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Contents
Contributors
Preface
1.TheNatureofBondinginOrganicMolecules
AdamRenslo&DmitryKoltun
Introduction
TheNatureofCovalentandIonicBonds
Box1.1—Drawingorganicmolecules
PolarizationofCovalentBonds
AtomicOrbitalsandValenceBondTheory
HybridizationofOrbitalsandTetrahedralCarbon
HybridOrbitalsofOxygenandNitrogenandCommonFunctionalGroups
Box1.2—Functionalgroupscontainingphosphorusorsulfur
Aromaticity
HeteroaromaticRingSystemsinDrugStructures
Summary
Exercises
2.Non-CovalentInteractions
AdamRenslo
Introduction
EnthalpicandEntropicContributionstoLigand/DrugBinding
TheStrengthofNon-CovalentInteractions


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DesolvationandtheHydrophobicEffect
IonicInteractions
Box2.1—Ionicinteractionsinaprotonchannelfrominfluenzavirus

HydrogenBonds
C–HBondsasHydrogenBondDonors
ArylRingsasHydrogenBondAcceptors
Box2.2—Aπ-hydrogenbondinglutathioneS-transferase
Aryl-ArylInteractions
Cation-πInteractions
Box2.3—Hydrophobicandcation-πinteractionsinthebindingof
neurotransmittersanddrugs
HalogenBonds
Box2.4—C–Fbondsashydrogenbondacceptorsandinorthogonal
interactionswithcarbonylgroups
Summary
CaseStudy—InhibitorsofFactorXaasAnticoagulants
Exercises
3.Stereochemistry
AdamRenslo
Introduction
ChiralityandtheShapeofMolecules
Stereoisomers—SomeImportantDefinitions
Box3.1—Determiningisomericandstereochemicalrelationshipsbetween
molecules
AvoidingConfusion
Stereoisomersof1,3-Dimethylcyclohexane
ChiralityCenters
AssigningtheConfigurationofChiralityCenters


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Box3.2—Cahn–Ingold–Prelogrulesinbrief

ConfigurationalAssignmentandStereochemicalRelationships
MesoCompounds
ChiralityCentersatNon-CarbonAtoms
OtherSourcesofChiralityandStereoisomerism
Box3.3—Atropisomerism
Summary
CaseStudy—RacemicandNon-RacemicDrugs
Exercises
4.ConformationsofOrganicMolecules
AdamRenslo
Introduction
NewmanProjectionsandDihedralAngles
ConformationsandEnergiesofEthane—TorsionalStrain
ConformationsandEnergiesofLargerAcyclicMolecules—StericStrain
ConformationsofSmallRings
Box4.1—Thethreemajortypesofstraininorganicmolecules
ConformationsofCyclohexaneandRelatedSix-MemberedRings
EstimatingtheConformationalPreferencesofSubstitutedCyclohexanes
Box4.2—Drawingchairconformations
ConformationallyConstrainedRingSystems
Box4.3—Conformationalconstraintinopiateanalgesics
Summary
CaseStudy—NeuraminidaseInhibitorsandtheInfluenzaVirus
Exercises
5.Acid-BaseChemistryofOrganicMolecules


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SusanMiller

Introduction
ThreeTheoriesofAcidsandBases
Self-IonizationofWaterandthepHScale
AvoidingConfusion—Useof“Acid”and“Base”andRelatedTerms
TheAcidDissociationConstantKaandpKaasaMeasureofAcidStrength
ElectronegativityandSizeofAtomsandAcid/BaseStrength
AtomHybridizationandAcid/BaseStrength
ResonanceElectronicEffectsonAcid/BaseStrength
InductiveElectronicEffectsofSubstituentsonAcid/BaseStrength
CombinedInductiveandResonanceEffectsonAcid/BaseStrength
ProximityandThrough-SpaceEffectsonAcid/BaseStrength
TheHenderson–HasselbalchRelationshipandAcid/BaseEquilibriaasa
FunctionofpH
Summary
CaseStudy—DiscoveryofTagamet
Exercises
6.NucleophilicSubstitution,Addition,andEliminationReactions
JieJackLi&AdamRenslo
Introduction
Nucleophiles
Electrophiles
Box6.1—Electrophilesincancerdrugs
LeavingGroups
NucleophilicAliphaticSubstitutionReactions—SN2
Box6.2—SN2reactionsinbiologicalchemistry
NucleophilicAliphaticSubstitutionReactions—SN1


