stereochemistry content review - med-pathway stereoch… · stereochemistry of covalently bonded...

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MCATSTEREOCHEMISTRYINTRODUCTIONANDOUTLINEThis section will definitely increase your MCAT Stereochemistryknowledgeandskills.Stereochemistryandisomerizationareimportantin medicine and are notoriously tested on the MCAT. Formally, thesetopicsare listedunder contentCategory5B: “Natureofmoleculesandintermolecularinteractions”. AdiscussionofeachtopicisaccompaniedbyaseriesofrigorousMCATstylequestions.ContentCategory5Bexamines themajorityof content that focusesonisomers. In Content Category 5D, carbohydrate stereochemistry islisted.We have integrated carbohydrates as part of the discussion ofdiastereomers.TheMCATtests,ofteninintegratedfashion,multiplefacetsof isomers,including their chemistry, physics, and of course, their biologicalsignificance.Youwillbeexpectedtorecognizevarioustypesofisomers,understandtheirphysicalandchemicalpropertiesandappreciatetheirbiological functioning that nicely illustrates the structure-functionparadigm of biomolecules. As enzymes recognize one type ofstereoisomer (i.e. L amino acids vs D amino acids), expect for theirbiological relevanceandapplications to alsobe testeddespite the factthat the topic of isomers are formally listed in the physical sciencessection. Expect to see some biological application questions in thephysicalsciencessection.Below is the list for Stereochemistry in the AAMC MCAT2015 ContentOutline.Thissectionwillexamineeachtopic,butwillbepresentedinaslightlydifferentorder. Eachentryshouldbeconsideredasa learningobjective/goalthatwillbetestedattheend.



Stereochemistryofcovalentlybondedmolecules�Isomers� Structuralisomers� Stereoisomers(diastereomers,enantiomers,cis/transisomers)� Conformationalisomers� Polarizationoflight,specificrotation� Absoluteandrelativeconfiguration� ConventionforwritingRandSforms�AnomersandepimersIsomers. Isomers are molecules that possess identical molecularformulasandmasses,yettheirthree-dimensionalstructuresvaryduetodifferencesinthespatialorientationoftheirconstituentatoms.SeveralvariousclassesandpropertiesofisomersrelevanttotheMCATwillbeexaminedhere.Structural isomers. Also called constitutional isomers, structuralisomers of molecules (such as pentane; see Table) possess differentbond connections, while maintaining identical molecular formulas(C5H12), and molecular masses (72.15 g/mole). However, structuralisomershavedifferentphysicalandchemicalproperties. Forexample,the three structural isomers of pentane have different boiling andmelting points. Significantly, both n-pentane and isopentane (IUPACname 2-methylbutane) are liquids at room temperature, butneopentane (IUPAC: 2, 2-dimethylpropane) is a gas at roomtemperature. The difference can be explained through theunderstandingthatboilingpointisdependentonintermolecularforces.The variations in physical properties between isopentane and



neopentane clearly illustrate thedistinctphysicalproperties that existbetweenmoleculeswithidenticalmolecularformula.Conformationalisomers.Duetofreerotationaroundsigma(σ)bonds,molecules can exist in various rotational states. Such conformationalisomershave the exactbond connections, yetdiffer in their rotationalstates. This is illustratedbelowwith1-chloropropane. PanelA showsthe perspective diagram focusing on the orientation of the groups oncarbonatomsC1-C2.Notethatthetwolargestgroupsareorientatedonoppositesidesofthecarbonbackbone,butafterrotationaroundC1,thetwo groups are facing outwards. These two rotational outcomes areconsideredconformationalisomers,orconformers.In many cases, conformational isomers are represented by Newmanprojections that examine the molecule through a view of thelongitudinal axisof the carbonskeleton.Newmanprojectionsexaminethe rotational states around carbon-carbon σ bonds. Throughexamination of Panel B,we learn that these projections are drawnbystarting with the initially viewed carbon as a point in a vertex. Thisvertex is bound to four separate constituents, including the secondlongitudinal carbon that is representedbya sphere (Panel B). Stablecarbon atoms are bonded to up to four constituent atoms. Rememberthat the valence of carbon is 4 (electron configuration: 1s22p4). Asshown, theanti-conformation has the two largestgroupsbonded toC1andC2astheyarelying180°apart.Afterrotating60°,thetwogroupslieclosertogetherintheguacheconformation.Boththeantiandgaucheare considered as “staggered” forms. A further 60° rotation producesthe eclipsed form. This is the conformation where both groups lieclosest together. Such steric hindrance creates electron repulsion,making the eclipsed form the least energetically favorable of theconformationalisomers(PanelC).



