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ORGANICCHEMISTRYOUTLINEAtMed-Pathway,we loveOrganicChemistry (Ochem) as it provides avery good foundation for understanding various aspects of medicineincluding biochemistry, drug development, and drug design. Med-Pathway’sveryownDr.PhilCarpenterstudiedOChemundertheworldfamousDr. Bruice atUCSB andwas aMasterTrainer andTeacher forMCAT©Ochemforyears.Wepresentacomprehensivesubjectreviewalongwith100challengingquestions to prepare you for Ochem mastery on the MCAT. Med-PathwayOChemReviewhasbeenderivedfromacarefulconsiderationof the AAMC MCAT© Content Guideline. Stereochemistry and AminoAcidsandProteinsarediscussedindetailinothersubjectmodules.Themoduleisdividedintothreesections.Thefollowingtopicsarediscussedandassessedineachchapterofthismodule.Theassessmentquestionsarelistedseparatelyonmed-pathway.comChapterI � Carbon:Bonding,Hybridization,andSaturation� InductionandResonance� GeneralNomenclature� Alkanes(Freeradicalhalogenation,Conformationofcycloalkanes)� Alkenes� Alcohols (Nomenclature, Physical Properties, Acidity, Synthesis,Oxidation,SN1andSN2SubstitutionReactions,PreparationofMesylatesandTosylates,ProtectionofAlcohols� CarbonylChemistry:Aldehydes&Ketones(PhysicalPreparation&Synthesis, Oxidation-Reduction, Keto-enol tautomerization, Aldolcondensationreactions,kinetic&thermodynamicenolates,formationofacetals&hemiketals,formationofimines&enamines)� Cyanohydrins

ChapterII� Carboxylicacids&Theirderivatives� Decarboxylation&Carboxylation� AcylHalides� AcidAnhydrides� Esters� ClaissenCondensation� Amides� AmidesandProteinStructure(HydrolysisofPeptideBonds)� RelativeReactivityofCarbonylCompoundsChapterIII � Carbohydrates(Nomenclature,Formationofhemiacetals&acetals,mutarotationandanomers,glycogen&cellulose,reducingsugarsandtheBenedict’stest)� Fattyacids&Lipids(saturatedvsunsaturated,formationofmicelles,triglycerides,saponification,phospholipids,phosphatids,sphingolipids)� Cholesterol� BileAcids� Steroids� Prostaglandins� Fat-solublevitamins(VitaminD,VitaminA,VitaminK,VitaminEandlipidperoxides

CHAPTERICarbonCarbon is central to organic chemistry. The stability of carbon-carbonbondsisessentialfortheelementbeingamajoringredientinimportantbiopolymers such as proteins, nucleic acids, and polysaccharides.Because carbon is an electro neutral atom, its bonding to moreelectronegative atoms generates polar bonds (dipoles) that formulatepotentialsitesofchemistry.Wewillseethispointoverandover.Withanatomicnumberofsix,carbonhasfourelectronsthatparticipatein the generation of covalent bonds as shown below. Recall that theorbitals of valence electrons combine to formnewhybrid orbitals. Befamiliar with how hybridization of orbitals andmolecular shapes arerelated.

Singlebondsareknownassigmabonds(σ)anddoublebondsarealsocalled pi bonds (π) bonds. A double bond contains one σ and one πbond.Atriplebondcontainsoneσandtwoπbonds.There are a few points regarding hybridization that are important toknow:1)Thegreaterthescharacter,thegreaterthebonddissociationenergy.2)Thegreaterthescharacter,theshorterandstrongerthebond.

3) Therefore, carbon-carbon triple bonds are shorter than doublebonds,butrequiremoreenergytodissociateastheyhavehigherbonddissociationenergies.4)Acidity is inverselyproportional to s character.Thus, thehydrogenatoms inacetylene (C2H2),amolecule thathasa triplebond,aremoreacidicthanthehydrogenatomsinethylene(C2H4),amoleculethathasasingledoublebond.DegreesofunsaturationThenumberofdoublebondsand/orringsinacompoundisreferredtoas itsdegrees(orunits)ofunsaturation.Thiscanbe figuredoutgiventhe molecular formula of the compound. Remember that allhydrocarbonshaveanevennumberofhydrogenatoms,otherwisetheyhavechargedcarbonatoms(+or-)orfreeradicals.Saturatedcompoundsarethosethatcontainonlysigmabondsandhaveallcarbonswithamaximalnumberofbondedhydrogenatoms(2N+2where N = the number of carbons atoms). A general formula for thedegreesofunsaturationofacompoundcanbedescribedas:Degreesofunsaturation=2N+2–X/2whereC=#ofcarbonatomsN=#ofhydrogenatomsX=#HalogensH=#Hydrogenatoms#Oxygenatoms=0Andnitrogenatomsn=n+1,x=x+1Usingthisformula,thenumberofunits(degrees)ofunsaturationofbenzene(C6H6)canbecalculatedas:Degreesofunsaturation=2N+2–X/2

2(6)+2-6/2=4unitsofunsaturation.Thisshouldmakesenseasbenzenehasoneringand3doublebonds.ChemicalInductionIn chemistry, induction refers to the uneven distribution of electronswithinasigmabond.AlthoughbondsareusuallydepictedinLewisdotaswellasstickstructuresasequallysharingelectrons,thetransmissionof charge through dipoles often unequally distributes electrons. Suchpolarization of electrons (i.e. induction) within bonds is largelydetermined by the electronegativity of the participating atoms. Thestrength of inductive groups depends ondistance from the group andtheatomthatitisactingon.Theimagebelowshowssomeimportantexamplesofinduction.PanelA shows water and the carbonyl unit. Note the presence of theelectronegative oxygen atoms bound to either hydrogen (water) orcarbon (carbonyl). As oxygen is more electronegative than eitherhydrogenor carbon, the electrons in thebondarenot shared equally,resultingindipolemoments.Thisisreflectedinthepartialpositiveandnegativecharges.

PanelBshowsthreecarbocations(tertiary,secondary,andprimary).Incontrast to oxygen, alkyl groups donate their electrons throughinduction.Asaconsequence,tertiarycarbocationsaremorestablethansecondary and primary carbocations as the relative induction ofelectronsreducestheoverallpositivechargeonthecarbon.Recallthatcarbon is electro neutral and more stable carbocations have chargesmoretowardsneutrality.Panel C showschlorinatedderivativesofaceticacid.Aschlorine isanelectronegativehalogen,itwilldrawelectronstowardsitself,evenoverdistances. Notice that the pKa of acetic acid is normally 4.86, butdecreases as a functionof thenumberof chlorine atoms added to themoleculeincreases.ThepKaoftrichloroaceticacidis0.7.Thisisduetothe inductiveeffectsofchlorine.Asmoreelectronwithdrawinggroupsareadded toaceticacid, theO-Hbondbecomesmoreacidicandmorecapableofreleasingtheproton.ResonanceThe structure of molecules is commonly described through Lewisstructures.However,somemoleculescanbedrawnwithmorethanoneLewis structure. In some cases, delocalized pi electrons exist asresonance hybrid structures and can be described through multipleLewis structures. Importantly, each form contributes in proportion tothe overall stability of the molecule. Resonance structures are nottransientstates,butratherthetruemolecularstructureistheresonance

hybridandthisstructurerepresentstheoveralllowesttotalenergy.Therefore, resonance is important for molecular stability. Theresonance structures for benzene (C6H6) are shown. Note that tworesonancestructuresofbenzenecanbewrittenintheLewisdotformat.Aswritten, benzene has both single anddouble carbon-carbonbonds,but the average bond length for the carbon-carbon bonds in benzenefalls in between what is expected for single and double bonds (seeimage).Thatis,thebondlengthsinbenzeneareinbetweensingleanddoublebondsduetoresonancedelocalizationof thepielectrons.Notethatthepielectronscanmovefromonespacetoanother,buttheatomsthemselvesdonotmove.Thisisshownforaniline.

Noticethat intheresonancestructuresofaniline,thenegativechargesare in the ortho and para positions and this explainswhy addition ofgroupstoanilineoccuratthesetwopositions.Thebasicrulesfordeterminingthemostoptimalresonancestructuresareasfollows:1)Maintaintheoctetruleforatoms2)Minimizeformalcharges,butelectronegativeatomsprefernegativecharges3)Maintainaromaticity4)Minimizeformalcharges5)Minimizeseparationofcharges

NomenclatureCommonandIUPACnameswillbeusedontheMCAT.Thegeneralrulesareasfollows:A)Countthelongestcontinuouscarbonchain.B)Assignnumberstocarbonatomsinthechainsuchthatthesumoftheattachedsubstituentgroupsisthelowest.C)Namethesubstituentgroups.D)Namethecompoundusingsubstituentgroupsinalphabeticalorder.Insomecases,thefunctionalgroupscanbenamedastheparentalcompoundintermsofthesubstituents.Let’sexaminesomeexamples.Morewillbepresentedasthechemistryofeachfunctionalgroupisdiscussed.

Organiccompoundscontainalargearrayoffunctionalgroups.Alkanes,alkenes, and alkynes differ in the number of double bonds betweencarbon-carbon covalent bonds. The following functional groups willappearon theMCATandwillbediscussedhere.Othergroupssuchasalkenesandetherswillalsobeexamined.Alkynesarerareinbiologicalsystemsanddonotappeartobenaturallypresentinhumans.ALKANESSaturatedhydrocarbonsareknownasalkanesandhavetheformulaofCNH2N+2. They are relatively unreactive, but undergo two significantreactions: A.CombustionB.Freeradicalsubstitution

A.CombustionreactionsInthepresenceofheatandoxygen,alkanesareoxidizedtoCO2andH2O.Theseexothermicreactionsreleasealotofheat.B.FreeradicalsubstitutionAlkanescanbehalogenatedinfreeradicalreactions.Theresultingalkylhalidesareoftenusedfurtherassubstratesinadditionalreactions.Freeradicals are highly reactive molecules. The reaction occurs in thepresence of light or heat to induce homolytic dissociation of thediatomic halogen. All free radical reactions occur with three majorsteps:1)Initiation2)Propagation3)Termination.Showninthefigureisthefreeradicalchlorinationofmethane,thesimplestalkane.

Initiation: The diatomic chlorine molecule is split in a homolyticfashion by light or heat. Homolytic cleavage generates free radicalchlorineatomsthatcontainoneunpairedelectron.Note that initiationincreasesthenumberoffreeradicalsinthesystem.