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NeighboringGroupAssistanceinSN1Reactions
NucleophilicAromaticSubstitution—SNAr
AdditionReactions
EliminationReactions—E1andE2
Summary
CaseStudy—DrugsThatFormaCovalentBondtoTheirTarget
Exercises
7.ReactionsofCarbonylSpecies
AdamRenslo
Introduction
NatureoftheCarbonylGroup
RelativeReactivityofCarbonyl-ContainingFunctionalGroups
HydrationofAldehydesandKetones
ReactionsofAldehydesandKetoneswithAlcohols
Box7.1—Glucuronidationinthemetabolismofdrugs
IminesandEnamines
Box7.2—Iminesindrug-proteinconjugates
OximesandHydrazones
ChemicalHydrolysisofEsterandAmideBonds
EnzymaticHydrolysisofPeptideBondsbyProteases
Box7.3—Drugsdesignedtoinhibitproteases
Summary
CaseStudy—Odanacatib
Exercises
8.RadicalChemistry
JohnFlygare&AdamRenslo


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Introduction
Formation,Stability,andMolecularOrbitalViewofRadicals
RadicalReactions
ReactionsofMolecularOxygen
Iron-MediatedRadicalReactionsinDrugMetabolism
Box8.1—Fentonchemistryintheactionofantimalarialdrugs
Summary
CaseStudy—Calicheamicinγ1
Exercises
SolutionstoExercises
Index


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Contributors

JohnFlygarehastaughtorco-taughtcoursesinorganicchemistry,
biochemistry,andmedicinalchemistryatStanfordUniversitysince1997,witha
combinedtotalenrollmentofover5,000students.Heisalsoaprojectleaderat
GenentechinSouthSanFranciscowhereheleadsdrugdiscoveryteamsin
diseaseareasincludingoncology,infectiousdiseases,andneurodegeneration.
Severalcompoundsfromtheseprogramsarecurrentlyinhumanclinicaltrials.
HereceivedhisPhDinorganicchemistryfromNorthwesternUniversityand
wasanNIHPostdoctoralFellowatStanfordUniversity.

DmitryKoltunreceivedhisundergraduateeducationatHigherChemical
CollegeoftheRussianAcademyofSciencesandhisPhDdegreefrom
UniversityofMinnesotawithProf.ThomasHoyein1999.Hebeganhiscareer
atMediChemLifeSciencesinChicago,thenmovedtoCVTherapeuticsinPalo

Alto,California.HeiscurrentlyaseniorresearchscientistintheMedicinal
ChemistryDepartmentatGileadSciencesinFosterCity,California.Helivesin
FosterCity,CaliforniawithhiswifeElenaanddaughtersVeraandSonya.

JieJackLiearnedhisPhDinorganicchemistryin1995atIndianaUniversity.


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AfterapostdoctoralfellowshipatMIT,heworkedasamedicinalchemistat
PfizerandBristol-MyersSquibbfrom1997to2012.Sincethenhehasbeenan
associateprofessorofchemistryattheUniversityofSanFrancisco,teaching
organicandmedicinalchemistry.Hehaspublished23booksforspecialistand
layaudiences,coveringtopicsrangingfromorganicandmedicinalchemistryto
thehistoryofdrugdiscovery.