Ringstructuresoftenexistinmultipleconformations.Intheexampleofcyclohexane, the six-membered ring structure is often presented as aflat,planarstructure.However,ifthisdepictionwereaccurate,thebondangleswouldbe120°C.Asthebondsincyclohexanearesp3hybridized,themost stable structurewould have angles of 109.5 °C. Thus, beingplanarisnotfavorableforcyclohexane.Toaccommodateoptimalbondanglescyclohexaneexistsinthechairandboatconformationalisomers(conformers)asshownbelow.



Geometric (cis/trans) isomers. Unlike conformational isomers thatarise through rotation around σ bonds, geometric isomers arise as aresult of the consequence of the failure to rotate around bonds.Geometric isomerization is listed on theMCAT checklist as “cis/transisomers”. Cis refers to groups on the same side and trans indicatesgroupsonoppositesidesofcarbonbonds.The common feature of geometric isomers is that they all possessstructuresthathavesomeformofrestrictedrotationaroundabond.Asrotational restriction around double bonds is prohibited, geometricisomers are often seen inmoleculeswithπ bonds (sp2 carbon-carbondoublebonds).Geometricisomerizationisalsofoundinringstructures.Note as shownbelow that the cis and trans-1, 2 dichlorocyclopentanegeometric isomers are also diastereomers. This class of stereoisomerswillbediscussedbelow.



Twogeometricisomersexistfor2-butene:thecisandtransforms.Thecis isomer is the formthathas the twohydrogenatomsbondedto thesp2carbononthesamesideofthedoublebond;transiswhentheylieonoppositesides.Theboilingpoints(cis=-139°Candtrans=-105°C)andmeltingpoints(cis=4.0°Candtrans=1.0°C)forthetwoisomersaredifferent.Geometric isomers for alkenes are formally designated with the E/Zsystem. Herearetherulesforassignments.Toeachofthetwocarbonatoms participating in the double bond, group priority numbers areassignedbaseduponatomicnumber.Astheatomicnumberofcarbonisgreaterthanhydrogen(C>H),theCH3methylgrouphasapriorityof1andthehydrogenhasapriorityof2.Bydefinition,Eisomershaveeachofthetwonumber1assignmentsonoppositesidesofthedoublebond.If the two 1 assignments are on the same side, then the isomer isclassified as “Z”. In most, but not all, cases, the E isomer representstrans.Stereoisomers(diastereomers,enantiomers,cis/transisomers)Isomersthatdifferintheir3D-spatialarrangementofatomsaretermedstereoisomers. Any molecule that cannot be superimposed on itsmirrorimageexhibitschirality.Thesimplestwaytoenvisionchirality



is 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.Theredasteriskdesignatesthechiralcarbonstereocenter.Thetwo molecules are non-superimposable mirror images. Enantiomerspossess identical physical properties (i.e. boiling and melting points)withtheexceptionofhowtheyinteractwithlight(discussedbelow).A1:1mixture of enantiomers is called a racemicmixture. Any ratio ofenantiomersdeviatingfrom1:1iscalledascalemicmixture.