Propagation: Thisoccurs in twosteps.Themethanealkane interactswiththefreeradicalchlorineatom.Ahydrogenatomisabstractedfromthealkane,generatingaprimary,freeradicalintermediateandanotherchlorinefreeradical.Thisinitiatesachainreaction.Inthesecondstep,thealkylfreeradicalcollideswithadiatomicchloridemoleculeformingthealkylhalideandanotherchlorideradical.Termination:Anyreaction thatdecreases thenumberof freeradicalsin the system is a termination event. Two termination reactions areshownbelow.StereochemistryinFreeRadicalHalogenationFreeradicalhalogenationreactionsoftenproducestereoisomers.Beforewe examine a specific example, let’s review some basic tenants ofstereoisomers.Isomersthatdifferintheir3D-spatialarrangementofatomsaretermedstereoisomers. Any molecule that cannot be superimposed on itsmirrorimageexhibitschirality.Thesimplestwaytoenvisionchiralityis to note that your left hand cannot be superimposed on your righthand: they are mirror images of each other. Chirality refers to“handedness”andexiststhroughoutnature.Helicesinnucleicacidsandproteins have handedness. Thus, chirality is a term referring tohandednessorsymmetry,andisanintrinsicpropertyofstereoisomers.A molecule and its non-superimposable mirror image are calledenantiomers. The two enantiomers of the amino acid alanine areshown below. The red asterisk designates the chiral carbonstereocenter. The two molecules are non-superimposable mirrorimages. Enantiomerspossess identicalphysicalproperties (i.e.boilingandmeltingpoints)withtheexceptionofhowthey interactwith light.This is furtherelaboratedonintheMed-PathwayStereochemistryandIsomers Testing Module. A 1:1 mixture of enantiomers is called aracemicmixture.Anyratioofenantiomersdeviatingfrom1:1iscalledascalemicmixture.Stereoisomers possess one or more stereogenic atoms orstereocenters. According to Mislow and Siegel, a stereocenter

representsaposition inamoleculewheretheexchangeof twogroupsgeneratesastereoisomer. Stereocentersareoftenreferredtoaschiralorasymmetric centers.Althoughmanyatomscanexhibit chirality, theMCATwilllargely,ifnotexclusively,focusoncarbon.

The freeradical chlorinationofbutanegeneratesa racemicmixtureof2-chlorobutane. Note that butane can generate both primary andsecondaryfreeradicals.Becausesecondaryfreeradicalsaremorestablethanprimaryfreeradicals,thepredominantproductswillsubstitutedatposition2.Asshownabovefor freeradicalhalogenationreactions, theimagebelowshowsthegenerationofthefreeradicalintermediateafterabstractionofthesecondaryhydrogen.Importantly,thisintermediateisplanar,meaning that in the second step, the chlorine free radical canreact from either the top or the bottom of the plane. As a result, twoproducts are created with equal probability. Note that the product ischiral as the carbon at the reaction center has four differentsubstituents bound to it. As discussed in the Stereochemistry andIsomersTestingModule,oneistermedRandtheotheristermedS.

SelectivityinfreeradicalhalogenationIn the example of free radical chlorination of butane (CH3CH2CH2CH3)shown above, there are two types of hydrogen atoms that canparticipate in the reaction: primary (1°) and secondary (2°). Althoughchlorination will occur at all unique hydrogen positions, the majorproducts(racemicmixture)arethosesubstitutionsthattakeplacewiththe2°hydrogenatoms.Thisisbecause2°freeradicalintermediatesaremorestablethan1°hydrogenatoms.The relative stability of free radicals is shown below. Note that thebenzylradicalisthemoststableonebecauseofresonancestabilization,and the relative stabilities of the alkyl radicals are governed byinduction. Recall that alkyl groups (represented by R) are electrondonating. Therefore, the more R groups on a carbon atom with oneunpaired electron, the more that carbon atom is effectively closer tosatisfyingitsoctetstructure.

CONFORMATIONSOFCYCLOALKANESRingstructuresoftenexistinmultipleconformations.Intheexampleofcyclohexane, the six-membered ring structure is often presented as aflat,planarstructure.However,ifthisdepictionwereaccurate,thebondangleswouldbe120°.Asthebondsincyclohexanearesp3hybridized,the most stable structure would have angles of 109.5°. Thus, beingplanarisnotfavorableforcyclohexane.Toaccommodateoptimalbondangles,cyclohexaneexistsinthechairandboatconformationalisomers(conformers)asshownbelow.Whenringstructuressuchascyclohexanehavesubstitutedgroups(i.e.1,3,dimethylcyclohexane),bothcisandtransconfigurationsresult.Themost stable forms are those that have the groups in the equatorialpositionsduetostericeffects.

Cyclohexaneanditsderivativesareoftendrawnfromatopdownviewas well as the chair view. One common MCAT line of questioningregarding cyclohexane and its derivatives tests the ability to convertfromoneformtotheother.Tointerconvertbetweenthetopdownviewandthechairstructure,wedraw cyclohexane with equatorial and axial groups as shown (“TheWheel”). Notehowtheequatorialandaxialgroupsalternateasyougoaround the wheel. As you observe the two views of cis-1, 2dichlorocyclohexane, convince yourself that the two chlorine atomsbothlieabovetheplaneinthechairstructure.Thus,theyarecis.

ALKENESAlkenes are hydrocarbons that contain double bonds (sp2 carbons).Alkanes are more stable than alkenes due to differences in bondenergies betweenσ andπ bonds. Alkanes only contain C-C andC-Hσ

bonds, but alkenes contain C-C bonds that contain both a σ and a πbond.ComparetheapproximatebondenergiesofanaverageC-Csinglebond (~ 350 kJ/mol), an average C-H bond (~360 kJ/mol), and theaverageC-Cπbond(260kJ/mol).Whenconsidering thesevalues, it isapparentthat theC-CbondinalkanestakesconsiderablymoreenergytobreakrelativetotheC-Cπbondinalkenes.Thus,thealkaneismorestable,butthealkeneismorereactive.

Thepresenceofthedoublebondinanalkeneisindicatedbythe“ene”suffix.Thosealkeneswithtwodoublebondsaredesignatedas“dienes”.Themoleculesarenumberedsuchthatthepositionofthedoublebondhas the lowestnumber(see2-buteneabove). Cyclicalalkenessuchas

cyclopentanearenotnumberedasitisassumedthatthedoublebondisbetweenthe1and2carbonatoms.As for alkanes, the longest chain of carbon atoms that contains thefunctional group is numbered such that the functional group (doublebond)isgiventhelowestnumber.Takethecaseof2-ethyl-1-buteneforexample. Although the longest continuous chain contains 5 carbons(shown in yellow), the longest chain containing the double bondfunctional group is four. Thus, the parental name is butane, and thepropernameis2-ethyl-1-butene.The energy barrier for rotation around double bonds is high (~260kJ/mol).Thisisover20foldhigherthantherotationaroundC-Csigmabonds.Asaconsequence,atomsattachedtothesp2carbonsinalkenesare virtually “locked” in position. However, in response to sufficientlevelsoflight,isomerizationofcis-retinaltotrans-retinalisimportantinvisionandthisisfurtherdiscussedinthecontextofVitaminA.Alkenes such as 2-butene can exist in either the cis or trans form asshownintheimage.Thecisformhasthe“R”groupsonthesamesideofthedoublebondandthetransformhasthe“R”groupsonoppositesidesof the double bond. Such geometric isomers have different physicalproperties including dipole moments as well as boiling points. Theboilingpointsofcis-2-buteneandtrans-2-buteneare3.7°Cand0.9°C,respectively. Unlike cis-2-butene, trans-2-butene has no net dipolemoment.

Insomecases,usingthecisandtranssystemtodesignatealkenesdoesnotwork.Thisoccurswhenfourdifferentatomsarebondedtothesp2carbonsofthealkene.Inthiscase,theZandEsystemisused.Forthis,prioritiesareassignedtoeachoftheatomsattachedtothesp2carbons.Thehighestprioritygoestotheatomwiththehighestatomicnumber.Ifthehighestprioritiesareonthesameside,thenthealkeneisdesignatedas“Z”,andifthehighestprioritiesareonoppositesides,thenthealkeneisdesignatedas“E”.AlkeneReactivityAlkenesareelectronrichcompounds(i.e.nucleophiles)becauseof thepielectronsthatlieaboveandbelowtheplane.Thepibondisreactiveand fareasier tobreak thansigmabonds.Theelectronrichpibond isattracted to positively charged atomic centers (i.e. electrophile). Thisreactionwithalkenesunderscoresacentralthemeinorganicchemistry:the attraction between electron-rich species (nucleophiles) andelectron-poorspecies(i.e.electrophiles).

ElectrophilicadditionreactionsElectrophilic addition across a double bond generates two new sigmabonds from a pi bond. The mechanism of the reaction between 1-propene and HCl is shown below. The pi electrons attack theelectrophileandthisgeneratesacarbocation intermediate.Notice thattwo different carbocation species can be formed: a primary and asecondary.As thesecondarycarbocation is themoststableof thetwo,thisspecieswillbethemoststableintermediateandwillreactwiththechlorine nucleophile to form the product 2-chloroethane. Therefore,becausethereactionthatisfavoredistheonethatcreatesthemost

stable carbocation intermediate, electrophilic addition reactions areconsidered“regioselective”.CarbocationrearrangementsSomemoleculeswithcarbocationintermediateswillrearrangetoformmorestablecarbocationintermediates(i.e.2°!3°).Anexampleofthisis shown below with 3-methyl-1-butene. Note that during therearrangement, ahydrideanion (H:-) ismoved fromone carbon toanadjacent carbon. This is known as the 1, 2 hydride shift. Thenomenclature of using 1, 2 refers to the fact that the shift occurs onadjacentcarbonatoms.

Additionally, methyl groups can also shift to form more stablecarbocations in a process known as a 1, 2 methyl shift. It is really amethide shift. This is shownbelowwith 3, 3 dimethyl-1-hexene.Notethat a secondary carbocation is initially formed, but throughdisplacementofamethylgroupviaashift,atertiarycarbocationwillbeformed. Themajor products are derived from this rearrangement. Asthe tertiary carbocation intermediate is sp2 planar, the chloridenucleophilecanattackfromthetoporthebottomoftheplane.Additionofchlorideatthispositiongeneratesanewchiralcenter.Therefore,themajorproductsconstitutearacemicmixture.

FormationofalkenesfromeliminationreactionsAlkenescanbeformedviaeliminationreactionsthatusealkylhalidesassubstrates.Alcohols canalsobeusedand this isdiscussedbelow.Themechanism of this concerted reaction is shown below. A strong baseabstracts a proton that is in the Beta position relative to the leavinggroup.Thismeansthattheprotonisattachedtoacarbonatomthat isadjacenttotheC-Clbond.Afterwards,theelectrons“collapse”toformanewalkene.During thisprocess, a good leavinggroup (i.e.halogen) iseliminated provided that it is in theanti-conformation (180 degrees

apartasshown).Therefore,eliminationreactionsinvolvingalkenesaresensitivetotheconformationofthesubstrate.ThemoststableproductsformedfollowZaistev’srule.ThisstatesthatthealkenewiththemostR groups (alkyl) attached to the sp2 carbons are the most stable.Further,thetransisomerismorestablethanthecisisomer.Aswewillsee below, alcohols are also good substrates for the formation ofalkenes.Thisoccursthroughdehydrationreactions.ALCOHOLSNomenclature. Alcohols aremolecules that contain anOH functionalgroup (R-OH), a polar non-covalent bond. Monoalcohols have thegenericformulaofCNH2N+1OH.Alcohols are named in a similar manner to alkanes, but moleculescontainingthe-OHgrouphavetheIUPACsuffixof–olprovidedthatthealcohol functional group has the highest priority. In those moleculeswhere theOH functional groupdoesnothave thehighestpriority (i.e.ketone,aldehyde,carboxylicacid),thentheprefix“hydroxy”isused.

