprotonismoreacidicthanHβ


Hydra2onandDehydra2on

•  Hydra,onofalkenesanddehydra,onofalcoholsaretheforwardandreverseofthesamereac,on

•  Theyhavethesameintermediatesandthesamerate‐limi,ngsteps(theprincipleofmicroscopicreversibility)

•  Theacidisacatalystinbothreac,ons•  Rateforalcoholdehydra,on:Ter,ary>secondary>primary


ProductDistribu2on

•  Regiochemistry

•  Rearrangements


AlkylHalidesfromAlcohols

•  Alcoholsreactwithhydrogenhalides(HX)togivealkylhalides

910.2Reac8onsofAlcoholswithHydrogenHalides


•  Keqvaluesforthesereac,onsarenotlarge•  Applica,onofLeChâtelier’sprincipleisrequired

•  Commonly,thealkylhalideproductisnotsolubleandwillseparateoutasasecondlayer

•  AlargeexcessofH‐Xmayalsobeusedtodrivethereac,ontocomple,on



•  Ter,aryalcohols(andmanysecondaryalcohols):



•  Primaryalcohols:


AlkylHalidevsDehydra2on

•  Alkylhalideforma,onanddehydra,ontoalkenesarealterna8vebranchesofacommonmechanism


SulfonateEsterDeriva2vesofAlcohols

•  Animportantmethodfortheac8va8onofalcoholstowardsubs,tu,onandelimina,onreac,ons

•  Sulfonateestersarederiva,vesofsulfonicacids

1410.3SulfonateandInorganicEsterDeriva8vesofAlcohols


•  Theacidichydrogenofasulfonicacidisreplacedbyanalkylorarylgroup



•  Abbrevia,onsarecommonlyusedbychemists


Prepara2onofSulfonateEsters

•  Alcohols+sulfonylchloridesproducesulfonateesters

•  Thisisanucleophilicsubs,tu,onreac,on


Reac2vityofSulfonateEsters

•  Alkyltosylates(R‐OTs)andmesylates(R‐OMs)havenearlythesamereac8vityasR‐Br

•  R‐OTs≈R‐OMs≈R‐Br

•  Sulfonateanionsaregoodleavinggroups



•  Subs,tu,onreac,ons:

•  Elimina,onreac,ons:



•  Thetrifluoromethanesulfonateesterishighlyreac,ve


Alkyla2ngAgents

•  Thenucleophileissaidtobealkylatedbythealkylhalide

•  Acompoundthatisagoodalkyla2ngagentisonethatreactsrapidlywithanucleophile


EsterDeriva2vesofStrongInorganicAcids

•  Alkylestersofstronginorganicacidsarehighlypotentalkyla,ngagents


Reac2onsofAlcoholswithSOCl2

•  Thereac,onofalcoholswithHClisgenerallynotsa,sfactory

•  Abebermethodemploysthionylchloride

•  Bestforprimaryandsecondaryalcohols


Reac2onsofAlcoholswithSOCl2

•  SOCl2providesconversiontoagoodleavinggroupandthechloridenucleophiletogether


Reac2onsofAlcoholswithPBr3

•  ArelatedmethodforpreparingR‐Brusesphosphoroustribromide

•  Canbeusedwithacid‐sensi,vegroups•  Lesschanceofrearrangement(cf.HBr)


Reac2onsofAlcoholswithPBr3

•  PBr3providesconversiontoagoodleavinggroupandthebromidenucleophiletogether


MethodsforConver2ngR‐OHtoR‐X

•  Reac,onwithhydrogenhalides(HX)•  Forma,onofsulfonateestersfollowedbySN2withahalideion

•  Reac,onwithSOCl2orPBr3

2710.4ConversionofAlcoholsintoAlkylHalides:Summary

PrimaryR‐OH→R‐X

•  SOCl2

•  HBrorPBr3•  UsePBr3toavoidstronglyacidiccondi,onsand/orrearrangements

•  HIorKIwithH3PO4


SecondaryR‐OH→R‐X

•  SOCl2(ifnoβ‐alkylsubs,tu,on)

