Introduction to Organic Chemistry 2018 moreburton.chem.ox.ac.uk/handout-2_intro.pdf · Introduction...

Introduction to Organic Chemistry 25

Introduction to Organic Chemistry

Handout 2 - Stereochemistry

http://burton.chem.ox.ac.uk/teaching.html

◼ OrganicChemistry J.Clayden,N.Greeves,S.Warren◼ StereochemistryataGlance J.Eames&J.M.Peach◼ Themajorityoforganicchemistrytextbookshavegoodchaptersonthetopicscoveredbytheselectures

◼ ElielStereochemistryofOrganicCompounds(advancedreferencetext)

Me

OH

NH2OH

O

Me

OH

NH2OH

O

Me

OH

NH2HO

O

Me

OH

NH2HO

O

diastereomers diastereomersdiastereomers

enantiomers

enantiomers

A B

C D


◼ representationsofformulaeinorganicchemistry

◼ guidelinesfordrawingskeletalstructuresi) drawchainsofatomsaszig-zagsii) donotdrawCatomsunlessthereisgoodreasontodrawthemiii) donotdrawC-Hbondsunlessthereisgoodreasontodrawtheniv) donotdrawHsattachedtocarbonatomsunlessthereisgoodreasontodrawthemv) makedrawingsrealistic

◼ skeletalrepresentationsarefarlessclutteredandasaresultaremuchclearerthandrawingallcarbonandhydrogenatomsexplicitly,theyalsogiveamuchbetterrepresentationofthelikelybondanglesandhencehybridisation statesofthecarbonatoms

◼ skeletalrepresentationsallowfunctionalgroups(sitesofreactivity)tobeclearlyseen


◼ representingstructuresinthreedimensions

◼ awedgedbond indicatesthebondisprojectingoutinfrontoftheplaneofthepaper◼ adashedbond indicatesthebondisprojectingbehindtheplaneofthepaper◼ awavybond indicatesoneoftwothings:eitherunknownorunspecifiedstereochemistryoramixtureoftwostereoisomers


0 60 120

5

4

3

2

1

11

10

9

8

7

6

12

180 240

H

H

H

H

H H H

H

H

H

H H H

H

H

H

H H

H H

H

H

H H

H H

H

H

H H

◼ C2H6 - ethane

◼ generallyonlythemostandleaststableconformationsarediscussed

relativ

een

ergy/kJmol

-1

torsionangle/f °12

.6kJm

ol-1

eachH/Hinteraction4.2kJmol-1

◼ virtuallyaninfinitenumberofconformations

◼ conformation – anyspatialarrangementofatomsofamoleculesthatcanbeachievedbyrotationaboutsinglebonds


0 60 120

10

8

6

4

2

22

20

18

16

14

12

24

180 240 300 360

H H

Me

Me

H H

φ◼ conformationalanalysisofbutaneissimilartothatofethane

◼ staggeredconformationsareenergyminima

MeMe

f isthetorsionangle

Me

HH

Me

HHrelativ

een

ergy/kJmol

-1

torsionangle/f °fullyeclipsed gauche eclipsed staggered eclipsed gauche

21.3kJm

ol-1

15.1kJm

ol-1

3.7kJmol-1

◼ eclipsedconformationsareenergymaxima

◼ lowestenergyconformationhasMegroupsasfarapartaspossible

◼ highestenergyconformationhasMegroupseclipsingoneanother


STEREOCHEMISTRY– fromtheGreekstereós (στερεός) meaningsolid

◼ isomers– non-identicalmoleculeswiththesamemolecularformula

◼ constitutionofamoleculeisdefinedbythesequenceofbonds(atomconnectivity)betweenatomswithoutreferencetotheirdirectionsinspace– constitutionalisomershavethesamemolecularformulabutdifferentconnectivity