Alcoholsareclassifiedas1°,2°,and3°.Theimagebelowshowsseveralofsuchalcohols.

However,thenamesofsomealcoholsdonotconformtosystematicnomenclature.Someexamplesoftheseareshownbelow.

PhysicalPropertiesofalcoholsBoiling Point. Alcohols have relatively higher boiling points due totheir ability to formhydrogenbonds.Appreciate thathydrogenbondsbetweendonorsandacceptorsarecomposedofelectronegativeatoms(i.e.F,O,N),hydrogen,andasecondelectronegativeatom.Inthecaseofalcohols,thehydrogeninthe–O-Hgroup,byvirtueofbeingcovalentlylinkedtotheelectronegativeOatom, isadonor.Acceptoratomscouldbe the oxygen in H2O as well as the carbonyl oxygen in a ketone(R2C=O).

The amino acid side chains of Tyrosine, Serine and Threonine havealcohol functional groups. These side chains are involved in hydrogenbonding as well as other reactions such as phosphorylation andglycosylation.

AcidityofalcoholsAlcoholsareweakBronsted-Lowryacids.R-OH!R-O-+H+

The conjugate base of an alcohol is termed an alkoxide and theconjugateacidof analcohol is calledanoxonium ion (ROH2+).This isderivedfromtheprotonationofanalcoholasfollows:R-OH+H2O! R-OH2++HO-Anyfactorthatgeneratesamorestableconjugatebasewillincreasetheacidityofanalcohol (oranyothermolecule for thatmatter).Commonfactorscontributingtothisincludeinduction,resonance,andsolvation.Aliphatic alcohols have pKa values in the range of 15-20. They aretherefore very weak acids, especially when compared to carboxylicacidsthathavepKavaluesof~2.0.RememberthatthepKaisdefinedas:pKa=-log[Ka]

whereKadescribesthegenericaciddissociationreaction:HA=H++A-Ka=[H+][A-]/[HA]HA=conjugateacid;A-=conjugatebaseLargerKavaluesmean thatmoreproducts are formedat equilibrium.Therefore, relatively smaller pKa values are indicative of relativelystrongeracids(andcorrespondingweakerconjugatebases).In contrast, aryl alcohols (i.e. those containing a benzene ring) havelowerpKavaluesrelativetotheiraliphaticcounterparts.Thisisduetoresonance stabilization of the conjugate base. Additionally, thepresenceofadditionalfunctionalgroupscandrasticallyalterthepKaasshown below. Note that the electronwithdrawing groups attached tothebenzene ring reduce thepKavalues,meaning that thepresenceofsuch groups stabilizes the conjugate base. This is both an inductiveeffectandaresonanceeffect.

The immediatestericenvironmentsurroundingtheoxygenatomofanalcohol influences its physical properties. This includes boiling pointsand acidic strength. A significant physical principle behind acidicstrength is the solvation effect, the ability of water to interact andstabilizethealkoxideanionupondissociationoftheprotonfromtheOHgroupofthealcohol.Notethatduetostericeffects,aprimaryalcoholis

moresolvatedthantertiaryalcohols.Deducefromthisthatmethanolismoreacidicthan2-methylpropanol.

SynthesisofalcoholsBiologicalsynthesis.Alcoholsaresynthesizedasintermediatesinfattyacidmetabolismandare synthesized as end products in some forms of fermentation.Alcoholsaregeneratedasintermediatesinthecontextofthecatabolismof fatty acids (Step 3) through a hydration reaction. In this reaction,water is added across the double bond of an alkene:H2O+alkene=alcohol

The reverse reaction occurs during fatty acid synthesis and is anexampleofadehydrationevent.Thesereactionsarecommoninbiologyand increase the bond order as a compound with a double bond(alkene)isgeneratedfromareactantwithasinglebond.FattyacidmetabolismisanimportanttopicontheMCATaswellasinmedicine.Becausefattyacidsynthesisisessentiallythereversepathwayofcatabolism,alcoholsarealsogeneratedinthispathway(notshown).Fattyacidcatabolismoccursinthemitochondriaandrequiresoxygen.Fattyacidsderivedfromadiposetissuearecatabolizedinvarioustissuessuchastheliver.Theprocessissummarized:Step1.ThefattyacidisinitiallyactivatedtogenerateafattyacylCoA.Step2.Theβcarbonisoxidizedtothelevelofthealkene.Step3.Additionofwater(hydration)tothealkenecreates3-hydroxyacylCoA,analcoholintermediate.Step4.Oxidationofthealcoholgeneratesaketone.Step5.AβketothiolaseenzymeusesCoASHtogenerateAcetylCoAaswellasafattyacidofN-2carbons.

FermentationFermentation isananaerobicprocess thatoccurs inbothbacteriaandyeast. Ethanol is the end product of fermentation in yeast and itsformation occurs through the partial oxidation of glucose as shownbelow. Onemoleof glucose is converted into2molesofpyruvateviaglycolysis. Pyruvate decarboxylase releases CO2 to generateacetaldehyde. Alcohol dehydrogenase then reduces the aldehyde toethanol.

In humans, alcohol is metabolized to acetaldehyde by the action ofalcohol dehydrogenase. The expression of alcohol dehydrogenaseallowsfortheconsumptionandmetabolismofalcohol.ManypeopleofAsiandescenthaveavariantofthisenzymethatcausesthebuildupofpotentially toxic levels of acetaldehyde that is causal for the “alcoholflush reaction”. Therefore, alcohols undergo oxidation reactions.Primary alcohols such as ethanol are metabolically oxidized intoaldehydesthatcanbefurtheroxidizedintocarboxylicacids.Secondaryalcohols are oxidized into ketones and tertiary alcohols cannot beoxidizedasshownbelow.In the laboratory, 1° alcohols canbe oxidized to the aldehyde state ofoxidation via mild oxidizing agents such as PCC (Pyridiniumchlorochromate). However, strong oxidizing agents such as potassiumpermanganate (KMnO4) and potassium dichromate (K2Cr2O7) canoxidizethe1°alcoholtothelevelofthecarboxylicacid.

Alcoholsandsubstitutionreactions(SN1andSN2)Alcohols undergo substitution (and elimination) reactions. We willexaminebothSN1andSN2mechanismsastheyarespecificallylistedintheAAMCContentGuideline.Elimination reactionsarenot specificallylisted in the Content Guideline, so they will be deemphasized here.However,theywerediscussedaboveinthecontextofalkenes.Inmanycases, substitution reactions compete with elimination reactions.However, in biological enzymes one is preferred over the other giventhatenzymescatalyzethereactions.Althoughothercompoundsbesidesalcohols (i.e. alkyl halides) undergo SN1 and SN2 reactions, we willintroducetheconceptintermsofalcohols.Youshouldbeabletoapplytheseprinciplestoadditionalreactionsoutsideofalcohols.SN1 reactions (Substitution nucleophilic first order reactions) occurthroughtheformationofacarbocationintermediate.Theratelawcanbe written as r =k[electrophile) as the formation of the carbocationelectrophileistheratelimitingstep.Therefore,thesereactionsarefirstorder.Recall thatelectrophilesusuallyhaveapositivecharge(fullorpartial)and love electrons. As they can accept electrons from nucleophiles,electrophilescanalsobethoughtofasLewisacids.The mechanism of a generic SN1 reaction is shown below with a 3°alcoholbondedtothreedifferentalkylgroups(R1,R2,andR3).Notethatthecarbonbondedtothealcoholicgroupisasymmetric(orchiral).Thiswillhaveimplicationsforthestereochemistryoftheproduct.Alcohols are notoriously poor leaving groups as HO- is a strong base.However, when the reaction is performed at low pH, the alcoholbecomesprotonated.ThiswillgeneratetheH2OleavinggroupthatisabetterleavinggroupthanOH-.Recallthattheweakestbaseisalwaysthebest leaving group. This is becauseweakbases hold electronsweakerthanstrongbases.Thereforethebondwillbebrokeneasier.SN1 reactions are performedwithpolar protic solvents. Appreciatethatproticsolventsarecapableofforminghydrogenbondsastheyhavea hydrogen atom bonded to a nitrogen or an oxygen atom. The polar

protic solvent stabilizes the carbocation and provides the energy todissociatetheleavinggroupfromthetertiarycarbon.InmanycasesforSN1reactions,thenucleophileisthesameasthesolvent(solvolysis).The carbocation has an empty p orbital and is therefore planar instructure(i.e.sp2hybridized).Asshown,thenucleophile(i.e.negativelychargedhalogen) canattack theplanar carbocation intermediate fromeither the top or the bottomof the plane (i.e.wedged or hatched linestructure).Asaresult twodifferentbondsare formedwiththecarbonatom(i.e.enantiomers=racemicmixture).

Although SN1 reactions proceed through carbocation intermediates,primary, vinyl, and methyl carbocations rarely, if ever, undergo SN1reactionsduetotheirinstability.Therelativestabilityofcarbocationsisshown below. Note that carbocation stability is enhanced by thepresence of alkyl substituents as they tend to donate electrons. Thisdecreases the positive charge on carbon, effectively making it moreelectro neutral. Further, resonance contributes to the stability ofcarbocations as seen for the primary benzyl and primary allyliccarbocations.

CarbocationrearrangementsinAlcoholreactionsWehaveseenthatsomemoleculeswithcarbocationintermediateswillrearrangetoformmorestablecarbocationintermediates(i.e.2°!3°).Anexampleof thiswithalcohols isshownbelow.Notethatduringtherearrangement, ahydrideanion (H:-) ismoved fromone carbon to anadjacent carbon. This is known as the 1, 2 hydride shift. Thenomenclature of using 1, 2 refers to the fact that the shift occurs onadjacent carbon atoms. Additionally, methyl groups can also shift toformmorestablecarbocationsinaprocessknownasa1,2methylshiftandwasshownabovewithalkenereactivity.Thebottomlineisthat

when you have a reactionwith a carbocation intermediate, youmustexamineitspotentialtorearrangetoamorestableintermediate.SN2ReactionsSubstitution nucleophilic second order (SN2) reactions occur withalcohols(aswellasothermoleculessuchasalkylhalides).Theratelawiswrittenas:r=k[electrophile][nucleophile]The reaction is considered a “concerted” reaction because thenucleophile attacks the electrophilic carbon at the same time that theleaving group is ejected from the molecule. Therefore, a pentavalentintermediateexistsforabrieftime(notshown).SN2reactionsoccurinpolaraproticsolvents.Inthiscase,theacidicpHallowsforprotonationofthealcohol.AswesawwiththeSN1reaction,

thiswillgenerateabetter leavinggroupthantheHO- leavinggroup.Aproticsolventwouldbeexpectedtosolvatethenucleophileandhinderitsabilitytoattacktheelectrophiliccenter.Asshowninthefigure, thenegatively charged nucleophile attacks from the opposite side of theleaving group (“backside attack”). As a result, the SN2 reactionworksbestwhenthepathtotheelectrophiliccarbonisleasthindered.Thatis,sterichindrancewithalkylgroupsimpedesSN2reactions.Therefore,incontrasttoSN1reactions,whicharefavoredinpolarproticsolvents,SN2reactions proceed in polar aprotic solvents and rarely, if ever, occurwith3°carbonatoms.

