Stereochemistry

KNG-CHM102–Lecture3

Samemolformula,butgroupsarrangeddifferentlyinspace

Samemolformula,butdifferentchemicalstructures

trans cis

Geometricalisomers

OpFcalisomers Non-superimposablemirrorimages

Non-superimposablemirrorimages

ChiralityAchiral

Non-superimposablemirrorimages Nonsuperimposablemirror-imagemoleculesarecalledenan$omers(fromtheGreekenan$on,whichmeans“opposite”)

Solidwedgesbondsthatpointoutoftheplaneofthepapertowardtheviewer

HatchedwedgesBondsthatpointbackfromtheplaneofthepaperawayfromtheviewer

RepresenFngchiralmolecules

Fischerprojec$ons

VerFcallinesextendbackfromtheplaneofthepaperawayfromtheviewer

Horizontallinesprojectoutoftheplaneofthepapertowardtheviewer

EmilFischer(1852–1919)GermanyHebecameachemistagainstthewishesofhisfather,asuccessfulmerchant,whowantedhimtoenterthefamilybusiness.ProfessorofchemistryattheUniversi$esofErlangen,Würzburg,andBerlin.NobelPrize1902chemistryworkonsugarsDuringWorldWarI,heorganizedGermanchemicalproduc$on.Twoofhisthreesonsdiedinthatwar.

NamingEnanFomers:TheR,SSystemofNomenclature

1.Arrangethegroupsaccordingtopriority:atomicnumbersoftheatomsdirectlyaYachedtotheasymmetriccarbon

2.Orientthemoleculesothatthegroup(oratom)withthelowestpriority(4)isdirectedawayfromyou.Drawanimaginaryarrowfromthegroup(oratom)withthehighestpriority(1)tothegroup(oratom)withthenexthighestpriority(2).Arrowpointsclockwise-RconfiguraFon(Risforrectus,LaFnfor“right”).Arrowpointscounterclockwise-theSconfiguraFon(Sisforsinister,LaFnfor“le]”).

Drawingthearrowfromgroup1togroup2,youcandrawpastthegroupwiththelowestpriority(4),butNOTpastthegroupwiththenextlowestpriority(3).

Assigningconfigura$onofacompoundfromFischerprojec$on

Group(oratom)withthelowestpriority(4)isonaver$calbond

Group(oratom)withthelowestpriorityisonahorizontalbond

AnswerfromthedirecFonofthearrowwillbetheoppositeofthecorrectanswer

OpFcalAcFvity

•  NormallightconsistsofelectromagneFcwavesthatoscillateinalldirecFons.

•  Plane-polarizedlight(orsimplypolarizedlight),oscillatesonlyinasingleplanepassingthroughthepathofpropagaFon.

•  PolarizedlightisproducedbypassingnormallightthroughapolarizersuchasapolarizedlensoraNicolprism.

Polarizedsunglassesallowonlylightoscilla$nginasingleplanetopassthroughthem,-blockreflec$ons(glare)moreeffec$velythannonpolarizedsunglasses.

Achiralcompounddoesnotrotatetheplaneofpolariza$on.Itisop$callyinac$ve

Achiralcompoundrotatestheplaneofpolariza$on:clockwiseorcounterclockwiseTwoEnanFomersrotatetheplaneofpolarizaFonexactlythesameamountinoppositedirecFons.

Polarimeter

AmountofrotaFonvarieswiththewavelengthofthelightusedThelightsourceforapolarimetermustproducemonochromaFc(singlewavelength)light.Polarimetersuselightfromasodiumarc(sodiumD-line;589nmwavelength)

Observedrota$onαitismeasuredindegrees.Itdependson•  ConcentraFonofthesample•  Lengthofthesampletube.•  Temperature•  Wavelengthofthelightsource.

Polarimeter

))(,()(][ionconcentratdmlength

rotationobservedrotationspecific αα ==

Concentration: pure liquid in g/mL; solution in g per 100 mL of solvent

before after

CharacterisFcofopFcallyacFvecompoundsThespecificrota$onisthenumberofdegreesofrotaFoncausedbyasoluFonof1.0gofthecompoundpermLofsolu$oninasampletube1.0dmlongataspecifiedtemperatureandwavelength.SpecificrotaFoncalculatedfromtheobservedrotaFon

Tistemperaturein°Cλ  isthewavelengthoftheincidentlight(sodiumD-line)listhelengthofthesampletubeindecimeterscistheconcentraFonofthesampleingramspermilliliterofsoluFon

SpecificrotaFon

Mirrorimagestructures(enanFomers)rotatetheplaneofpolarizaFonthesameamountbutintheoppositedirecFon

•  RortheSconfiguraFondoesnottellthedirecFonthecompoundrotatestheplaneofpolarizaFon

•  SomecompoundswiththeRconfiguraFonrotatetheplanetotheright(+)andsomerotatetheplanetothele](-)

AmixtureofequalamountsoftwoenanFomers—suchas(R)-(-)lacFcacidand(S)-(+)lacFcacid—iscalledaracemicmixture(±)Racemicmixturesdonotrotatetheplaneofpolarizedlight.Thesymbolisusedtospecifyaracemicmixture.