SusanM.MillerreceivedherPhDinorganicchemistryandmechanistic
enzymologyfromtheUniversityofCaliforniaBerkeley.Afterpostdoctoralwork
inbiologicalchemistryattheUniversityofMichiganinAnnArbor,shejoined
theSchoolofPharmacyattheUniversityofCalifornia,SanFrancisco,in1993
wheresheisnowprofessorofpharmaceuticalchemistry.Herresearchinterests
liebroadlyinmechanisticandstructure/functionstudiesofredoxenzymesand
enzymesinvolvedinbiosyntheticpathwaysforantimicrobials.Sheteaches
aspectsofmechanisticorganicchemistryandenzymologyinbothprofessional
pharmacyandgraduatechemistryandbiophysicsprograms.

AdamRensloearnedaBAinchemistryfromSt.OlafCollegein1993anda
PhDinorganicchemistryfromMassachusettsInstituteofTechnologyin1998.
AfterpostdoctoralstudiesattheScrippsResearchInstitute,heworkedasa
medicinalchemistinthepharmaceuticalindustryfor6years.In2006hejoined

thefacultyintheDepartmentofPharmaceuticalChemistryattheUniversityof
California,SanFrancisco.Hisresearchinterestsincludethedevelopmentofnew
approachesfortargeteddrugdeliveryininfectiousdiseaseandcancer.He
teachessyntheticorganicandmedicinalchemistryinboththeprofessional
pharmacyandgraduatechemistryandchemicalbiologyprograms.


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Preface
Thechemistryofcarbon-basedmolecules—theirstructures,intermolecular
interactions,andreactivity—underlieslifeasweknowitandthusalsothe
beneficial(andsometimesundesired)effectsofthemedicinesweuse.Thefact
thatrathersimpleorganicmoleculescanbeprofoundlyeffectiveintreating
humandiseaseinallitscomplexitymustrankamongthemostsignificant
findingsofmedicineandbasicscience.Formanystudents,thisrealization
fomentsadesiretopursueacareerinoneofthevariousfieldsrelatedtothe
discovery,study,orappropriateadministrationofmedicines.Inmyowncase,
thismeantembarkingonthestudyoforganicchemistryandlearninghowto
synthesizeorganicmoleculesinthelaboratory.Later,asamedicinalchemist
workinginthepharmaceuticalindustry,Iexperiencedthethrillofseeingafew
milligrams(merespecks!)ofanewlysynthesizedcompoundcureanotherwise
lethalinfectioninamouse.Afewsuchcompoundswouldlaterbedestinedfor
studiesinhumanpatients,beginningthelongandoftenperilouspathtowardthe
approvalofanewdrug.
Thistextbookisinformedbymyexperiencesasapracticingmedicinal
chemistandasaneducatorofpharmacystudentsattheUniversityofCalifornia,
SanFrancisco.Initsorganizationandcontent,thetextislargelybasedona
semester-longcourseinorganicchemistrytaughttofirst-yearPharmDstudents
atUCSF.Itisintendedasateachingtextbook,acompanionforstudentsof

pharmacyormedicinalchemistry,thatcanbecoveredinitsentiretyinasingle
semester.Giventhis,thetextisnecessarilylimitedinitsscopeandisnot
intendedtoreplaceanyoftheexcellentandcomprehensivehandbooksof
medicinalandpharmaceuticalchemistrythatareavailable.Whatiscoveredhere
arethosetopicswehavefoundmostrelevantandinstructiveinproviding
studentsofpharmacywithasolidgroundinginorganicchemistryasitrelatesto
drugstructureandaction.
Thefirstfourchaptersofthetextcoverthefundamentalsofdrugstructure
andbinding—thenatureofthechemicalbondsindrugstructure,thetypesof
non-covalentintermolecularinteractionsdrugsformwiththeirtargets,andtheir
three-dimensionalshapeandconformations.Thefinalfourchaptersare