◼ stereoisomers – isomerswiththesameconnectivity– i.e.AlinkedtoBlinkedtoCetc.,butdifferentdispositionofatomsinspace

stereoisomerscannotbeinterconvertedbyrotationaboutsinglebonds(morelater)

◼ stereoisomerscanbedividedintotwomutuallyexclusiveclasses–enantiomersanddiastereoisomers (diastereomers)

STEREOISOMERS

ENANTIOMERSDIASTEREOISOMERS


◼ enantiomers (fromtheGreekforopposite– énanti (έναντι)– arestereoisomerswhicharerelatedasnon-superimposableobjectandmirrorimage(non-identicalmoleculesrelatedasobjectandmirrorimage)

◼molecules(andobjects)whichhaveanon-superimposablemirrorimagearecalledchiral (fromtheGreekforhand– chéri (χέρι))

◼ compoundsinwhichoneormorecarbonatomshavefournon-identicalsubstituentsarethelargestclassofchiralmolecules

◼ acarbonatom(orotheratom)bearingfourdifferentsubstituentsistermedastereogeniccentre orstereocentre –frequentlytermedachiralcentre

◼ converselyamolecule(orobject)istermedachiral ifitissuperimposableonitsmirrorimage


golfclubs- chiral

tennisrackets- achiral

hands- chiral

snails– chiral–usuallyright-handedhelix

left-handedsnailsarerarer

DNA– right-handedscrew

screws– chiral– right-handedscrew


HO

O

OHNH2

HON

N

HOO

O

H

NH

N

O

OOO

H

NH

N

O

O O

◼ enantiomershavedifferentpropertiesinachiral environmente.g.anenzyme

(+)-thalidomide,[α]D21 =+63(c 2.03,DMF)sedative,hypnotic,stopsmorningsickness

(–)-thalidomide,[α]D21 =–63(c 2.03,DMF)teratogen,foetal damage,congenitalmalformation

(+)-limoneneoranges

(–)-limoneneturpentine/lemon

(–)-carvonespearmint

(+)-carvonecaroway anddill

(S)-(–)-nicotine L-DOPA

◼ separatedenantiomersrotatetheplaneofplanepolarisedlightinequalbutoppositedirections– thisisopticalactivityandthesampleissaidtobeopticallyactive

◼ JeanBaptisteBiot (1774-1862)firstshowedthatsomenaturalsubstancescanrotatetheplaneofplanepolarisedlight

◼ enantiomershavethesamephysicalandchemicalpropertiesinanon-chiral(achiral)environment– i.e.theyareidentical(inanachiralenvironment)

◼ opticalactivitywasfirstdemonstratedbyPasteurin1848andledtotheidea oftetrahedralcarbon


MeOH

OH

O

NaOH, H2OMe

O NaOH

O(R)-D-(-)-lactic acid

[α]D = -3.8(R)-sodium lactate

[α]D = +13.5

HH

HMe CO2H

H NH2

CO2H

H NH2

hexahelicene[α]D = +3640!

(S)-L-(+)-alanine[α]D = +14.7

Ph

(S)-L-(–)-phenylalanine[α]D = –35.2

H

◼ schematicofapolarimeter

◼ opticalrotation.

sodiumlamp

solutionofsubstanceinpolarimetercell detector

wavelength,λconcentrationofsolution,c (g/mL)

celllengthl =1dm

Specificrotation:[α]DT =α /c × lα=observedrotationD =wavelengthofsodium“D”line– 589nmc =concentrationofsolutioning/mLl =lengthofcellindm (usually1dm)T=temperaturein°C

α

rotationtotherightdextrorotatory(+)rotationtotheleftlevorotatory(-)

◼ thereisnosimpleconnectionbetweenstructureandspecificrotation;however,singleenantiomersalwaysshowequalandoppositerotationifthespecificrotationismeasuredunderidenticalconditions

polarizingquartz


Br

Cl

Me

H

HO

HHO

CO2MeMe OH

OMeO

◼ a1:1mixtureofenantiomers istermedaracemicmixture(orracemate),aracemicmixture isopticallyinactive–doesnotrotatetheplaneofplanepolarisedlight