AsisthecaseforSN1reactions,therearestereochemicalconsiderationsforSN2reactions. Duetothebacksideattackofthenucleophile,anewbondisformedthatisoftheoppositeconfigurationoftheleavinggroup(seefigureabove).Therefore,SN2reactionsproceedthrough“inversionofconfiguration”.Intheexampleshownhere,theelectrophiliccarbonischiralastherearefourdifferentsubstituentgroupsboundto it(Ethyl,Methyl, Hydrogen, and OH). The resulting SN2 product will be ofoppositeconfigurationofthestartingreactantmolecule.AcomparisonofSN1andSN2mechanismsisshownbelow.

Additionalalcoholreactions1.SynthesisofAlkylHalidesAlcohols can be converted into alkyl halides through either of tworeactions:A) Thereactionbetweenanalcoholand thionyl chlorideproducesanalkylhalide.R-OH+SOCl2!R-Cl+SO2

B)Thiscanalsobeachievedwithphosphoroustrihalidesasshownwithphosphoroustrichloride:

R-OH+PCl3!R-Cl+HOPCl2

2.PreparationofMesylatesandTosylatesMesolytes and Tosylates are specifically listed in the AAMC MCATContentOutline.Theyareintimatelylinkedtothechemistryofalcohols.Ingeneral,alcoholsarepoorleavinggroupsbecausethehydroxylanionisa strongbase.Besidesprotonation,anotherway to convertalcoholsintogoodleavinggroupsistogenerateorganosulfonates. Incontrastto the SN1 and SN2 reactions, these reactions do not change anystereochemistry.Starting with an alcohol and eitherMesyl chloride (MsCl) or Tosylchloride(TsCl)asshownintheimage,anactivatedalcoholisgeneratedwith the OH nucleophile and the sulfur electrophile. The reaction isusuallyperformedwithpyridineandtheproductsaresulfonateestersthat are derivatives of sulfonic acid, a strong acid with a pKa ~ -3.0.This is 100,000 times more acidic than a carboxylic acid with a pKa~2.0! Addition of nucleophile to mesylates (OMs) or tosylates (OTs)readilycreatesasubstitutionproduct.Thisisbecausethesulfonateisagreatleavinggroupasitistheweakconjugatebaseofastrongacid.

ProtectionofalcoholsProtectionof alcohols is specifically listed in theAAMCMCATContentGuide(Downloadacopyfromoursite).Additionofaprotectinggroupto an alcohol, or any other functional group for that matter, is atemporarystepinasynthesis.Theprotectinggroupisremovedlaterinthesynthesis.Protectinggroupsareaddedtoafunctionalgroupwhenitisincompatiblewithasetofreactionconditions.Therefore,protection,asitsnamesuggests,canbeusedtomaskafunctionalgroupsuchasanalcohol fromperforminganundesiredsidereaction.Protectinggroupsmask functional groups and ensure chemo selectivity in organicsynthesis.Alcohols are versatilemolecules. In addition to participating in redoxreaction,alcoholscanactnucleophileswhendeprotonatedand leavinggroupswhenprotonated.Therefore,protectionofalcoholsisimportantinorganicchemistryreactions.Therearemultipleways toprotect alcohols.Oneexample is shown inthefigurebelow.PanelAshowsthedesiredreactionbetweenanalkynecarbanion and a molecule with two functional groups: a halogen(chlorine)andaprimaryalcohol.ThedesiredproductisformedthroughanSN2mechanismasshownbythearrow.However,themajorproduct(Panel B) is a closed heterocyclic structure that results from anintramolecularnucleophilicattack.So,howcanthedesiredproductbemade?TheansweristoprotectthealcoholandthisisshowninPanelC.NotehowtheprotectinggroupisatertiaryalcoholthatformsacarbocationthatengagesinaSN1reactionwith the primary alcohol of the reactant molecule. The product is atrimethyl ether linkage (R-O-R), a stable bulky group that masks thealcohol. Now, this protectedmolecule can be reactedwith the alkynecarbanionunderSN2conditions.Afterreleaseoftheprotectedgroupviaacidandheat,thedesiredproductisformed.

CARBONYLCHEMISTRYThecarbonylfunctionalgroupiscommonlyseeninbiomolecules. Dueto the strong electronegativity of oxygen, the generic C=O functionalgroup is a polar covalent bond. This dipole moment generates apotentiallyelectrophiliccenteratthecarbonatom.

AldehydesandKetonesThe general formula for aldehydes and ketones is shown below.AldehydeshaveoneRgroupandketoneshavetwoRgroupsattachedtotheircarbonylcarbonsasshown.

NomenclatureAldehydesarenamedwith the suffix “al” andketonesarenamedwiththe “one” suffix. Forketones, the carbonyl carbonshouldbe specifiedunless it is in a cyclical structure. In this case, the carbonyl carbon isassumedtobeinposition1.Someexamplesareshownbelow.Notethattheubiquinonemoleculehasbeentruncatedforsimplicity.

PhysicalPropertiesandSynthesisBoth aldehydes and ketones are hydrogen bond acceptors, oftenwithaminesandalcohols.Thisisshownbelow.Notetheoptimal180°bondangles between the donor and the acceptor. Aldehydes and ketoneshave lower boiling points relative to alcohols as the R-OH group canparticipateasbothdonorsandacceptors.

ReactivityOxidation-ReductionAswe saw earlierwith alcohols, aldehydes and ketones participate inoxidation-reduction reactions. Reducing agents such as LiAlH4 takeketonestoaldehydesandevenalkanes.One important redox reaction concerns ubiquinone, a ketone in theelectron transport chain. Also known as coenzyme Q, recall that thisimportant molecule is central to the electron transport chain andaccepts and donates electrons. Specifically, ubiquinone forms part ofelectron transport chain center II. Med-Pathway covers electrontransport in physical and chemical detail in the Biochemistry andThermodynamicsandKineticsdiagnosticmodules.

Keto-enoltautomersHydrogenatomsbondedtoalphacarbonsinketonesandaldehydesareacidicandparticipateinimportantbiologicalreactions, includingketo-enol tautomerizations and aldol condensation reactions. Note that thehydrogen atom immediately bonded to the carbonyl carbon ofaldehydesisnotacidic.As shown below for acetone, the acidic alpha hydrogen is abstractedfrom theketonemoleculebya strongbase (i.e. hydroxideor ethoxideanion).Thisgeneratesacarbanionthat isstabilizedbyresonancewiththecarbonylgroupasshown.Theresultingenolateanioncanpickupaprotonfromthemediatogenerateanenol.Therefore,moleculessuchasacetone can exist in a keto-enol equilibrium as shown. Note that theketo and enol forms are constitutional isomers and are calledtautomers.Inmostcases,theequilibriumisheavilyshiftedtowardstheketo form, but there are some exceptions. Importantly, phenolmostlyexistsintheenolformasthisformismoststabilizedbyresonance.Theketotautomerdoesnotenjoytheresonancestabilizationofthebenzenering.Inadditiontoresonance,hydrogenbondingcanalsostabilizetheenolformovertheketoform.

Aldolcondensationreaction

Thealdolcondensationreactionexploitsthechemistryoftheacidityofthe alpha hydrogen atom of either an aldehyde or ketone. In thisreaction,theenolateanionreactswithacarbonylcompound(aldehydeorketone)togenerateeitheraβ-hydroxyaldehydeorβ-hydroxyketone.After dehydration by heat (Step 3), an α, β unsaturated product (i.e.conjugatedeneone)isgenerated.Thereactionschemeisshownbelowforthealdolcondensationreactionofacetaldehyde.Step1 isperformedinthepresenceofastrongbaseat5°C.Thebasepullsofftheacidicalphahydrogenandgeneratesaresonance-stabilizedcarbanion that is a strong nucleophile. This targets the electrophiliccarbonylofanothermoleculeofacetaldehydeinsolution.Step 2 generates a β-hydroxyaldehyde. Upon heating, the moleculeloseswater(hencecondensation)toformtheα,βunsaturatedproduct(Step 3). Note that in the aldol condensation, the total number ofcarbons in the product is the sum of the number of carbons thatparticipateinthereaction.Thiswillcomeinhandywhenyouaretryingtofigureouttheproductsofanaldolcondensation.

RetroaldolcondensationThealdolcondensationreactionisreversible.Suchareaction,theretroaldol condensation, is specifically mentioned in The AAMC ContentGuide. A classic example of this reaction (shownbelow) occurs in theglycolytic pathway where the enzyme aldolase uses the substrateFructose 1, 6 biphosphate (F 1, 6-P2) and converts it into two smallcarbohydrates:3-phosphoglyceraldehyde(G-3P)anddihydroxyacetonephosphate(DHAP).Recallthattheseintermediatesarefurtheroxidizedand are precursors to pyruvate. As enzymes such as aldolase alsocatalyzethereversereactionduringtheprocessofgluconeogenesis,thealdolcondensationgeneratesF1,6-P2fromG-3PandDHAP.

Kineticandthermodynamicenolates.ThistopicfrequentlyappearsontheMCAT.WepresentithereaswellasintheThermodynamics/Kineticsmodule.

Reactionsthatproducemultipleproductscanhavebothkineticallyandthermodynamically controlled products. The most rapidly formedproductisthekineticproductandthemoststablyformedproductisthethermodynamic product. Through controlling various parameters (i.e.temperature, ionic strength, buffer, etc.), the reaction can be eitherkineticallyorthermodynamicallycontrolled.

Shown above is a typical MCAT style problem with a cyclical ketonemolecule.Therearetwopossibleproducts.Canyoutellwhichoneisthethermodynamicallycontrolledproductandwhichoneisthekineticallycontrolledproduct?

Notethattheproductsproducedfromeachreactionareenolates,andasthename implies, they aremolecules thathaveboth an alcohol groupandanalkenegroup.Therefore,arrivingatthecorrectanswerrequiresthatyoubringinsomeknowledgeofalkenechemistry.

As shown in the image, themost substitutedalkene is themost stableproduct as it forms the most stable enolate. In contrast, the kineticenolate is the molecule that has the most easily accessible alphahydrogenatoms.Thatis,thebasecanpulloffaprotonfastestfromtheleast stericallyhinderedmolecule.Note thepresenceof the additionalmethylgroupstericallyhindersaccessibilitytothealphaproton.

FormationofacetalsandhemiketalsAsshownbelow,aldehydesandketonesundergonucleophilicattackasthe partial positive charge on the carbonyl carbon is an electrophiliccenter.Thisgeneratesatetrahedralintermediate(PanelA)thatformsacentralthemeinthechemistryofthecarbonylfunctionalgroup.Asshownintheimage,whenthenucleophileattackingthealdehydeorthe ketone is an alcohol, hemiacetals andhemiketals are produced. Ingeneral, theseareunstablecompounds,but furtheradditionofalcoholgeneratesthestablecompounds,acetalsandketals.

Hemiacetals and acetals are commonly scene in the context ofcarbohydratechemistry.Asshown,glucoseisinahemiacetalform,butmaltose, a disaccharide of glucose, consists of acetal linkages in theglycosidicbond.Thiswillbeelaboratedoninthecarbohydratesection.