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concernedwithchemicalreactivityrelevanttodrugaction—thereactivityof
(some)drugstowardtheirtargets,themetabolismofnearlyalldrugs,andthe
reactionscarriedoutbytheenzymesthatmodifydrugsorcanbetargetedby
them.Throughoutthetext,thediscussionisintertwinedwithillustrative
examplesofdrugsynthesis,action,ormetabolism.Also,eachchapterconcludes
withadrug“casestudy”selectedtoemphasizeandreinforcetheconcepts
introducedinthatchapter.
Iamindebtedtoanumberofindividualswithoutwhomthisprojectcould
neverhavehappened.Ithasbeenadistinctprivilegetointeractwiththebright
andinquisitivePharmDstudentsthatUCSFisfortunateenoughtoattract.Their
willingfeedbackastowhatisandisnotworkingintheclassroomhasshaped
howweteachorganicchemistryatUCSF,andthisinturnisreflectedinthefinal
formofthebook.ImustlikewiseacknowledgecurrentandformerUCSF
colleagues(SusanM.Miller,ThomasScanlan,andPaulOrtizdeMontellano)
whocontributedtodevelopingtheorganicchemistrycurriculuminthePharmD

program.TheeditorsandproductiondesignersatMcGraw-HillEducationhave
beenapleasuretoworkwith.IwouldespeciallyliketothankMichaelWeitz,
PeterBoyle,andRuchikaAbrolfortheirassistanceandencouragement.Iam
gratefultoProfessorPeterBeak(UniversityofIllinoisatUrbana-Champaign)
forreadingthefinalmanuscript.Lastbutnotleast,Imustthankmycoauthors
andcontributors(JohnFlygare,DmitryKoltun,JieJackLi,andSusanM.
Miller),top-notchresearchersandeducatorswhoputtheirownstamponthe
chapterstowhichtheycontributed.WehopethatthisfirsteditionofThe
OrganicChemistryofMedicinalAgentswillproveusefulforstudentsand
instructorsalikeandwewelcomesuggestionsforimprovementsandadditionsto
futureeditions.
AdamRenslo


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Chapter1

TheNatureofBondinginOrganic
Molecules
AdamRenslo&DmitryKoltun

CHAPTEROUTLINE
1.1Introduction
1.2TheNatureofCovalentandIonicBonds
Box1.1—Drawingorganicmolecules
1.3PolarizationofCovalentBonds
1.4AtomicOrbitalsandValenceBondTheory
1.5HybridizationofOrbitalsandTetrahedralCarbon
1.6HybridOrbitalsofOxygenandNitrogenandCommonFunctionalGroups

Box1.2—FunctionalgroupscontainingPhosphorusorSulfur
1.7Aromaticity
1.8HeteroaromaticRingSystemsinDrugStructures
1.9Summary
1.10Exercises

1.1Introduction
Inthischapter,wewillreviewfundamentalconceptsofchemicalstructureand
bondingintheorganicmoleculesthatmakeupdrugsandtheirbiologicaltargets.
By“organic,”wemeanmoleculesthatareconstructedprimarilyfromthe
elementcarbon(C).Carbonexhibitsstrikingversatilityinitsabilitytoform
variousdifferentbondingarrangementswithothercarbonatomsaswellaswith
otherbiologicallyrelevantelementssuchasnitrogen(N),oxygen(O),sulfur(S),
andphosphorus(P).Itisthisversatilitythatallowedcarbon-basedlifetoemerge
onourplanet.Thus,tounderstandthemoleculesoflife—proteins,lipids,nucleic