◼ ifareactionistoproduceanexcessofoneenantiomerovertheotherthenthereactionmustbeconductedinachiral,non-racemicenvironmente.g.inthepresenceofanenzymeorenantiomericallyenrichedreagentorcatalyst

◼ no opticallyactivematerialcanbegeneratedifallthestaringmaterial,reagentsandconditionsareeitherachiralorracemici.e.opticallyinactive.i.e.ifachiralcompoundissynthesisedfromachiralorracemicreactants,reagentsandcatalyststhenitwillbeformedasaracemate

◼ achiral (non-chiral)moleculesdonot rotatetheplaneofplanepolarisedlightandareopticallyinactive

◼ themagnitudeofthespecificrotationdependsonthewavelength,thetemperature,theconcentrationandthesolvent,amongotherthings

◼ Note: asampleofachiralmoleculemaycontainasingleenantiomeroritmaybeamixtureofenantiomers,dependingonhowitwasmade

◼ whichofthefollowingmoleculesarechiral?

CO2Me


◼ configuration – thespatialarrangementofatomsthatdistinguishesstereoisomers

◼ testsforthepresenceofchirality

◼ ifamolecule(orobject)hasaplanesymmetryitcannotbechiral

◼ thepresenceofastereogeniccentre,a.k.a astereocentre(i.e.acarbonwithfourdifferentsubstituents,oftencalledachiralcentre),isareliabletestforchiralityifthemoleculehasonlyonestereocentre

◼ moleculeswithmorethanonestereocentrecanbeachiral(moreofthislater)

◼ theonlyreliabletesttodetermineifamoleculeischiral,isthetestofnon-superimposability ofthemirrorimagewiththeobject


N

MeN

Me

◼ chiralmoleculesarenotrestrictedtothosehavingacarbonatomcarryingfourdifferentsubstituents

◼ ifthenitrogensubstituentscanbe‘tied-back’topreventpyramidalinversionthentheaminemayberesolved

◼ generallyaminesthathavethreedifferentgroupsonnitrogencannotberesolvedintoseparateenantiomersasveryrapidpyramidalinversionoccursatroomtemperature

◼ sulfoxides,sulfinamides,phosphinesandphosphineoxidescanallbechiralandarefrequentlyconfigurationallystableatroomtemperature

Tröger’s baseachiralmolecule

◼ thecentralatom(PorS)cancarryfourdifferentsubstituentsoneofwhichcanbealonepairofelectrons


◼ stereoisomerswhicharenotrelatedtoeachotherasenantiomersaretermeddiastereomers

◼ diastereomershavedifferentphysicalandchemicalproperties– differentNMRspectra,IRspectra,meltingpoint,boilingpointetc.– theyaredifferent compounds

◼ allstereoisomerswhicharenotrelatedasnon-superimposableobjectandmirrorimagearerelatedasdiastereomers

◼ Note:itistherelationships,enantiomericanddiastereomeric, thataremutuallyexclusivei.e.twoparticularstereoisomersareeither enantiomers ordiastereomers;however,amoleculethatisenantiomeric tooneothermolecule,mayalsobediastereomerictoothermolecules

◼ rememberenantiomersarerelatedasnon-superimposableobjectandmirrorimageandhenceonlyhavedifferentpropertiesinachiralenvironment– theyareidenticalinanachiralenvironment– moreonthislater


Isomers:compoundswiththesamemolecularformula

Constitutionalisomers (structuralisomers):samemolecularformula,differentconnectivity

Enantiomers:Stereoisomersrelatedasnon-superimposableobjectandmirrorimage

Diastereomers:Allstereoisomersnotrelatedasenantiomers

Stereoisomers:Samemolecularformula,sameconnectivitydifferentdispositionofatomsinspace