•  HBrorPBr3•  UsePBr3toavoidstronglyacidiccondi,onsand/orrearrangements

•  Thesulfonateestermethodfollowedbydisplacementwithahalideisalsoeffec,ve


Ter2aryR‐OH→R‐X

•  Ingeneralforter,aryalcohols,anyofthehydrogenhalides(HCl,HBr,HI)areeffec,ve

•  Thesulfonateestermethodwillnotworkaster,aryalcoholscannotundergoSN2reac,ons


HalfReac2onsandOxida2onNumbers

•  Oxida2on:Atransforma,oninwhichelectronsarelost

•  Reduc2on:Atransforma,oninwhichelectronsaregained

•  Eachoxida,onmustbeaccompaniedbyareduc,on(andviceversa)

•  Halfreac2on:Showseithertheoxida,onorreduc,onbutnotboth

3110.5Oxida8onandReduc8oninOrganicChemistry

HalfReac2ons

1.UseH2Otobalancemissingoxygens

2.Useprotons(i.e.,H+)tobalancemissinghydrogens

3.Useelectronstobalancecharges

•  Ethanolhaslostfourelectronsinthisreac,on


Oxida2onNumbers

1.Assignanoxida,onleveltoeachcarbonatomthatundergoesachange

2.Determinetheoxida,onnumber(Nox)ofboththereactantandproduct

3.Calculatethedifferencetodetermineifthereac,onisanoxida,on,reduc,on,orneither

•  Ethanolhasbeenoxidized(ΔNox=+4)


Oxida2onNumbers

•  Followingthesamemethod,addi,onofBr2toanalkeneisanoxida,onreac,on

•  Notethatanoxida,ondoesnotdependontheintroduc,onofanoxygen

•  Moregenerally,considertheelectronega,vityofthenewelement


Oxida2onNumbers


OxidizingandReducingAgents

•  Whenanorganiccompoundisoxidized,thereagentthateffectsthereac,onisanoxidizingagent

•  Whenanorganiccompoundisreduced,thereagentthateffectsthereac,onisanreducingagent


OxidizingandReducingAgents

•  Considerchromateionasanoxidizingagenttoeffectthereac,onofethanol→ace,cacid

•  Whenchromateionoxidizesethanol,Cr3+isformed[hence,Cr(VI)→Cr(III)]


Wri2ngaBalanceEqua2on


Oxida2ontoAldehydesandKetones

•  Chromium‐basedreagentsareeffec,veatconver,ngalcoholstocarbonylcompounds

4010.6Oxida8onofAlcohols


•  Primaryalcoholsreacttogivealdehydes,butifH2Oispresenttheyarefurtheroxidized

•  H2Ocausesforma,onofaldehydehydrateswhichcanbeoxidizedlikeasecondaryROH



•  Anhydrousprepara,onscanbeconductedwithpyridiniumchlorochromate(PCC)

•  Thesolventtypicallyusedismethylenechloride


MechanismofCr(VI)Oxida2ons

•  Theα‐carbonmustbearatleastonehydrogen•  Hence,ter,aryalcoholsarenotoxidized•  Thefirststepsofthereac,oninvolveanacid‐catalyzeddisplacementofwater


MechanismofCr(VI)Oxida2ons

•  Aoerprotona,on,aβ‐elimina,onoccurs(E2)


Oxida2ontoCarboxylicAcids

•  Primaryalcoholscanbeoxidizedtocarboxylicacidsusingaqueoussolu,onsofCr(VI)

•  Alterna,vely,potassiumpermanganate(KMnO4)inalkalinesolu,onmayalsobeused


Oxida2oninLivingSystems

•  Oxida,onandreduc,onreac,onsarehighlyimportant

•  Atypicalbiologicaloxida,onistheconversionofethanoltoacetaldehyde

•  Theoxida,onoccursintheliverwithNAD+servingastheoxidizingagent

4610.7BiologicalOxida8onofEthanol


•  NAD+isoneofnature’smostimportantoxidizingagents;itisacoenzyme

•  Coenzymesaremoleculesrequired,alongwithenzymes,forcertainbiologicalreac,onstooccur