Stereoisomers possess one or more stereogenic atoms orstereocenters. According to Mislow and Siegel, a stereocenterrepresentsaposition inamoleculewheretheexchangeof twogroupsgeneratesa stereoisomer.Stereocentersareoften referred toas chiralorasymmetric centers.Althoughmanyatomscanexhibit chirality, theMCATwilllargely,ifnoexclusively,focusoncarbon.



Chiral molecules were firstobserved to interactwith lightand exhibit optical activity inthe 1800s. Monochromaticlight passing through a filter(Thinkoflightpassingthroughapicket fence.) ispolarized,oris able to pass through in oneplane (See image). Whenpassing througha samplewithoptical activity (i.e. chiralmolecule), the plane ofpolarized light rotates either clockwise (CW) or counter clockwise(CCW) at an angle α through its interaction with a chiral center. CWrotationisnotedas(+)ordextrorotatoryandCCWrotationiscalled(-)or levorotatory.Dextrorotatoryandlevorotatoryareoftenabbreviatedwithasmallcasedandl,respectively.Enantiomerswillrotatetheplaneof polarized light in opposite directions, butwith equalmagnitude. Aracemicmixturewill therefore not rotate the plane of polarized light.The direction andmagnitude of rotation of a chiralmoleculemust beexperimentallymeasuredbypolarimetry. It cannotbedeterminedbyvisualinspectionofthemolecule.Thespecificrotation[α]isthechangeinorientationofachiralmoleculewhenexamined throughamonochromatic sourceofpolarized light asillustrated.αdependsontheconcentrationofthesample,thelengthofthe sample cell, temperature, as well as the wavelength of the lightsource. The formula for specific rotation is given by:[α]=α/(c)(l)[α] = specific rotation, α = observed rotation, c = concentration ofmolecule(g/ml),andl=pathlengthoftubeindecimeters.Identifyingchiralcentersandchiralmolecules



sp3 tetrahedral carbon atoms (109.5° bond angles) that have fourdifferent substituent groups are identified as chiral centers. Forexample,onechiralcenterisfoundinalanineasshowninPanelA.Thechiral center is indicated with an asterisk. Observe that the chiral αcarbon is tetrahedral and bound to four different substituents. Itsmirrorimageisalsoshown.For a molecule with one chiral center, two enantiomers exist andpossess identical physical properties except for how they rotate theplaneofpolarizedlight.Ingeneral,thereare2NstereoisomerswhereN= thenumberof chiral centers.The twoexceptionsconcernmoleculeswithbridgedstructures(2N/2isomers)andthemesocompounds(2N-1).Shown below is the meso compound, 1,2 dihydroxycyclohexane. Themolecule has two chiral carbons (asterisks) but exhibits no opticalactivity. This is because themeso compound has an internal plane ofsymmetry.

Molecules that have internal planes of symmetry are achiral. Mesocompounds possess at least two chiral centers yet have no opticalactivity due to the internal plane of symmetry. Meso compounds aretherefore achiral. Therefore, the presence of chiral centers does notautomaticallymakeamoleculechiralandthisisbecauseofsymmetry.



Remember:Anymoleculethathasaplaneofsymmetrythatcandividethemolecule into two identicalmirror images is achiral, even if therearechiralcarboncenters.Absolute configuration. As enantiomers possess differing spatialarrangementsofatoms,theRandSsystemfornomenclaturehasbeenadoptedandtodifferentiatebetweenthem.Thissystemisalsoappliedtoother stereoisomers includingdiastereomersandmesocompounds.The R and S system is formally called Cahn-Ingold-Prelog system andthe rules are described and implemented below for 2, bromo, 2chloroethanoic acid, a molecule that has one chiral center and twoenantiomers.TheRandSisomersareshownbelow.