◼ flowchartofisomers


◼ a→b→c isclockwisethestereochemical descriptorisR◼ a→b→c isanticlockwisethestereochemicaldescriptorisS

Cahn-Ingold-PrelogSequenceRules

◼ itisimportanttobeabletolabeltheconfiguration ofastereocentre centreinmuchthesamewayasgeometricalisomersofdoublebondsaretermedcis andtrans

◼ R =Rectus(Latinfor‘right’)andS =Sinister(Latinfor‘left’)areusedtolabeltheconfigurationsofstereogeniccentres

◼ assignthepriorityofeachatomdirectlyattachedtothestereocentre onthebasisofatomicnumber– higheratomicnumber=higherpriority

◼ ifatomsdirectlyattachedtothestereocentre havethesameatomicnumbermovedowneachsubstituentoneatomatatimeuntilthefirst differenceisreached,withhigheratomicnumberalwaysbeingthefirstpointofdifference

◼ sameatomicnumberbutdifferentmassnumber– highermassnumbertakesprioritye.g.T>D>H

◼ drawmoleculewiththelowestprioritysubstituent(priorityd)attherear

substituent 1st atom 2nd atom priority

OH O a

CO2H C O b

CH3 C H c

H H d


Me CO2H

NH2

CO2H

NH2HS

CO2H

NH2

HSPh

O

OHF3C OMe

PhO

ClF3C OMe

OH

C CH

R

HCH

CCH

CR

C C R CC

CCC

CR

COH

OCO

OHOC

CO

HOC

substituent treatas 1st atom 2nd atom priority

OH OH O H a

CHO C O, O, H b

CH2OH CH2OH C O, H, H c

H H H d

◼ Cahn-Ingold-PrelogSequenceRules- continued

Treatdoubleandtriplebondsasmultiplesinglebonds:

◼ assignR andS stereochemical descriptorstothefollowingmolecules

treatas

treatas

treatas

HO2CCO2H

OH

OHHO2C

CO2HOH

OH

HN

O N

S

O

OOH

H


Me O

OMe

O

O

FO

CCl3

◼ Cahn-Ingold-PrelogSequenceRules- continued◼ theCIPrulescanbeextendedtotheassignmentofdoublebondgeometry.

◼ lookatoneendofthedoublebondanddecidewhichsubstituenthashigherpriority.

◼ lookattheotherendofthedoublebondanddecidewhichsubstituenthashigherpriority.

◼ doublebondis(Z)ifthethehigherordersubstituentsareonthesamesideofthedoublebond(Zusammen – togetherinGerman)

◼ doublebondis(E)ifthehigherordersubstituentsareontheoppositesideofthedoublebond(Entgegen – oppositeinGerman)

◼ assign(E)or(Z)tothefollowingalkenes


◼ someusefulstereochemicalprojections

◼ sawhorseprojection– lookingdowntheC–Cbondwithanangledprojection

◼ Newmanprojection– lookingdowntheC–Cbond

◼ Fisherprojectionsarenolongerausefulstereochemicalprojectionbutarehistoricallyimportante.g.tartaricacid


◼moleculeswithtwostereocentres– wewillusethedihydroxylationofalkenesusingosmiumtetroxideasanexample

◼ OsO4 isareagentthataddstwo‘OH’groupstothesamefaceofanalkene– syn addition(mechanisminlatercourse)

◼ threeprojectionsoftheproductsformedfromthesyn-additionoftwoOHgroupstothetoporbottomfaceof(E)-but-2-ene (trans-but-2-ene)

◼ theproductsformedfromadditiontoeitherfaceofthealkenearedifferent– theyarestereoisomers– theyareenantiomers

◼ aside - iftwogroupsareaddedtotheoppositefacesofanalkenethisistermedanti addition