The formation of gemdiols and cyanohydrins are two additionalnucleophilicreactionswithaldehydesandketonesthatarelistedontheAAMCchecklist.Bothoftheseareshownbelow.

CHAPTERIIFormationofiminesandenaminesImines are important biological molecules that are formed from theaddition of an aldehyde or ketone to a primary amine. An enamine isformed in the presence of a secondary amine. This is a condensationreaction (loss of water) that occurs in a weakly acidic buffer. Anexampleisshownbelowwithlysine(1°amine)andacetaldehyde.

Themechanismof imineformationisshownbelow.Notethatallstepsarereversible.Forsimplicity,thelysinesidechainisdenotedasR-NH2.NotethatundernormalconditionsatpH=5.0,theprimaryaminesidechainoflysinewouldexistlargelyintheprotonatedformasthepKaofaprimary amine is ~11.0. However, as lysine is part of the primarystructure of proteins, the pKa values can vary widely, meaning thatmoreoftheunprotonatedaminewouldbeavailableforthenucleophilicattackthatisessentialtothemechanismofimineformation.

Step1:Thecarbonylgroupofthealdehydeisprotonated,generatingamoreelectrophiliccarbonylcarbonthatisattackedbytheunprotonatedlysine.Atetrahedralintermediateisformed.Step2:Thetetrahedral intermediatehas itsalcoholgroupprotonated,turningtheweakOHleavinggroupintothestrongleavinggroupwater.In addition, a conjugate base pulls off a proton from the quaternaryamine.Step 3: The tetrahedral intermediate collapses, kicking outwater (i.e.condensation).

Steps4,5:Theprotonatedimine(Schiffbase)thatformsuponcollapseofthetetrahedralintermediateisinequilibriumwiththeunprotonatedimine,thefinalproduct.NotetheR-C=N-Rcharacteristicofimines.EnamineformationandreactivityEnamines are formed from aldehydes/ketones and secondary amines.When the lone pair of electrons on nitrogen is donated, a resonance-stabilizedcarbanionisformed.Therefore,enaminesarereactiveattheα carbon. Think of enamines as you do for enolates: resonancestabilized carbanions. These carbanions can attack variouselectrophilesandperformavarietyofreactionsincludingacylationandalkylation.

CYANOHYDRINREACTIONCyanohydrins are specifically listed in the AAMC MCAT ContentGuideline.Cyanohydrinsareformedthroughthereactionofthecyanideanion and an aldehyde or ketone. They can also be formed throughnitriles, a class of functional groups that used to be called cyanides.Cyanohydrins are intermediates in the Strecker synthesis of aminoacids. The formation of a generic cyanohydrin from a ketone andpotassiumcyanideisshownbelow.

CarboxylicAcids&TheirDerivativesCarboxylic acids have the general formula (R-COOH) and they areusually namedwith the suffix “oic”. When ionized, the suffix “ate” isoftenused.Thus,pyruvate is theconjugatebaseofpyruvicacid.Someexamplesareshownbelow.Due to resonance stabilization after ionization, carboxylic acids havehigherboilingpoints to comparablealcohols.Further, carboxylic acidsparticipateinhydrogenbonding.

DecarboxylationandcarboxylationreactionsDecarboxylation and carboxylation reactions occur at multiple placesthroughout metabolism. In most cases, enzymes catalyze thesereactions. Thiamine pyrophosphate (TPP: Vitamin B1) and pyridoxalphosphate (Vitamin B6) are co-factors that participate indecarboxylation whereas biotin (Vitamin B7) performs carboxylationreactions.Oneimportantcarboxylationreactionoccursduringfattyacidsynthesis.In this pathway, acetyl CoA is converted into malonyl CoA by theenzymeacetylCoAcarboxylase.Thisreaction is thecommittedstep infattyacidsynthesisandoccursinanATP-dependentmanner.Notehowacetyl CoA carboxylase uses bicarbonate as the source of the CO2 ispositivelyregulatedbyinsulinandnegativelyregulatedbyglucagon.

Two decarboxylation reactions are shown below. In Panel A, thespontaneousdecarboxylationofacetoacetate,aketonebodyproducedintheliver,toacetoneisshown.AcetoneisavolatilesubstancethatisoftendetectedinthebreathofpeoplewhohavetypeIdiabetesmellitus.Note thatacetoacetate isaβ-ketoacid.Decarboxylationofβ-ketoacidsoften occurs spontaneously because the carbanion that results afterdecarboxylationisstabilizedbyresonance.Panel B shows elements of the pyruvate dehydrogenase complex, agroupofmitochondrialenzymesthatoxidizespyruvateintoacetylCoA,a two-carboncarrierofactivatedcarbonatoms.Note that thereactionutilizesanE1enzymethat isboundto thiaminepyrophosphate(TPP),alsoknownasvitaminB1.

CarboxylicacidsDerivativesTherearenumerouscarboxylicacidderivatives.TheimportantonesfortheMCATareshownbelow.

A.AcylHalidesAcylhalidesarenamedviathe“yl”suffixandareformedviaalcoholsaswehaveseenabove in thediscussiononalcohols.Thionylhalidesandphosphorous trihalides can be used with alcohols to generate thecorrespondingacylhalide.Acyl halides are very reactive as the covalently linked halogen is astrongleavinggroup.Fourreactionswithamodelacylhalideareshownbelowintheimage.Themechanismfortheformationofeachcarboxylicacid derivative is analogous and proceeds through a nucleophilicsubstitution-eliminationreaction.Inthisreactionscheme,anucleophile

(i.e. hydroxide) attacks the electrophilic carbon in the carbonyl group.Thisformsatetrahedralintermediatethatcollapses.Asbromideistheweakestbase,itisthebestleavinggroup.Asaresultacarboxylicacidisformed.Theonlymechanismshownintheimageisfortheconversionof acyl halides into carboxylic acids. The formation of anhydrides,esters,andamidesoccursthroughasimilarmechanism.

B.AcidAnhydridesThe synthesis of acetic anhydride is shown in the image below alongwith the reactionof acetic anhydridewithmethanol.Note that for thenomenclature of anhydrides, the name of the acid is replaced withanhydride for symmetrical anhydrides (i.e. acetic anhydrides). Forasymmetricalanhydrides,theacidnamesareusedinalphabeticalorderfollowedbyanhydride.As seen above for acyl halides, anhydride synthesis as well asdegradation occurs through a nucleophilic substitution-eliminationreaction.The imagealsoshows thesynthesisofaceticanhydride from

two carboxylic acids through such a mechanism. Likewise, for thereactionofaceticanhydridewithmethanol,anucleophilicsubstitution-elimination reactionoccurs to formanacidandanester. Amidesandesterscanalsobeformedfromanhydridesbyreactingwithamines(notshown).

C.EstersFor naming esters, the “ate” suffix is used. The group attached to thecarbonyl oxygen is named first and then the group attached to thecarbonylcarbonisthennamedwiththe“ate”suffix.Esters are important biological molecules especially in the context offatty acid and triglyceride metabolism. Although a fatty acid plus analcohol can form an ester, biological systems activate fatty acidswithATPto formCoenzymeA(CoAorCoASH)derivatives thatareactuallythioesters.YouarelikelytoencounterestersontheMCATinthecontextoffattyacidmetabolism.Thesynthesisofanesterfromafatandanalcoholisshownbelow.Thisstepistheinitialoneinthesynthesisoftriglycerides.Notethatthefattyacidispalmiticacid(C16:0).Thefattyacidsynthaseenzymesynthesizesthismetabolite.However,inbiologicalsystemsfattyacidsareactivated

by thiokinases. These enzymes use ATP and Coenzyme A (CoA orCoASH) to generate thioesters, in this case palmitoyl CoA. Next,glycerol-3 phosphate, an activated form of the glycerol alcohol,performs a nucleophilic-substitution reaction that generates the ester.Thereactionisactuallya“transesterificaton”reactionasanewesterisgenerated fromanotherone.After twomoreroundsofesterificationatriglyceride is made. Triglyceride synthesis occurs in the liver,intestines,andadiposetissue.

Esters undergo substitution-elimination reactions with a number ofmolecules including alcohols, amines, and water. The reaction

mechanisms are similar in that a nucleophile attacks the electrophiliccarbonyl of the ester, generating a tetrahedral intermediate thatcollapsesandkicksoutaleavinggrouptorestorethecarbonylgroup.Themostcommonreactionwithestersthatyouseewillbehydrolysis,especially of triglycerides. This and two other reactions are shownbelow. Observe that water is a good nucleophile with its lone pair ofelectrons.Theseelectronsattacktheelectrophiliccarbonyloftheesterlinkage.Afterformationandcollapseofthetetrahedralintermediate,analcoholleaves.Therefore,thegenericdescriptionofthehydrolysisofanesterthatyouwillnotforgetis:ESTER+H2O=ACID+ALCOHOLImportantly,someestersoccurinacyclicalformat.Suchstructuresareknown as lactones. Their hydrolysis also produces an acid and analcohol,butbothfunctionalgroupsareonthesamemoleculeasshown.Thethirdreactionshowsthehydrolysisofatriglyceride.Thisoccursinadipose tissue in response to low blood sugar (i.e. running, fasting,sleeping).Undertheseconditions,epinephrinestimulatestheactivityofhormone sensitive lipase, an enzyme that hydrolyzes triglyceridesintofattyacids(R-COOHandalcohols(glycerol).

ClaissenCondensationReactionInaddition tonucleophilic-substitutioneliminationreactionsobservedforhydrolysisofesters, estersalsoundergo theClaissencondensationreaction. As observed above for ketones and aldehydes in the Aldolcondensation reaction, the Claissen condensation exploits the acidic αhydrogen atoms present in esters. After a strong base pulls off thisacidic proton, a resonance-stabilized carbanion acts as a nucleophilethat attacks a second ester molecule. A tetrahedral intermediate isformedanduponcollapsekicksoutanalcohol in theprotonated form(R-OH).

AmidesAmidescanbelinearorcyclicalstructures. Cyclicalamidesareknownas lactams. Amide nomenclature replaces the “oic” in acid with thesuffix-amide.Thecarbonylcarbonisassumedtobeinthe#1position.Secondaryamidesaredesignatedwithanuppercase“N” toshowthatthe alkyl group is bonded to the nitrogen. The alkyl group is named.SomeexamplesareshownbelowintheFormationofAmidesschematic.

Aswe have seen for the formation of othermolecules, amides can beformed by nucleophilic substitution-elimination reactions. Amides canbe synthesized from primary and secondary amines when combinedwith esters, acyl halides, acid anhydrides, and esters. Amides are notnormally synthesized from carboxylic acids as an acid plus a base(amine)willgenerateasalt.Panel A in “Formation of Amides” shows the reaction mechanismbetweenaprimary amine (Ethylamine) andanester (Methyl acetate).Note that the acid catalysis protonates the carbonyl carbon aswell asthe oxygen in the leaving group. Protonation of the carbonyl oxygengenerates a stronger electrophilic carbon. The lone pair of electronsresiding on the ethylamine nucleophile attacks this carbon atom andforms a tetrahedral intermediate. Upon collapse of the tetrahedralintermediate, methanol leaves and the amide linkage is formed. Notethatprotonationoftheoxygenintheesterlinkagegeneratesmethanol(CH3OH)istheleavinggroupratherthanthemethoxideanion(CH3O-).As methanol is a weaker base than methoxide, it is a much betterleavinggroup.Thus,acidcatalysisgeneratesbothabetterelectrophile

fortheamineaswellasabetterleavinggroupduringtheformationoftheamide.Panels B and C illustrate the formation of esters from primary andsecondary amines with acetyl chloride and acetic anhydride,respectively.ThemechanismsofthesereactionsarenotshownbutareanalogoustothereactionshowninPanelA.AmidesandProteinstructureAmides are very important biological molecules, especially in thecontext of protein structure and function. This is because the peptidebondthatformsthebackboneofproteinstructureisanamidelinkage.Peptidebondsare synthesizedduringribosomal translation. Due totheformationofresonancestructures(seeimage),peptidebondshavepartial double bond character. As rotation is limited around doublebonds, peptide bonds adopt a planar structure that usually favors thetranspositionasshownwiththearrowspointinginoppositedirections.