NotethatfortheSisomer,drawinganarrowfrom1-3generatesaCCWdirection.FortheRisomer,thedrawnarrowfrompriorities1-3,isalsoCCW. However, because the #4 priority H atom is NOT in the back



(wedge vs hedged line), the direction is changed to a CW arrow. Thisgivestheassignmentasan“R”.Although not applicable in this specific case, the 4th rule for assigningabsolute configuration applies to chiral compounds with isotopes.When isotopes are bonded to a carbon stereocenter, the rules forassigning priorities state that the highest mass number receives thehighestpriority.Forexampleinthecaseofhydrogen,Tritium(3H,massnumber3from1protonand2neutrons)wouldhaveahigherprioritythandeuterium(2H,massnumber2from1protonand1neutron),andhydrogen(1H)thathasoneprotonandzeroneutrons.Insomecases,assigninganabsoluteconfigurationtomoleculesisnotasstraight forward asdeterminingprioritynumbers.Take the caseof 2-chloropropionicacidasshownbelow.Thechiralcarbonisshownwithanasterisk.Although it iseasytoassignthe#1and#4prioritiesasClandH,respectively,the#2and#3priorityassignmentsis lessclearasboth atoms appear to be carbon. As shown, in these situations,determine the “next” three bound atoms. In this case, this is thedifference between a carbon and twohydrogen atoms (C,H,H) and acarbonandtwooxygenatoms(C,O,O).Althoughthecarbonsareequalinatomicnumber,sinceO>H,the#2priorityisdefinedandassignedasshown.



RelationshipbetweenR/S and, + and –, andd/l system.Wehaveseenthatchiralmoleculesrotatetheplaneofpolarizedlightineitheraclockwise(+)orcounterclockwise(-)manner,which is linkedtothed(dextrorotatory) and l (levorotatory) nomenclature. This is used todistinguish how a chiralmolecule rotates the plane of polarized light.The (+)-d and (-)-l systemdescribes howan entiremolecule interactswithpolarizedlight.Incontrast,theRandSsystemdefinestheabsoluteconfigurationofindividualchiralcenterswithinamolecule.Thereisnorelationshipbetweenthetwosystemsofnomenclature,meaningthatachiralmoleculewithasinglestereocenterassignedRdoesnotindicatehowthismoleculewillrotatetheplaneofpolarizedlight(+or-).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 upper case D and Lnomenclature.Upper case D and L nomenclature refers to an alternative system fordesignating absolute configuration for amino acids and sugars.Therefore, D and L isomers can also be assigned through theR and SsystembyapplicationoftheCahn-Ingold-Prelogrules.Thesepointsareillustrated in the figurewith serine as the example.Historically,whenglyceraldehyde is drawn in a Fischer projection, if the OH group isdrawnontherightthenthemoleculeistheDisomer.IftheOHisontheleft, then this represents the L enantiomer. If the chiral carbons inDand L glyceraldehyde were assigned an absolute configuration basedupontheCahn-Ingold-Prelogrules,thentheDisomerrepresentstheRconfiguration and the L enantiomer represents the L configuration.However, you cannot always assume that D and L configurationswillnotequatetoRandSassignments.Theconventionforaminoacidssuchasserineisslightlydifferent(see image). If theα-NH3+groupisontherightintheFischerprojection,thentheDconfigurationisassigned.Theconversion into the R and S system is shown through the priorityassignments.



Biological significance. It is common for various enantiomers to bebiologically active in one form, but not another. This is naturally seenwiththeL-aminoacidsastheyareincorporatedintoproteins,buttheDisomerisnot.Thisisfurtherseenwithcarbohydratesastheyallexistinthe D configuration in the human body. Thus, pharmaceutical drugdesignandsynthesisishighlyrelevantforthestudyofstereochemistry.Understanding stereochemistry is a prerequisite the development ofpharmaceuticals.Oneexampleofthesignificanceofstereochemistryconcernsthetwoenantiomersofnaproxen,anover thecounteranti-inflammatorydrug.Immediately spot that the opposite orientation of the methyl groupsbonded to the sp3 chiral center. One molecule will be in the SconfigurationandtheotherwillnecessarilybeintheRconfigurationasshown.EnantiomershaveoppositeconfigurationatEACHstereocenter.However,only theS isomer isomeractsasa therapeuticallybeneficialdrug by inhibiting cyclooxygenase-dependent synthesis ofprostaglandins;theRisomercausesliverdamage.