Me

HO

HH Me

OH

OH

MeHH

HO

Me

H MeMeH

OH

H Me

OH

H Me

Me

MeH

H

HO

MeH

OH

MeH

MeOH

OH

Me

MeOH

OH

MeMe

Me

◼ (Z)–but-2-ene

add2xOHgroupstopface

add2xOHgroupsbottomface



add2xOHgroupsbottomface


◼ threeprojectionsoftheproductsformedfromthesyn-additionoftwoOHgroupstothetoporbottomfaceof(Z)-but-2-ene(cis-but-2-ene)

(Z)-but-2-ene

cis-but-2-ene

(Z)-but-2-ene

◼ theproductsformedfromadditiontoeitherfaceofthealkenearethesamei.e.onlyonestereoisomerisformed

◼ thisstereoisomerhasaplaneofsymmetryandisthusachiral(notchiralandisopticallyinactive)

◼ thisstereoisomeristermedameso compound

meso compound- achiral

identical

RS

RS


◼ therearethereforethreestereoisomersofbutane-2,3-diol

◼ asimpledefinitionofameso compoundisastereoisomerwithtwoormorestereocentres butwhichisitselfachiral

afullerdefinitionisthata‘meso compoundisanachiralmemberofasetofdiastereomers thatincludesatleastonechiralmember’Elliel


CO2HHO2C

HO2COH

OH

CO2H

HO

HHO2C

OH

H OH

H CO2H

OH

H

CO2HHO

OH

HO2C

HO2CCO2H

OH

OHCO2H

HO2COH

OH

HO2C

OHH

CO2H

HO H

CO2H

HO H

HO2C

OHH

•

HO2CCO2H

OH

OHCO2H

HO2COH

OH

HO2C

OHH

CO2H

H OH

CO2H

HO H

HO2C

HHO

◼ 2-stereogeniccentres– tartaricacid– potentialdescriptorcombinationsRR,SS,RS,SR

a

b

c

dR

a

b

c

d

R

Sa

bc

d

a

b

c

dS

S,S

objectandmirrorimagearethesame(superimposable)achiral,meso,form SR=RS=meso

a

b

c

d

R

a

b

c

dS

a

bc

dR

a

b

c

dS

pairofenantiomers(non-superimposableobjectandmirrorimage)

◼ asdrawntheconformersofthemeso compoundhaveacentreofinversioni (•)

••

•

◼molecules(objects)withacentreofinversioncannotbechiral

◼ redrawinginadifferentconformationrevealsaplaneofsymmetry(s,ofteneasiertospotthani)indicatingthatthisstereoisomerisachiral

◼ ifamoleculecangainaccesstoaconformationwhichisnon-superimposableonitsmirrorimagethenitwillbeachiral

◼ ifamoleculecangainaccesstoaconformationthathasaplaneofsymmetryorcentreofinversion(ormoregenerallyanimproperaxisofrotationSn)thenitwillbeachiral

R,R

◼ thereare3steresiomers oftartaricacid,apairofenantiomers,andthemeso-form

CO2HHO2C

HO2COH

OH

CO2H

HO

HHO2C

OH

H OH

H CO2H

OH

H

CO2HHO

OH

HO2C


Cl

Br

Cl

Br

Cl

Br

Cl

Br

◼ 2-stereogeniccentres- 1,2-dichlorocyclopropane– 3stereoisomers

◼ incompoundswith2stereocentres,whenthegroupsarenotthesametherearealways4stereoisomers

◼ ifacompoundhasn stereogeniccentres(ormoregenerallystereogenicelements)thenthemaximumnumberofstereoisomersis2n

◼ 2-stereogeniccentres– 3-aminobutan-2-ol4stereoisomers,2pairsofenantiomers

◼ formoleculeswithmultiplestereocentresallstereocentresmustbeinvertedtoconvertoneenantiomerintotheoppositeenantiomer


enantiomers

enantiomers

A B

C D

NH2

OH

NH2

OH

NH2

OH

NH2

OH


enantiomers

enantiomers

A B

C D

◼ 2-stereogeniccentres– 1-bromo-2-chlorocyclopentane4stereoisomers,2pairsofenantiomers