HydrolysisofPeptideBondsProtease enzymes catalyze the hydrolysis of amide (peptide) bonds.Belowisahypotheticalschemeforacid/basecatalyzedhydrolysisofapeptidebondusingtwokeyactivesiteresidues:lysine(Lys)andserine(Ser).Inthisscenario,anunchargedlysinesidechainactsasabasebyaccepting a proton from water, generating the stronger, negativelycharged hydroxyl nucleophile. As shown, the HO- nucleophile attacksthe electrophilic carbon at the carbonyl group of the peptide bond,formingatetrahedralintermediate.Notethat theserineresidue formsahydrogenbondwiththecarbonyloxygenandhelpskeepthepeptidebondsituatedintheactivesiteoftheenzyme.Duringthecollapseofthetetrahedralintermediate,thenewlyprotonated lysineresiduebehavesasaBronsted-Lowry acid throughdonating its proton to the nitrogen atom in the peptide bond. Thisgenerates a stronger leaving group (NH2 vs NH-). Recall that the bestleaving group is always the weakest base. (Weak bases do not shareelectronsverywell,makingthebondeasiertobreak.)Withoutreceivingtheprotonfromlysine,theleavinggroupwouldbeR1NH-,butwiththeaddition of the proton, the leaving group becomes R1NH2, a neutralspeciesandweakerbasethanR1NH-.

RelativereactivityofcarbonylcompoundsWe have examined four types of carbonyl compounds: acyl halides,anhydrides, esters, and amides. Each class of compound undergoesnucleophilic-substitutioneliminationreactionsasdescribedabove.Therelative reactivity of these derivatives is shown below. As discussedpreviously,theweakestconjugatebaseisalwaysthebestleavinggroup.Weakbasessuchaschloridearestableleavinggroupsandhavestrongconjugateacids(HClisastrongacid).Incontrast,strongbasessuchasR-NH-arereactiveandarepoor leavinggroups.Therefore,amidesarethemoststableofthecarbonylderivativecompounds.

ChapterIIICarbohydrates,Lipids,Steroids,andVitaminsCarbohydratesCarbohydrates are molecules that usually have the general formulaCNH2NON.Theyareobviouslyimportantinmetabolism.Thissectionwillfocus on their structures and reactivity. Common carbohydrates aresugars,starches,andcellulose.Theyusuallycontainaldehydeorketonegroups and exist as monomers (monosaccharides) or polymers(polysaccharides).Monosaccharidescannotbehydrolyzed intosmallerunits and are therefore the smallest of the carbohydrates.Polysaccharides are monomers linked together through glycosidicbonds.Carbohydratesareclassifiedbythreemajorcriteria:1)Thetypeofcarbonylgroup.Ifthecarbohydratehasanaldehydeorketone group, it is called an aldose or ketose, respectively. Somecarbohydratesalsocontainadditionalfunctionalgroups(acids,amides).2)Thenumberofcarbonatomsinthemolecule.Carbohydrateswithfive and six carbons are called pentoses and hexoses, respectively. Apentoseisoftenreferredtoasafuranoseandahexoseisoftenreferredtoasapyranose.3) Chiral handedness. Carbon atoms in carbohydrates are oftenasymmetric in that they are bound to four distinct substituents. Thismeansthat theyarestereocenters thatcanexist ineitheranRoranSconfiguration. We will not go into depth with respect to absoluteconfiguration here. However, chirality is extensively covered in theStereochemistryandIsomersmoduleofMed-Pathway.Thesystemfornamingcarbohydratesisbaseduponchiralityandusesthe D and L nomenclature. The assignment of D and L refers to thestereochemicalassignmentoftheasymmetriccarbonfurthestfromthe

carbonyl group (carbon #1) in the Fischer projection. This is shownbelowforthetwoisomersofglyceraldehyde,thesimplestcarbohydrate.IftheOHgroupattachedtothepenultimatecarbonisontherightside,thenthecarbohydrateisdesignatedas“D”.Ifitisontheleftside,thenitisdesignatedas“L”.DandLglyceraldehydearemirrorimagesofeachotherandarethereforeenantiomers.

RelationshipbetweenR/Sand,+and–,andd/lsystemThenomenclatureofcarbohydratescanbetricky.Recallthatchiralmoleculesrotatetheplaneofpolarizedlightineitheraclockwise(+)orcounterclockwise(-)manner,whichis linkedtothed(dextrorotatory)and l (levorotatory) nomenclature. This is used to distinguish how achiralmolecule rotates theplaneofpolarized light.The (+)-dand(-)-lsystemdescribeshowanentiremoleculeinteractswithpolarizedlight.In contrast, the R and S system defines the absolute configuration ofindividual chiral centers within a molecule. There is no relationshipbetweenthetwonomenclaturesystems;meaningthatachiralmoleculewith a single stereocenter assigned R does not indicate how thismoleculewillrotatetheplaneofpolarized light(+or -). Thismustbedeterminedexperimentally.

Further, when considering the d and l system, it is necessary todistinguish themeaning of the lower case nomenclature (direction ofrotation in response to polarized light) to the uppercase D and Lnomenclature.UppercaseDandLnomenclaturereferstoanalternativesystem for designating absolute configuration for amino acids andsugars.Therefore,DandL isomerscanalsobeassignedthroughtheRandSsystembyapplicationoftheCahn-Ingold-Prelogrules.Historically,whenglyceraldehydeisdrawninaFischerprojection,iftheOHgroupisdrawnontherightthenthemoleculeistheDisomer.IftheOHisdrawnontheleft,thenthisrepresentstheLisomer.Asstated,DandLisomersarealsoknownasenantiomers.IfthechiralcarbonsinDand L glyceraldehyde were assigned an absolute configuration basedupontheCahn-Ingold-Prelogrules,thenitisusuallythecasethattheD isomer represents the R configuration and the L enantiomerrepresents the L configuration. However, you cannot always assumethatDandLconfigurationswillnotequatetoRandSassignments.Theconventionforaminoacidssuchasserineisslightlydifferent.Iftheα-NH3+ group is on the right in the Fischer projection, then the Dconfiguration is assigned. The conversion into the R and S system isshownthroughthepriorityassignments.BiologicalsignificanceFor enantiomers, it is common for one only one of the isomers to bebiologicallyactive.ThisisnaturallyseenwiththeL-aminoacidsastheyareincorporatedintoproteins,buttheDisomersarenot.ThisisfurtherseenwithcarbohydratesastheynaturallyexistintheDconfigurationinthe human body. Thus, stereochemistry is highly relevant topharmaceutical drug design and synthesis. Understandingstereochemistry is a prerequisite for the development ofpharmaceuticals….andtheMCAT!CommonCarbohydratesThe image below shows some common carbohydrates and theirchemicalproperties.InPanelA,theketosefructoseisshowinbothits

linear Fischer projection and its circularized Haworth projection.Fructose and glucose are structural isomers; their interconversion isfacilitated by basic conditions. Note that fructose is a ketose and thecarbonyl carbon is carbon#2 in the closedcircular structure.Further,thiscarbonis inahemiacetal linkageandthesignificanceofthiswillbediscussedbelow.

Panel B shows the structure of sucrose, a disaccharide composed ofglucose and fructose. This is common table sugar. Note that carbonatoms1and2fromglucoseandsucroseformaglycosidicbond.Thisisanacetallinkageandisverystable.Furthernotethattheorientationoftheoxygeninthelinkageispointingdownbelowtheplane.Thisissaidtobeintheαconfiguration.SucroseisalsocalledGlu-α-1,2-Fru.PanelCshowsgalactose.NotethattheHOgroupattachedtocarbon#4ingalactoseispointingup.Incontrast,theHOgroupattachedtocarbon#4inglucosepointsdown(seePanelD).Noticethattheothergroups

are in identical orientations.Therefore, the groups attached to carbon#4are inoppositechiral configurations,makinggalactoseandglucoseare epimers; they have multiple chiral carbon centers but differ inconfigurationatonlyoneofthem.Appreciatethatepimersareatypeofdiastereomer.Panel D shows the structure of lactose, a disaccharide composed ofgalactoseandglucose.Notethattheoxygenatomintheglycosidicbond(betweencarbonatoms1and4)ispointingupandisthereforeintheβconfiguration. As for sucrose, the glycosidic bond in lactose is in anacetal linkage. Lactose is alsowritten as β-D-galactopyranosyl-(1!4)-D-glucose. Humans express the enzyme lactase, but there are somepeople with mutations. Such lactose malabsorbers often experiencecramps and diarrhea after consuming food sources with lactose (i.e.dairyproducts).Acetalsandhemiacetalswerefirstmentionedinthecarbonylchemistryofaldehydesandketonessection.Recallthattheyareformedfromacarbonyl and an alcohol. Hemiacetals are labile bonds, but acetals arestable and must be hydrolyzed by an enzyme. Thus, formation of ahemiacetalisareversiblereaction,buttheformationofanacetalisnot.Therefore, glycosidic linkages, which are acetal linkages, are verystablebonds.

MutarotationandanomersGlucose is an aldose (aldehyde sugar) and exists inmultiple forms asshownbelowinthefigure.Analogoustoglyceraldehyde,intheFischerprojectionforglucose,themostoxidizedcarbonisdesignatedas#1andifthelastchiralOHgroup(#5)inontherightthentheglucosemoleculeisintheDconfiguration(left=Lconfiguration).