MechanismofNAD+Oxida2on

•  NAD+iselectron‐deficient

•  Theenzymeholdsthealcohol(specifically,it’sα‐H)incloseproximitytoNAD+


MechanismofNAD+Oxida2on

•  Thecarboca,oncharacteronNAD+promptsahydridemigra,onfromthealcohol


ChemicalEquivalenceandNonequivalence

•  First,cons2tu2onallyequivalency:

•  Ingeneral,cons8tu8onallynonequivalentgroupsarechemicallynonequivalent

•  Thisimpliescons,tu,onallynonequivalentgroupsexhibitdifferentchemicalbehavior

5110.8ChemicalandStereochemicalGroupRela8onships

ChemicalEquivalenceandNonequivalence

•  Cons8tu8onalequivalentgroupsmaybechemicallynonequivalent

•  Chemicalequivalencybetweentwogroupsdependsontheirstereochemicalrela8onship

•  Equivalencyisrevealedbyasubs2tu2ontest


Subs2tu2onTest

•  Subs,tuteeachcons,tu,onallyequivalentgroupwithafic,,ousgroupandcompare

•  Ifiden,calmoleculesareobtained,thegroupsarehomotopic


Subs2tu2onTest

•  Ifenan,omersareobtained,thegroupsareenan2otopic

•  Enan,otopicgroupsarechemicallynonequivalenttowardchiralreagents,butarechemicallyequivalenttoachiralreagents


Subs2tu2onTest

•  Ifdiasteromersareobtained,thegroupsarediastereotopic

•  Diastereotopicgroupsarechemicallynonequivalentunderallcondi8ons


DiastereotopicGroupReac2vity


RecognizingDiastereotopicGroups

•  Diastereotopicgroupsshouldbereadilyiden,fiedintwocases:


FlowchartforClassifyingGroups


TheAlcoholDehydrogenaseReac2on

•  Theenan8otopichydrogensofethanolarereadilydis,nguishedinthisbiologicalreac,on

•  Adeuteriumlabelhelpstrackthereac,on


TheAlcoholDehydrogenaseReac2on

•  Thechiralenvironmentoftheenzymedis,nguishesbetweenthetwoα‐H’s


Oxida2onofThiols

•  Oxida,onofthiolsfollowsadifferentcoursethanthatofalcohols

6110.9Oxida8onofThiols

Oxida2onofThiols

•  Avarietyofoxidizingagentsmaybeusedtopreparesulfonicacidsfromthiolsordisulfides

•  KMnO4mayalsobeused


Oxida2onofThiols

•  DisulfidesmaybepreparedfromthiolswithBr2,I2inbase,ormerelystandinginair(O2)


SynthesisofAlcohols

•  Theprepara,onoforganiccompoundsfromotherorganiccompoundsiscalledorganicsynthesis

•  Considerthesynthe,cmethodsavailabletopreparealcoholsfromalkenes:

6410.10SynthesisofAlcohols

DesignofOrganicSynthesis

•  Commonly,asynthesisofacompoundrequiresmorethanonestep

•  Asynthesisinvolvingmorethanonestepiscalledamul2‐stepsynthesis

•  Themoleculetobesynthesizedisthetargetmolecule

6510.11DesignofOrganicSynthesis

DesignofOrganicSynthesis

•  Toassessthebestroutefromstar,ngmaterialtotargetmolecule…workbackwards!

•  Thisprocessiscalledretrosynthe2canalysis•  Thispromptsques,onssuchas:

•  “Whatisthebestwaytomakeanalkene?”

•  “Whatisthebestwaytomakeacarboxylicacid?”

6610.11DesignofOrganicSynthesis

chapter 10 · chapter 10 the chemistry of alcohols and thiols organic chemistry, 5th ed. marc...

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