OH

OH

OH

PhCH=CH

OH

Me

O

OBr

BrOH

Me Me

◼ toinvestigatehowmanystereoisomersacompoundhasthefollowingmethodmaybeuseful:

i) ifacompoundhasn stereogeniccentres(ormoregenerallystereogenicelements)thenthemaximumnumberofstereoisomerswillbe2n – ifyouhavemorethan2n youhavemadeamistake

ii) ifthecompoundisacyclicdrawitinzig-zagfashioniii) identifythestereocentresiv) decidehowmanydiastereomerstherearebyputtingsubstituents,withdefinedstereochemistryon

thestereocentresv) lookforpossibleplanesofsymmetry(orcentresofinversion)andhencedecidewhichdiastereomers

arechiral– identifymeso compounds– thepresenceofmeso compoundsreducesthenumberofstereoisomers

vi) drawtheenantiomersofanychiraldiastereomersbyinvertingallofthestereogeniccentres- chiralsteroisomers always comeinpairsi.e.twoenantiomers

◼ drawallthestereoisomersofthefollowingcompounds.Whatarethestereochemical relationshipsbetweenthevariouspairsofstereoisomers?Whichofthestereoisomersarechiral?Identifyanymesocompounds

HOOH

OH

OHO

H


◼ racemisation– theconversionofoneenantiomer(oranexcessofoneenantiomer)intoa1:1mixtureofenantiomers(aracemate orracemicmixture)

◼ e.g.SN1reaction(moreofthisinlatercourses)

◼ onrecombination,Br– hasequalprobabilityofattackingeithersideofthecarbocationleadingtoaracemicmixture

Energy

reactioncoordinate

Ph

EtMe

Ph

BrEt

Me

Ph

BrEtMe

activationenergy,E

a


◼ sofarwehavemainlylookedat‘central’chirality– wewillnowbrieflylookatplanar,axialandhelicalchirality

◼ chiralityisamolecularproperty(infactapropertyofanobject)soitisnotnecessaryforamoleculetopossesastereocentre(chiralcentre)inordertobechiral

◼ thenecessaryandsufficientconditionforamoleculetobechiralisthatitisnon-superimposableonitsmirrorimage(i.e.thatitlacksanimproperaxisofrotation(Sn))

◼ allenes

◼ whichofthefollowingmoleculesarechiral?

•H

Me Me

H•

H

Me H

H Cl

H

CO2H

H

HO

H

H

OH• •

Br

Me

Et

ClC

H

Me Me

H


O2N

HO2CNO2

CO2HO2N

HO2CCO2H

NO2NO2

CO2HHO2C

NO2

◼ atropisomers andaxialchirality– biphenyls

◼ atropisomers maybedefinedasstereoisomersresultingfromrestrictedrotationaboutsinglebonds

◼ the(arbitrary)definitionofatropisomers isthattheyhaveahalflifeofatleast1000satagiventemperature(>90kJ•mol-1 at300K)– therotationalbarrierneedstobehighenoughthattheseparateisomericspeciescanbeisolated

chiralaxis

severesterichindrancemeansrotationaroundthecentralC-Csinglebondonlyoccursathightemperatureandthiscompoundcanberesolved

non-superimposable

Ph2P

PPh2

PPh2

Ph2PPPh2

PPh2

HH

HH

HH

HH

helicenes

cyclophanes

strainedalkenes

◼ trans-cyclooctene isstabletoracemisationindefinitelyat20°C(chiral)

◼ cis-cyclooctene isachiraltrans-cyclooctene

enantiomers

enantiomers

enantiomers

enantiomers


◼ ResolutionofRacemates – separationofa1:1mixtureofenantiomersi.e.(±)mixture,intopure(+)and(–)forms