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acids,hormones,etc.—andthedrugsthatinteractwiththem,wemuststartwith
asolidunderstandingofstructureandbondinginorganicmolecules.Inthis
chapter,wewillbeginbycontrastingthenatureofionicandcovalentbonding
andwilldescribethepolarizationofcovalentbonds.Wewillthendivedeeper
intothenatureofthecovalentbond,discussingatomicandmolecularorbitals,
the“hybridization”oforbitals,andaromaticity.Finally,wewillreviewsome
importantfunctionalgroupsandorganicringsystemsthatfigureprominentlyin
thestructuresofbiologicalmoleculesanddrugs.
Inthechaptersthatfollowwewilllearnmoreabouttheintermolecular
interactions,mostlynon-covalent,thatgovernthebindingofadrugmoleculeto
itsintended(andsometimesunintended)biologicaltargets.Fornow,itis

importanttorecognizethatadrugmolecule’sparticularstructure—itsshapeand
thenatureandconnectivityofitsatoms—determineswhatbiologicalactivitiesit
willhave.Ifamolecule’sstructureleadstointeractionsinthebodythatcorrect
anabnormality,restorenormalfunctionofacell,orkillapathogenicor
cancerouscell,anewmedicineisborn.Theseeminglyendlesswaysinwhich
organicmoleculescanbeassembledhasallowedscientiststocreateourcurrent
pharmacopeiaandaffordsconfidencethatstillmorenewmedicineswillbe
developedtoaddresscurrentlyunmetmedicalneeds.

1.2TheNatureofCovalentandIonicBonds
Atomsarecomprisedofanucleuscontainingpositivelychargedprotonsand
unchargedneutronssurroundedbynegativelychargedelectrons.Onaccountof
theirverylowmass,electronsbehaveasbothparticlesandwaves.Thepeculiar
wave-likenatureoftheelectroniswhatpreventsthisnegativelychargedparticle
fromsimply“falling”intothepositivelychargednucleus,towhichitisclearly
attracted.Wave-likeelectronsarespatiallyconfinedtospecificatomic“orbitals”
surroundingthenucleus.Whileatomicandmolecularorbitals(Sections1.4and
1.5)underlieourcurrentunderstandingofchemicalbonding,theirexistencewas
hintedatmuchearlierbyacertainperiodicityinthechemicalreactivityofthe
elements.ItwasthisobservationthatallowedMendeleevtoconstructhis
periodictableoftheelements.Apartialperiodictableincludingjustthefirst
three“periods”(rows)ofelementsmostrelevanttoorganicchemistryis
providedhere(Figure1.1).


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Figure1.1Periodictableofthefirst18elements(atomicnumberZ=1through18).Groups(columns)1–8
representthe“maingroup”elementsandaretheelementsmostrelevanttoorganicchemistryanddrug
structures.Electronicconfigurationsareprovidedincondensedformat,withconfigurationofvalence

electronsshownexplicitlyandinnersphereelectronsindicatedbythecorrespondingnoblegas
configuration,either[He]or[Ne].

Theperiodictablearrangestheelementsinorderofincreasingnumberof
protons(atomicnumber,Z)andby“groups”(columns)ofelementswithsimilar
chemicalreactivity.Thisperiodicityledtoanunderstandingofchemical
reactivityandbondingasbeingrelatedtothefillingofelectron“shells”
surroundingthenucleus.Tounderstandwhychemicalbondsformatall,itis
usefultoconsiderthosefewelementsthatgenerallydonotformbonds—the
noblegases.Foundatthefarright-handsideoftheperiodictable,noblegases
suchashelium(He),neon(Ne),andargon(Ar)are“noblyunreactive”because
theiroutermostelectronshellisperfectlyfilled.Ifheliumrequiresonlytwo
electronstocompleteitsoutermostshell,thenneonandargonrequirean
additional8and16electrons,respectively,todoso.Thedrivingforcefor
chemicalbondingcanthusbeunderstoodasadesireofatomstoachieve
perfectlyfilledelectronshells(anoblegas“configuration”)byformingbondsto
otheratoms.Thiscanbeachievedinoneoftwoways—bytheexchangeof
electronsinanionicbondorbythesharingofelectronsinacovalentbond.
Thechemistryofcarboninvolvescovalentbondingandsowewilldiscuss
ionicbondingonlybrieflyhere.Commontablesalt(sodiumchloride,Na+Cl−)
providesthemostfamiliarexampleofanionicbondbetweentwoatoms.
Lookingattheperiodictableweseethatbothsodiumandchlorinearejustone
columnaway(andthusoneelectronaway)fromanoblegasconfiguration.
Transferofanelectronfromsodiumtochlorineproducesasodiumcation(Na+)
andchlorideanion(Cl−),eachwiththeelectronicconfigurationofneon(i.e.,a