Very little glucose exists in the free, linear form. Rather the hydroxylgroupatposition5 (shown in red in image) acts as anucleophile andattacks the aldehyde carbon at position #1, or the anomeric carbon.Becausethecarbonylcarbonisinaplanar,sp2-hybridizedform,theOHattacks fromeitheraboveor frombelowtheplane.Thiscreatesanewhemiacetal linkage that is sp3hybridizedandchiral.Convinceyourselfthat this is a hemiacetal linkage. The anomeric carbon is a newlycreated stereocenter as it is a carbon bonded to four different

substituent atoms. Therefore, there are two possible structuresresultingfromthecircularizationoflinearglucose:onewithahydroxylgroup pointing up (β) and with one pointing down (α). The term“anomers” is used to describe the relationship between these twostructures.Asthenewlinkageattheanomericcarbonisinahemiacetallinkage,itis labile,asopposedtothestableacetal linkagefoundintheglycosidicbondof adisaccharide.Thus, there is rapid conversionbetween theαandβ formsinsolutionthroughthe linear intermediate.Astheβ formcan be converted into the α form through a linear intermediate,monosaccharidessuchas fructoseandglucoseundergomutarotation.Note that at equilibrium, theβ form (65%) ismore stable than theαform(35%).ThereasonforthiscanbeseenbycomparingtheHaworthandchairstructuresofglucoseasshownintherightpaneloftheimageabove. This is because the β form in a Haworth represents theequatorial form in a chair conformation. Groups that occupy theequatorialposition inachairconformationaremorestablethanthosethatoccupyanaxialpositionduetolesssterichindrance.As the anomers have opposite chiral configurations (i.e. R vs S) atcarbon #1, yet the same configuration at the other chiral centers inglucose, theαandβ formsofglucosearealsorelatedtoeachotherasdiastereomers.Further,diastereomersthatdifferinconfigurationaboutone carbon are also referred to as epimers. Thus, some anomers areepimers, but not all epimers are anomers! But they are alldiastereomers,meaningthatthattheyhaveatleasttwochiralcenters.GlycogenandCelluloseGlycogen is an important polymer of glucose that is stored in tissuessuch as the liver and spleen. Glycogen is to animals as starch is toplants:theyarebothstorageformsofglucose.Glycogenisanimportantsource of energy for tissues, and its synthesis and degradation areheavily regulated processes (see below). Glycogen synthase addsglucose units to a growing glycogen chain under conditions of energyexcess (i.e. high insulin).UDP-glucose, an activated sugar, is used as asubstrate for glycogen synthase. In contrast, during times of energy

need (i.e., high epinephrine and glucagon), the glycogen polymer isbroken down by phosphorylase, an enzyme that releases a glucose-1phosphatemolecule from the glycogenpolymer. After conversion intoglucose6-phosphate,theactivatedglucosemonomercanenterintotheglycolyticpathwayforoxidation.

Note that the glycogen polymer as shown in the figure has α 1, 4glycosidic bonds. Glycogen also contains α 1, 6 linkages that assist inmakingthepolymermoresoluble(notshown).Incontrasttoglycogen,celluloseisapolymerofglucose,butcontainsβ1, 4 linkages. Humansdonot express anenzymecapableof cleavingthis particular bond. Therefore, cellulose is a type of “fiber”, acarbohydrate polymer that cannot be digested. Cellulose is a widelypresentinnatureandisacomponentofthecellwallofplantsandalgaeandisthereforeoftenconsumedinthediet.ReducingsugarsSome sugars act as reducing agents because they have free aldehydegroups(Noteketogroupscanbeconvertedintoaldehydes,especiallyinthe presence of base). The part of the molecule where this occurs is

knownasthereducingend.Onetestforthepresenceofreducinggroupson sugars is known as the Benedict’s test. In the presence of analdehyde (i.e. glucose) and copper in a basic solution (hydroxide), thealdehyde can be oxidized to an acid (See below). Therefore, thealdehydeisareducingagent.Initially,thecoppersolutionisblue,butinthe presence of the aldehyde reducing agent, Cu2O is formed and thesolutionturnsred.NotethatBenedict’sreagentisnotspecificforsugarsperse,butratherisspecificforaldehydegroups.

Fattyacids&Lipids:DescriptionsandTypesFattyacidsandlipidsareimportantbiomoleculesthatarecertaintobeseenontheMCAT. Wehavealreadyseenthesewithrespecttoesters.Althoughthetermsfattyacidandlipidareoftenusedinterchangeably,alipid is a molecule that is either a fatty acid or its derivative and isinsoluble in water but soluble in an organic reagent. Many of thesemolecules have polar head groups and a hydrophobic core and arethereforeclassifiedasamphiphiles.Fatty acid metabolism (i.e. storage and utilization) is paramount tonumerous aspects of biology andmedicine. Fatty acids aremoleculeswith longaliphaticchainsandaterminalcarboxylgroup.Thealiphaticchains could be branched and may or may not be saturated. Inbiologicalsystems,mostfattyacidshaveanevennumberofcarbons.

Fattyacidsrarelycirculatefreelyinserum.Rather,theyareoftenfoundesterified in various forms: triglycerides, cholesterol esters, andphospholipids.Shownbelowarethreeimportantfattyacids.Palmiticacidisthemostcommon fatty acid. Designated as C16:0 due to the 16 carbons and 0degreesofsaturation,palmiticacidistheterminalfattyacidsynthesizedbycytosolicfattyacidsynthase.Longerchainfattyacidsaresynthesizedin the endoplasmic reticulum. Note that the carbon adjacent to thecarboxylcarbonisdesignatedastheαcarbonorthe#1carbon.Thelastcarbon,regardlessof thenumberofcarbons inthechain isdesignatedastheωcarbon.Duringfattyacidoxidationinthemitochondria,theβcarbonofpalmiticacidisoxidized.

Phytanicacid isa16carbonbranchedchainfattyacid.Alsoknownas3,7,11,15tetramethylhexadecanoicacid,phytanicacidisnotproducedinthehumanbody.Rather,humansconsumethisintheirdietsbyeatingruminant animals and some forms of fish. Phytanic acid cannot be

degraded by the β oxidation machinery in the mitochondria as thepresenceofthemethylgroupattheβpositionstericallyinterfereswiththeenzymesinvolvedinthisprocess.Rather,phytanicacidisdegradedintheperoxisomebytheprocessofαoxidation.Linoleicacidisnotproducedbythehumanbodyandisconsideredanessential fattyacid. It isoftentakenasasupplement.Withtwodoublebondsinthecisposition,linoleicacidisknownasanomega-6fattyacidthatisoftenfoundinflaxseedoil.Linoleicacidisoftenrepresentedas18:2 Δ9,12 where the2andΔrepresents thenumberandpositionsofthe double bonds, respectively. Linoleic acid is a precursor toarachidonicacidwhichitselfisaprecursortoimportantinflammatoryregulatorssuchasprostaglandins,leukotrienes,andthromboxanes.As prostaglandins are important in chemistry and medicine, they arespecificallylistedontheAAMCMCATcontentoutline.Wewillexaminethisinmoredetailbelow.SaturatedvsunsaturatedfattyacidsMostanimalfatsaresaturated,butnotableexceptionslikelinoleicacidexist.Theintroductionofadoublebondinunsaturatedfattyacidsalterstheir properties. Saturated fatty acids are usually solid at roomtemperature, while unsaturated are liquids. However, at bodytemperature, both are liquids. The presence of the double bond inunsaturated fats causes the molecule to kink or bend. This causes areductioninthemeltingtemperatureasthevanderWaalsinteractionsbetweenthechainsoffattyacidsarereduced.StructuralformationoffattyacidsFattyacidsandbilesalts (derived fromcholesterol) formmicellesatacriticalmicellarconcentration(CMC).Thisisshownintheimage.Belowthe CMC value, the lipids exist as a solution ofmonomers. Above theCMC, the lipid formsmicelles, or colloidal suspensions of surfactants.Theconcentrationoflipidsrequiredtoformmicellescanbedeterminedthrough multiple methods including conductivity and absorbance.Cholesterol, bile salts, and lipids such asphosphatidylcholine, all form

micelles that incorporatedietary fatty acids for absorption into theGItract.

TriglyceridesTriglyceridesareestersandthestorageformoffatandaresynthesizedprimarilyintheliver,intestines,andadiposetissue.Theyaregeneratedfromexcesscarbon(i.e.sugar,proteins)andstoredintheadipose.Wehave seen triglycerides before as they are esters and are synthesizedfromfattyacidsandglycerol.The image shows the mechanism of esterification of glycerol frompalmiticacid.FattyacidssuchaspalmiticacidareinitiallyactivatedbyATPandCoenzymeA.ThisgeneratesderivativesofcoenzymeA.Thesehighenergy,activatedthioestersareesterifiedwithglycerol.Asglycerolisatri-alcohol,itcanaccommodatethreefattyacidchains.

Fatty acids and triglycerides are very hydrophobic. Therefore, theirtransportthroughthebodyposesachallengewithrespecttosolubility.To circumvent this, fatty acids and triglycerides are transported withvariouspartners that solubilize them.Forexample, fattyacidsderivedfromthehydrolysisof triglycerides in timesofenergyneedareboundtoserumalbumin.Triglycerides synthesized fromcaloric excess arepackaged into eitherchylomicronsorverylowdensity lipoproteins(VLDLs). Seetheimagebelowforelaboration.Theseimportantlipoproteinparticlesareofhighclinical value. Chylomicrons are formed in the intestines from

consumptionofdietaryfattyacids(i.e.meatanddairyproducts).VLDLparticlesaregenerated in the liver fromconsumptionofexcesssugarsand amino acids. Both chylomicrons and VLDL particles arrive at theadipose tissue where they encounter lipoprotein lipase (LPL), anenzyme that hydrolyzes the esters into carboxylic acids and glycerol.Thefreefattyacidsareimportedintotheadiposetissuewheretheyarereconstituted into triglycerides for storage. Note that triglyceridescannotfreelycrosscellmembranes.

SaponificationSaponificationistheprocessofproducingsoapfromtriglyceridessuchasstearin,amolecule formedfromthreemoleculesofstearicacidandglycerol.Themajorsourceoftriglyceridesisanimalfatsandvegetableoils.Whenstearinistreatedwithastronghydroxidebase(i.e.lye),theester is hydrolyzed into three molecules of stearic acid and glycerol.Saponificationisalsoamajormethodforproducingindustrialglycerol.Themechanismof saponification is similar to thehydrolysisofesters:nucleophilicsubstitution-eliminationreactions.Thehydroxideanionisa strong nucleophile that attacks the electrophilic carbonyl carbon intheester.Thetetrahedralintermediateisformedanduponcollapseanacidandanalcoholarecreated.

PhospholipidsandphosphatidsPhospholipids are major components of cell membranes and formmembrane bilayers. This is unlike fatty acids that form micelles asdescribed above. Phospholipids are important for maintainingstructural integrity of the cell and also perform important signalingfunctions. Phospholipids contain a polar phosphate head and a tailconsistingoftwohydrophobicchains(genericallydesignatedasR1andR2).Twoexamplesareshownbelow.Notethatbothphosphatidicacidand phosphatodylserine are both synthesized from a glycerolbackbone that contains three alcohols. R1 and R2 are esters and thecharged phosphate head forms the third phosphoester. In the case ofphosphatidylserine (PS), the amino acid serine is linked to thephosphate head group. PS is a key membrane component and isimportantinapoptoticsignaling.

SphingolipidsSphingolipidsareatypeoflipidcontainingthesphingosinebackbone.Sphingosine is a lipid derived from serine andpalmitoyl CoA.This isshown below. Ceramides are sphingolipids, waxy phospholipidssynthesizedfromsphingosineandanyofseveralfattyacids(i.e.C16:0).As we have described, C16:0 is shorthand nomenclature for palmiticacid,acommonsaturatedfattyacid.Theselipidsnormallyresideincellmembranes where they serve important structural and cell signalingroles. Sphingolipid catabolism occurs in the lysosome, an acidicorganelle often referred to as the “recycling” center of the cell.Dysfunctional sphingolipid catabolism formulates a class of diseasesknown as “sphingolipidoses” where sphingolipid accumulation leadsto its aberrant deposition in organs. Med-Pathway examinesexperimentaltreatmentoftheNiemannPicksphingolipiddiseaseinthe“CellBiology&Genetics”Testingmodule.