◼ problem:enantiomershaveidenticalphysicalpropertiesthereforetheyareverydifficulttoseparate

◼ if aracematecrystallisesitcaneithercrystallisesothateachcrystalcontainsbothenantiomers(aracemiccrystal)orsuchthateachcrystaliseither(R)or(S)– thisistermedaconglomerateandapproximately5-10%ofchiralcrystallinematerialscrystalliseinthismanner

◼ sodiumammoniumtartratecrystallisesasaconglomerate,whichallowedPasteurtoseparatetheenantiomericcrystalsbyhand

O2CCO2

OH

OH

NH4Na

O2CCO2

OH

OH

NH4Na O2CCO2

OH

OH

NH4Na

O2CCO2

OH

OH

NH4Naseparatecrystals

[α]D20 =–12(c =20inwater)(–)-tartaricacid- unnatural

[α]D20 =+12.4(c =20inwater)(+)-tartaricacid- natural

◼ thisisnotageneralsolutiontotheseparationofenantiomersas:i)notallracemates arecrystallineii)themajorityofchiralcrystallinematerialsarenotconglomerates


O OBn

O

NH

MeLiAlH4

HO OBn

(S)-(-)-alcoholsingle enantiomer

◼ separatingdiastereomers– diastereomersaredifferentmolecules,andhavedifferentphysicalproperties,◼ weshouldthereforeexpecttobeabletoseparatediastereomersbystandardmethodsincluding:chromatographyonsilica,crystallisation,distillationetc.◼ thispropertyofdiastereomersindirectlyallowstheseparationofmixturesofenantiomers◼ aracemicmixtureisa1:1mixtureofenantiomers◼ ifwereacttheracemicmixturewithasingleenantiomerofareagentwewillproducediastereomerswhichare(atleasttheoretically)separable

HO OBnMe N

(S)-(+)-1-(1-naphthyl) ethyl isocyanate

CO, Et3N

O OBn

O

NH

Me

O OBn

O

NH

Me

+

O OBn

O

NH

Me

O OBn

O

NH

Me

racemic

separatediastereomersbychromatography


CO2H

PhMe

Me

CO2H

PhMe

Me

racemic mixture of acids

Ph Me

NH2 enantiopure(R)-α-methylbenzylamine

CO2

PhMe

Me

CO2

PhMe

Me

Ph Me

NH3

Ph Me

NH3

diastereomeric salts

(R, R)-salt crystallised from solution

CO2

PhMe

MePh Me

NH3 acidifyCO2H

PhMe

Me(R)-acid

(S, R)-salt remains in solution

CO2

PhMe

Me

Ph Me

NH3

acidifyCO2H

PhMe

Me(S)-acid

◼ itcanbemuchmoreefficienttodoaresolutionbyselectivecrystallisationofdiastereomeric salts◼ diastereomeric salts,muchlikediastereomers,havedifferentphysicalpropertiesincludingmeltingpointsandsolubilityandhenceselectivecrystallisationisfrequentlypossible


RbO2C CO2Na

OH

OH(+)-tartaric acidsodium rubidium salt(R, R)

HO

O

HOH

◼ absoluteandrelativeconfiguration

◼ before1951wedidnotknowtheabsoluteconfigurationofanymoleculei.e.wedidnotknowwhattheactual3-Darrangementofatomswas.Forexamplewecouldnottellif(+)- tartaricacidwas(R,R)or(S,S)

◼ Rosenhoff hadarbitrarilyassignedtheabsoluteconfigurationofD-(+)-glyceraldehydeas(R)

◼manycompoundswereassignedabsoluteconfigurationbytediouschemicaldegradation,iftheywererelatedtotheassignedconfigurationofD-glyceraldehydetheywerecalledD-compounds,regardlessofthedirectionofopticalrotation(iftheywererelatedtotheenantiomerofD-glyceraldehydetheywerecalledL-compounds)

◼ in1951JohannesMartinBijvoet (1892-1980)usedX-raycrystallographytoassigntheabsoluteconfigurationtosodiumrubidium(+)-tartratetetrahydrate– Rosenhoff hadguessedcorrectly.