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filledouterelectronshell).The“bond”inNa+Cl−canbethoughtofasthe

electrostaticattractionbetweenthesodiumandchlorideions.Thebenign,
unreactivenatureofNa+Cl−canbecontrastedwithelementalsodiummetal
(Na),whichreactsviolentlywithwater,andelementalchlorinegas(diatomic
Cl2),whichwasusedasawarfareagentinWorldWarI.
Carbondoesnotformionicbondsbecauseachievinganoblegas
configurationwouldrequirethatitacquireandstabilizefouradditional
electrons,resultinginatetra-anionwithanoverallchargeof−4.Smallatoms
suchasC,N,andOarenotcapableofexistinginsuchhighlychargedstates.
Instead,carbonachievesanoblegasconfigurationbyformingfourcovalent
bonds.Eachbondcomprisestwoelectrons,oneprovidedbythecarbonatomand
oneprovidedbyitsbondingpartner.Withfourbondsoftwoelectronseach,a
carbonatomhasobtainedtheeightelectrons(anoctet)requiredtoexactlyfillits
outermostelectronshell.Whilewecommonlyshownbondsassimplelines,the
chemistGilbertN.Lewisdevelopedanotationinwhichabondisshownasa
pairofdots,meanttorepresentthepairofsharedelectronsthatmakeupthe
bond.Lewisstructurescanbeusedtoshownotonlysinglebondsbutalso
doubleandtriplebonds,asillustrated(Figure1.2).Whilethisnotationhasclear
limitationsfordrawinglargermolecules,westilluseLewisnotationtoshowand
keeptrackofnonbondedlonepairelectrons.

Figure1.2Ethane,ethylene,andacetyleneshownasLewisdrawingsandaslinedrawings.

Sincecarbonmustformfourbondstoachieveanoblegasconfiguration,we
saythatcarbonhasavalenceoffour.Byinspectingtheperiodictable(Figure
1.1),wecanfurthermorepredictthatnitrogenshouldhaveavalenceofthreeand
oxygenavalenceoftwo,sincenitrogenandoxygenwillrequirethreeortwo
additionalsharedelectrons,respectively,toachieveanoblegasconfiguration.
Hydrogenisonlyonecolumnremovedfromheliuminthefirstrowofthe



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periodictableandsoithasavalenceofone.Similarly,thehalogens(Cl,Br,I)
haveavalenceofonesincethisgroup(column)isimmediatelyadjacenttothe
noblegassesandthusisjustonesharedelectronawayfromafilledshell.
Evenwiththisrathercrudenotionoffillingelectron“shells,”wecanalready
makesenseofagreatvarietyoforganiccompoundsformedfromcombinations
ofC,N,O,andH.Somebiologicallyrelevantmoleculesareshown(Figure1.3)
usingLewisstructurestoillustratebondingandthefillingofelectronshellsfor
H(twoelectronsrequired)andC,N,andOatoms(eightelectronsrequired).
Notethatallthebondingandnonbondingelectronsassociatedwithagivenatom
counttowardthetotalsharedelectroncount.Thusthetriplebondinhydrogen
cyanide(HCN)contributessixsharedelectronstoboththeCandNatoms.
Thesesixelectrons,whencombinedwithapairofelectronsintheH–Cbond
andthenonbondedelectronpaironthenitrogenatom,produceatotalelectron
countofeightforbothCandN(Figure1.3).

Figure1.3StructuresofsimpleorganicmoleculesshownaslinedrawingsandcompleteLewisstructures.