The image below shows several types of ceramides, lipids that aresynthesized from sphingosine, a lipid derived frompalmitoyl CoA andserine.Additionof a fattyacylmoietygeneratesa ceramide.Note thatbecausevariousfattyacidscanbeaddedtosphingosinethattherecanbe different ceramides. Hence, the term: “A ceramide”. Addition ofphosphocholine generates a sphingomyelin, but addition of sugar(s)(i.e. glucoseor lactose)generatesacerebroside andadditionof sialicacidproducesaganglioside.

Cholesterol,Bile,andSteroids

Cholesterol isanimportantcomponentofanimalcellmembranesthatprovidesmembranefluidity.Thus, it isnosurprisethatorganisms(i.e.shellfish)thatliveatrelativelycoldtemperatureshaveabundantlevelsof cholesterol in their membranes. As the structure of cholesterolshows, it ishighlynonpolar and composedof27 carbonatomswith ahydroxylgroup.Thesolubilityofcholesterolisverylow,about10-12M.Thus, cholesterol is an alcohol. It is also an alkene. Esterification ofcholesterol by enzymes such as LCAT generates more hydrophobicformsofthelipid.The synthesis of cholesterol is a complex pathway consisting ofnumerous steps. As shown in the figure below, the mevalonatepathwayiskeyinunderstandingthesynthesisofcholesterol.Further,itis an important point in the application of cholesterol lowering drugsknownasstatins.Someofthekeyfeaturesofthepathwayaredescribed.First, observe that cholesterol is synthesized from acetyl CoA. Fromhere, mevalonate pyrophosphate is generated and converted into theisoprenoids: isopentyl pyrophosphate and dimethylallyl-pyrophsophate. Note that these five carbon species (i.e. terpenoids)are fundamental building blocks of nature. Cholesterol is built bycombining these activated five carbon species by generating geranylpyrophosphate (10 carbons) and eventually squalene, a 30-carbonderivative of the isoprenoids. Squalene ismodified into the27-carbonspeciescholesterol.Cholesterolisaprecursorforsteroidhormones(i.e.testosterone and estrogen). Further, ispoprenoids such as farnesylpyrophosphate can be added to proteins. Such posttranslational

modificationsaregenericallyreferredtoas“prenylation”andservetokeepproteinsanchoredintothecellmembrane.

SynthesisofBileSaltsBile is made in the liver and secreted into the duodenum duringdigestion. It is important for emulsifying fats, a process that makesthem better substrates for pancreatic lipases. Cholesterol is theprecursor in the synthesis of bile salts.Thepathways for synthesizingbilesaltsareshownbelow.NotethateachonehasadistinctpKavalue.Appreciate that lowerpKavaluesallowfor theacid tobechargedatalowerpH.Chargedspeciesaremoresolublethanunchargedones.

STEROIDSInadditiontobileacids,steroidhormonesarederivedfromcholesterol.Cholesterolisinitiallyconvertedintopregnenalonebythecholesterolside chain cleavage enzyme. Anterior pituitary hormones controlexpression of this cytochrome P450 enzyme. Pregnenalone is thecommonprecursor to the steroid hormones as shown. Appreciate thesimilaritiesbetweencholesterol(30carbons)andtheotherhormones,especiallywith respect to the four-ring structure.The synthesisof thevarious steroid hormones occurs in many steps through variouschemicalreactionsthatyouhavealreadyseen, includingoxidationandreduction.Don’tmemorizethestructures,butrather,expecttheMCATto test your organic chemistry knowledge by asking you to figure outwhich type of reaction/enzyme would perform a given step.Significantly,notice that testosteroneandestradiolare related toeachotherasketo-enoltautomers.

ProstaglandinsProstaglandins are importantmediators in the inflammatory responseand their synthesis is the target of numerous drugs, including aspirinand ibuprofen. Prostaglandins are derived from signal transductionpathways at the surface of the cell. Signaling pathways that activatephospholipaseA2releasefattyacidsfromtheC-2carbonoftheglycerolbackbone.Thisgeneratesarachidonicacid(C20:4Δ5,8,11,14),asignalingmoleculethatisconvertedintovariousprostaglandinmediators(PGG2,PGH2,andPGD2)bytheactionoftwocyclooxygenase(COX)enzymes,COX1andCOX2(seebelow).Theseenzymesaresimilarinstructureandfunction,buthavedifferentmodesofexpression.

COX enzymes are inhibited by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). COX1 is constitutively expressed, butCOX2 is inducible in response to various signals, including those thatactivateinflammatorypathwayssuchastumornecrosisfactor(TNF).COX1 and COX2 are redox enzymes that generate the prostanoids,including prostaglandins and prostacyclin as well as leukotrienes. Inplatelets, only COX1 is present and it generates thromboxane A2, amediator of platelet aggregation and blood clotting. In addition, COXenzymes regulate angiogenesis, production of the mucus lining, andblood pressure in renal arterioles. Because of their pivotal role in thecritical physiological processes, inhibition of COX enzymes is a highlyactiveareaofstudy.FatSolubleVitaminsThefat-solublevitaminsarevitaminsD,A,K,andE.Thebioavailabilityof fat-soluble vitamins is regulated by their cognate binding proteins.Forexample,vitaminDbindingprotein(DBP),amemberofthealbuminfamily, is synthesized in the liver and binds tightly to the majorcirculatingformofthesterolvitaminD3.Althoughrequiredfornormalhomeostasis, the fat-soluble vitamins can be toxic in high doses(hypervitamintosis).VitaminDThe synthesis of vitamin D occurs in multiple places as shown below in the image. Cholecalciferol,theinactiveprecursortovitaminD,isgeneratedin the skin via the action of UV light on 7-dehydrocholesterol.Cholecalciferol is then transported to the liver where it is modifiedthrough hydroxylation to create 25, hydroxycholecalciferol[25(OH)D3].Thiscompoundistransportedtothekidneyandactivatedvia a PTH-induced renal hydroxylase to generate the active form ofvitaminD3thatiscommonlyabbreviatedas1,25(OH)2D3.A major function of vitamin D3 and its vitamers is to regulate theintestinal absorption of ions such as calcium and phosphate. Indeed,

deficiencies in vitaminD3 arewell known to result in poorly calcifiedandimproperlystructuredbone(i.e.ricketsandosteomalacia).

The active form of vitamin D activates transcriptional programs intargetcellsasshownintheimage.VitaminDcirculateswithitsbindingprotein (VDB)anddiffuses throughcellmembraneswhere it interactswiththevitaminDreceptor(VDR).InconjunctionwithRXR,vitaminDregulatesgeneexpressionasshown.

VitaminAVitamin A is composed of various compounds as shown below thatparticipate inmanycellularprocesses.Althoughmostnotorious for itsroleinvision,themostcommonfunctionofvitaminAistoregulategeneexpressionintheformofretinoicacid.Suchregulationisimportantinprocessessuchasdevelopmentandimmunity.

β-carotenes and other carotenoids (i.e. lycopene) are pro-vitaminsconsumed from various plants and are converted into vitamin Acompoundsintheintestineasshownbelow. Theseareconvertedintoretinyl esters and transported with chylomicrons in the lymph andblood to the liverandadipose tissue. Retinols secreted from the liverandadiposecirculatewiththeretinolbindingprotein(RBP)andarriveat target tissues. Once across themembrane, free retinol is convertedintoretinoicacidwhereitparticipatesingeneexpressionprograms.

Various forms of vitamin A are critical in the visual cycle. Indeed,deficienciesinvitaminAarenotoriousfornightblindness.Asimplifiedversionofthevisualcycleintheretinaisshownbelow.KeytothisisthevisualpigmentrhodopsinthatconsistsoftheG-proteinopsincovalentlylinkedto11-cisretinal,achromophore.Uponinteractingwithlight,11-cis retinal is photo isomerized into all trans retinal. This cis to transisomerizationinducesaconformationalchangeinopsinthatgeneratesasignal cascade that hyperpolarizes the photoreceptor cell. This is themolecularbasisforvision.During the visual cycle, 11-cis retinal, bound through a Schiff base toopsin, is converted into all trans retinal (Panel A), an isomerizationevent that releases the retinoid fromopsin and transduces a signal tothebrain.Thesystemisre-chargedbyconvertingalltransretinalbackinto 11 cis-retinal (Panel B). Although shown in the figure with astraightarrow,therearemultipleintermediatestepsinthisconversion.

VitaminKTheprinciplefunctionofvitaminKistoparticipateinbloodclottingandbone metabolism through the carboxylation of various vitamin-Kdependentproteins.Deficiencies invitaminK leadtoosteoporosisand

easy bruising. Inhibition of the vitamin K biochemical pathwayformulates a class of drugs known as “blood thinners”. This will beelaboratedonbelow.The vitamin K family is comprised of various derivatives of 1, 4Naphthoquinoneasshown.Wehaveseenbiologicalquinonesbeforeinelectron transport. Therefore, vitamin K might be expected toparticipate in redox reactions. Vitamin K1 is made by plants and isplentiful in green leafy vegetables. The gut micro biota can convertVitaminK1intovitaminK2andcanextendthelengthoftheisoprenoidchain. Thus, vitamin K2 has several forms. Vitamin K3 is a syntheticform.TheVitaminKcycleVitaminK is a cofactor for enzymes that carboxylate glutamate (GLU)residues in vitamin-K dependent proteins. This forms γ-glutamylcarboxylated(GLA)sidechains.Thisredoxreactionisaccompaniedbythe consumption of oxygen and the formation of water as shown. γ-glutamyl carboxylase concomitantly forms an epoxide intermediate inthe vitamin K cycle. Conversion of the epoxide back into the active

hydroquinone form is conducted by vitamin K epoxide reductase(VKOR).ThisenzymeperformstwoseparatestepsintheprocessandasecondenzymeiscapableofreducingvitaminKtothedihydroquinoneform. Notably,VKOR is inhibitedbywarfarin (i.e.Coumadin), awell-studiedpharmacologicalagentthatisusedasananti-coagulant(“bloodthinner”).ClottingfactorsforII,VII,IX,andXareaffectedbywarfarin.VitaminEVitamin E comprises a group of compounds (i.e. tocopherols andtocotrienois)andisanantioxidantfoundinmembranes.VitaminEhasbeen shown to have numerous health benefits. Vitamin E deficiencyleads to abnormalities in fat absorption. This can lead to neurologicalproblemsduetoperturbations innervemembraneandconduction.Asshown in the image,all formsofvitaminEcontainachromanedoubleringequippedwithahydroxyl function that reduces free radicals.ThehydrophobicsidechainallowsforthepositioningofvitaminEintothemembrane.

ThechiefroleofvitaminEistopreventfreeradicalchainreactionsforlipidperoxidationeventsthatoccurinthemembrane(seeimage).Tocopheroxyl radicals (α-TO") are generated from lipid peroxideradicals (ROO") and participate in initiation and propagation events.Importantly, the reaction between α-TO" and ROO" generatesnon-radicalterminationproducts.

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