D-(+)-glyceraldehyde


HO2CCO2H

OH

OH

(R, R)-tartaric acid

HO2CCO2H

OH

OH(S, S)-tartaric acid

HO2CCO2H

OH

OHmeso-tartaric acid

◼ absoluteandrelativeconfiguration

◼ absoluteandrelativeconfigurationcanthereforebedefinedasfollows:ifweknowwhichenantiomericseriesamoleculeisinweknowitsabsoluteconfiguration

ifweonlyknowitsrelativeconfigurationweonlyknowhowthestereogeniccentreswithinamoleculearerelatedtooneanother

◼ toputitanotherway:“Whenthestereochemistrydrawnonamoleculemeans‘thisdiastereomer’wesaywearerepresentingrelativeconfiguration;whenitmeans‘thisenantiomerofthisdiastereomer’wesaywearerepresentingitsabsoluteconfiguration”fromClayden,Greeves,Warren

samerelativedifferentabsoluteconfiguration

differentrelativeconfiguration

differentrelativeconfiguration

◼ generationofchirality– thechiralpoolAsstatedpreviouslyno opticallyactivematerialcanbegeneratedifallthestaringmaterial,reagentsandconditionsareeitherachiralorracemici.e.opticallyinactive.

Ultimatelytogeneratenon-racemicmaterial(materialwhichisopticallyactive)itisnecessarytoutilisemoleculesfromthechiralpooli.e.fromthevastarrayofenantiopure andenantioenrichedmoleculeswhichoccurinNature

TheChiralPool AminoacidsSugars Terpenes Hydroxyacidsetc.

H2N CO2H

R

O

OH

HO OH

HO OH

Me

HO OHO

O

OH

OH


◼ Glossaryofterms(workingdefinitions)

achiral – notchirali.e.molecule/objecthasasuperimposablemirrorimage.Ifamoleculecangainaccesstoaconformationwhichhasaplaneofsymmetry(orcentre

ofinversion)itwillbeachiral

chiral – molecules(andobjects)whichhaveanon-superimposablemirrorimage

chiralcentre– seestereogeniccentre

diastereomers – stereoisomers whicharenotrelatedasenantiomers

enantioenriched– consistingofanexcessofoneenantiomer

enantiopure – consistingofasingleenantiomer.

enantiomers - stereoisomers whicharerelatedasnon-superimposableobjectandmirrorimage

epimer – diastereomers relatedbythedifferenceinconfigurationatonechiralcentre

mesocompound- astereoisomer withtwoormorestereocentresbutwhichisitselfachiral(anachiralmemberofasetofdiastereomersthatincludesatleastone

chiralmember)

opticallyactive – rotatestheplaneofplanepolarisedlight– canonlyoccurwithnon-racemicsamples

racemateorracemicmixture – 50:50mixtureofenantiomers;aracemate isopticallyinactive.

racemisation – theconversionofoneenantiomer (oranexcessofoneenantiomer)intoa50:50mixtureofenantiomers

stereogeniccentre(stereocentre) – anatom(generallycarbon)withfournon-identical substituents– alsocalledachiralcentre

stereoisomers – isomerswiththesameconnectivity– i.e.AlinkedtoBlinkedtolinkedtoCetc.butdifferentdispositionofatomsinspace

Appendix

nameofgroup formula abbreviation

methyl –CH3 Me

ethyl –CH2CH3 Et

propyl –CH2CH2CH3 Pr

butyl –CH2CH2CH2CH3 Bu

phenyl –C6H5 Ph

acyl CH3CO AcO

Introduction to Organic Chemistry 2018 moreburton.chem.ox.ac.uk/handout-2_intro.pdf · Introduction...

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