It’sagoodideatobecomeproficientindrawingLewisstructuresasthis
approachhelpsusunderstandthelocationsofbondedandnonbondedelectrons
andreinforcestheideathatbondsarecomprisedofpairsofsharedelectrons.Of
course,usingLewisstructuresfordrug-sizedmoleculesisnotpracticalandso
chemistshavedevelopedshort-handnotationsfordrawingchemicalstructures.
ThesearereviewedinBox1.1andthisstandardnotationwillbeusedthroughout
mostofthistext.
Box1.1Drawingorganicmolecules.


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Chemistshaveadoptedadrawingconventionthatavoidstheneedtoexplicitly
showhydrogenatomsorevenwritea“C”foreachcarbonatom.Acarbon
atomisimplicitateach“joint”inastructure,oratanunlabeledterminus.
Hydrogenatomsaresimilarlyimplicit—eachcarbonisassumedtocontainas
manyboundhydrogensasnecessarytoachievetetravalency.Atomsotherthan
carbonandhydrogenareshownexplicitly,asarehydrogenatomsonnoncarbonatoms(e.g.,thehydroxylgroup–OHin1-butanol).Itisalsohelpfulto
showhydrogenatomsexplicitlyoncertainfunctionalgroupssuchas
aldehydes.Commonaromaticringslikephenylandpyridinearebestdepicted
withalternatingdoubleandsinglebonds.


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1.3PolarizationofCovalentBonds
Inourdiscussionofcovalentbondingintheprevioussection,wedescribedthe
electronsinvolvedinacovalentbondasbeingsharedbetweenthetwoatoms
involvedinthebond.Ifthebondedatomsareidenticalthentheelectronsinthat
bondwillindeedbesharedequally.However,whentwodifferentatomsforma
covalentbond,theelectronsinthebondwillusuallynotbesharedequally
betweenthebondedatomsandthebondissaidtobepolarized.Polarizationof
covalentbondsoccursbecausecertainatomshavemorepowertopullelectrons
towardtheirnucleusthanothers.Generally,atomslocatedfurthertotherightin
aperiod(row)oftheperiodictableexertastrongerpullonelectronsandaresaid
tobemoreelectronegative.Fluorineforexampleismoreelectronegativethan
carbon,andoxygenismoreelectronegativethannitrogen.Wecanillustratethe
polarizationofaC–Fbondinoneoftwoways,asshownbelow.Theδ+
nomenclatureindicatesapartialpositivechargeandtheδ−aregionofpartial
negativecharge.ThispolarizationoftheC–Fbond(withgreaterelectrondensity
onfluorine)canalsobeillustratedusingthespecialarrowshownbelowatright.

Bothofthesenotationswillbeusedinsubsequentsectionsandchaptersofthis
text.


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Toafirstapproximation,wecanestimateelectronegativityusingtheconcept
ofeffectivecharge,whichisequaltothetotalpositivechargeofthenucleus
minusthenegativechargeofthenon-valence(“innershell”)electrons.For
example,lithium(Li)hasanatomicnumberofthree(Z=3),andthusthree
protonsinthenucleusandanuclearchargeof+3.Lithiumhasasinglevalence
electronandtwoinnershellelectronssotheeffectivechargeoflithiumis+1(3
−2=1).Beinginthesamerowoftheperiodictableaslithium,fluorinealsohas
onlytwoinnershellelectrons.Withanatomicnumber9however,fluorinehas
aneffectivechargeof+7(9−2=7).Thus,ifonenegativelychargedelectronof
Liisexperiencingthepullofasinglepositivechargefromthenucleus,an
electronfromFisexperiencingapullthatisseventimesgreater.
Effectivechargeisusefulforestimatingrelativeelectronegativityfor
elementsinthesameperiod(row)oftheperiodictable,butitislesspredictive
whencomparingatomsfromdifferentperiodsanddifferentgroups,likesulfur
andnitrogen.Inthesecases,thePaulingelectronegativityscalebecomes
indispensable.DevisedbyLinusPauling,thetableassignseachatoman
electronegativitycoefficient,andthecovalentbondisalwayspolarizedinthe
directionofanatomwithalargercoefficient(Table1.1).FromthePauling
electronegativityscaleweseethatnitrogen(Paulingcoefficientof3.0)ismore
electronegativethansulfur(2.5).Wewillfrequentlyrefertotheelectronegativity
scaleinsubsequentchaptersasthisconceptisverypowerfulinhelpingto
understandchemicalreactivityandintermolecularinteractionsoffunctional
groups.
Table1.1PaulingElectronegativityScaleforSelectedElementsMost