Diastereomers and epimers possess at least two chiral carboncenters,yetaremoleculesthatdifferinabsolutechiralconfigurationinat leastonestereocenter.Diastereomersareshownbelow(PanelB) in2-chloro 3-bromopentanoic acid, a molecule with two chiral carboncenters.Inthiscasethereare2Nor4differentstereoisomers.Onlyoneisshown.Enantiomershaveoppositeconfigurationateachchiralcenter(i.e. R vs. S or RR vs SS). In contrasts diastereomers have oppositeconfigurations in at least one stereocenter (i.e. RRR vs RRS). Thosediastereomers that differ in absolute configuration around one chiralcenter are termed epimers. Therefore, all epimers are diastereomers,butnotalldiastereomersareepimers.Notethedifferencesinabsoluteconfiguration between enantiomers and diastereomers as shown inPanelD).



Anomers.Anomersareatypeofepimer.Theirformationisillustratedwith the classic sample of D-glucose as shown in the image. Glucosemoleculesare inequilibriumbetween the linear formand theirclosedcircular structures. In the linear form, the hydroxyl group bound tocarbon #5 (red in the image) serves as a nucleophile. A lone pair ofelectronsintheoxygenatomattacksthesp2carbonpresentinglucose.Becauseoftheplanarnatureofthecarbonylcarbon,thenucleophilecanattack from either of two positions (above or below the plane) asshown. This reaction introduces a new chiral center in the closedglucosemolecules.Inthemechanism,thehydroxylgroupperformsanucleophilicattackatcarbon#1.Asthiselectrophiliccenterliesinaplanarstructureduetothesp2hybridizationstatusofcarbon(120°bondangles),thehydroxylgroupcanattack fromeither the topor thebottom.Asaconsequence,two isomers α (hydroxyl is down) andβ (hydroxyl isup) are formed.Notethatthecombinedreactionofanalcohol(R-OH)withanaldehyde(CHO) generates a hemiacetal linkage. Because this newly formedhemiacetal bond is reversible (in contrast to an acetal), anomers caninterconvert in solution. The glucose molecule in solution exists inequilibriumbetweentheopen(1%)andclosedforms(99%).Asperthefigure,theβanomerispredominant(65%)because,asseeninthechairstructure,thehydroxylatC1isinthemorestableequatorialposition.



Uponfurtherinspectionofthestructuresofclosedcircularα-Dandβ-Dglucosemolecules,itisclearthatthenewlyformedbondatcarbon#1isinahemiacetallinkage. Unlikeacetallinkages,hemiacetallinkagesareunstable. Thus, the circularization of glucose is freely reversible. As aconsequence, glucose molecules are always opening and closing andopening back up again. At equilibrium, there is more α-D glucosepresentinsolution.The nomenclature and mechanism of the formation of the α and βanomersofD-glucosecanalsobediscernedfromtheFigure.NotethatGlucose exists in both a linear and a circularized closed form(represented by the Haworth and chair structures). In the linearFischer projection, if the hydroxyl group on the penultimate carbon(red) ison theright, then this represents theD-isomer. (TheL isomerhasthehydroxylgroupattachedtothepenultimatecarbondepictedontheleftsideinaFischerprojection.)The relationships between stereoisomers (i.e. structural andconformational isomers is missing) is shown in the following Venndiagram.



Relationship between isomers.

ISOMERS

STEREOISOMERS

DIASTEREOISOMERS EPIMERS

ANOMERS

ENANTIOMERS

stereochemistry content review - med-pathway stereoch… · stereochemistry of covalently bonded...

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