RelevanttoOrganicChemistryandDrugAction.


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1.4AtomicOrbitalsandValenceBondTheory
TheconceptofvalenceandtheLewisviewofcovalentbondingisusefultohelp
usunderstandwhyelementslikeH,C,N,andOcombineinvariouswaysin
organicmolecules.Unfortunately,thisviewfailstoexplainmanyother
importantfeaturesoforganicmolecules,suchasthethree-dimensional
arrangementofbondsandthefactthatrotationaboutC–Csinglebondsis
generallyfacilewhilerotationaboutC–Cdoubleortriplebondsisnot.Inthis
sectionwewillintroducetheconceptoftheatomicorbitalaswellasvalence
bondtheory,inwhichcovalentbondsareunderstoodasarisingfromthe
“overlap”ofatomicorbitalstoformmolecularorbitals.Atleastnotionally,the
overlapofatomicorbitalstoformbondscanbeequatedwiththesharingof
electronsaspositedintheLewisdescriptionofthecovalentbond.
Quantummechanicsisthefieldofphysicsthatdealswithmatterandenergy
atverysmallscales,wherethedualwave-particlenatureofmatterbecomes
important.Accordingtoquantummechanics,electronsdonotcirclethenucleus
inafixedorbitlikeaplanetarounditssun,butratherare“spreadout”inthreedimensionalspacearoundthenucleusasdefinedbyspecificsolutionstothe
Schrödingerequation.
Hψ=Eψ


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Eachsolutiontothisequationisassociatedwithaparticularwavefunction
(ψ),alsocalledanatomicorbital.Theeasiestwaytovisualizeanatomicorbital
istoconsideritsprobabilitydensity,thesquareofthewavefunction(ψ2),which

correspondstotheprobabilitythatanelectronwillbefoundinaparticular
regionofspacesurroundingthenucleus.Thelowestenergyatomicorbitalfor
thehydrogenatom(andbyextensionallotheratoms)isthe1sorbital,whichhas
asphericalprobabilitydensity(Figure1.4)andcanaccommodateatmosttwo
electrons,providedtheyhaveopposite“spin”asdictatedbythePauliexclusion
principle.Thefillingofa1sorbitalwithtwoelectronsisthemoreaccurate
pictureofwhatisgoingonwithHeanditsfilledelectron“shell.”Nexthighest
inenergyisthe2sorbital,whichisalsosphericalbutwithitselectrons,on
average,spendingmoretimefurtherfromthenucleus.Nexthigherinenergyare
threeenergeticallyequivalent2porbitals,oftendenoted2px,2py,and2pz.Thep
orbitalhasabilobedor“dumbbell”shapedprobabilitydensity,withanodeof
zeroprobabilityatthenucleus,wherethewavefunctionchangessign.Thethree
porbitalsareorientedalongdifferentaxeswhenshownonatypicalcoordinate
system(Figure1.5).Each2porbitalcanaccommodateuptotwospin-paired
electrons,foratotalofsix2pelectrons.

Figure1.4Boundarysurfaceof1sand2satomicorbitals.Thesphericalsurfacesshownrepresentthe
boundarywithinwhichtheprobabilityoffindinganelectronishigh(>90%).(Reproduced,with
permission,fromCareyFA,GiulianoRM.OrganicChemistry.9thed.NewYork:McGraw-HillEducation;
2014.)