Racemates

Op$calPurityandEnan$omericExcess

Observedspecificrota$onindicatesifitisasingleenan$omeroramixture:0°-aracemicmixture

Specificrota$onof(S)-(+)2-bromobutaneis+23.1°Ifasampleof2-bromobutanehasanobservedspecificrotaFon+9.2o-mixtureofenanFomerswithSconfiguraFon>theenanFomerwiththeRconfiguraFon.

Enan$omericexcess(ee)-howmuchexcessofoneenanFomeroverotherenanFomerinthemixture

Aslongasthecompoundischemicallypure,enanFomericexcessandopFcalpuritywillbethesame.40%ofthemixtureisexcessSenanFomerand60%isaracemicmixture

Halfoftheracemicmixture(30%)plustheamountofexcessSenanFomer(40%istheamountoftheSenanFomer(70%)presentinthemixture.Thus,70%ofthemixtureistheSenanFomerand30%istheRenanFomer.

IsomerswithMorethanOneAsymmetricCarbon

Moreasymmetriccarbonsacompoundhas,themorestereoisomersarepossibleforthecompound.

Maximumof2nstereoisomerswherenequalsthenumberofasymmetriccarbons.

(2S,3S)-3-Chloro-2-butanol;(2S,3S)-3-Chloro-2-butanol;(2S,3S)-3-Chloro-2-butanol;(2R,3R)-3-Chloro-2-butanol

Fourstereoisomersof3-chloro-2-butanol-twopairsofenanFomersDiastereomersarestereoisomersthatarenotenan$omers.

EnanFomerswithgroupsonthesamesideofthecarbonchainarecalledtheerythroenan$omersThosewithsimilargroupsonoppositesidesarecalledthethreoenan$omers

Somecompoundswithtwoasymmetriccarbonshaveonlythreestereoisomers.

MesoCompounds

The“missing”isomeristhemirrorimageof1because1anditsmirrorimagearethesamemolecule.

MesoCompounds

mesocompounds:Eventhoughameso(mee-zo)compoundhasasymmetriccarbons,itisanachiralmoleculebecauseitissuperimposableonitsmirrorimage.MesosistheGreekwordfor“middle.”

Ifacompoundhasaplaneofsymmetry,itwillnotbeop$callyac$veeventhoughithasasymmetriccarbons

Whichoneismesoisomer?

TheR,SSystemofNomenclatureforIsomerswithMorethanOneAsymmetricCarbon?

1-Bromo-2-methylcyclopentane-twoasymmetriccarbonsandfourstereoisomers.ThecisisomerexistsasapairofenanFomers,andthetransisomerexistsasapairofenanFomers.

Tartaricacid

1.  EnanFomerscannotbeseparatedbytheusualseparaFontechniques:

2.  fracFonaldisFllaFonorcrystallizaFonbecausetheiridenFcalboilingpointsandsolubiliFes

3.  LouisPasteurwasthefirsttoseparateapairofenanFomerssuccessfully.

4.  crystalsofsodiumammoniumtartrate-notedthatthecrystalswerenotidenFcal—someofthecrystalswere“right-handed”andsomewere“le]-handed.”

5.  Physicallyseparatedthetwokindsofcrystalswithapairoftweezers.

6.  FoundthatasoluFonoftheright-handedcrystalsrotatedtheplaneofpolarizedlightclockwise,whereasasoluFonofthele]handedcrystalsrotatedtheplaneofpolarizedlightcounterclockwise.

LouisPasteur(1822–1895)•  firsttodemonstratethat

microbescausespecificdiseases.\

•  microorganismscausegrapejuicetoferment,producingwine,causewinetoslowlybecomesour.

•  hea$ngthewinea[erfermenta$on,aprocesscalledpasteuriza$on,killstheorganismssotheycannotsourthewine.

SeparaFngEnanFomers

SeparaFngEnanFomers

ReacFonsofCompoundsthatContainanAsymmetricCarbon

Ifareac$ondoesnotbreakabondtotheasymmetriccarbon,thereactantandtheproductwillhavethesamerela$veconfigura$ons

IfareacFondoesbreakabondtotheasymmetriccarbon,youcannotpredicttheconfiguraFonoftheproductunlessyouknowthemechanismofthereacFon

AnachiralreagentreactsidenFcallywithbothenanFomers.AchiralreagentreactsdifferentlywitheachenanFomer.

EnanFomerscanbeseparatedeasilyiftheyaresubjectedtoreacFoncondiFonsthatcauseonlyoneofthemtoreact.EnanFomershavethesamechemicalproperFes,sotheyreactwithachiralreagentsatthesamerate.

DiscriminaFonofEnanFomersbychiralreagents

StereospecificcatalyFcreacFons

Ryogi Noyori

BINAP

Barry Sharpless

AddH2toalkene

Chiralepoxida$on

Receptors

ApprovedasasedaFveforuseinEuropeandCanadain1956.DextrorotatoryisomerhasstrongersedaFveproperFesLevorotatoryisomerwashighlyTeratogenic—causeshorriblebirthdefects—womenwhoweregiventhedrugduringthefirstthreemonthsofpregnancygavebirthtobabieswithawidevarietyofdefects,suchasdeformedlimbs.

WhyonlyoneenanFomerisboundbyareceptor.OneenanFomerfitsintothebindingsiteandonedoesnot.

StereochemistryofEnzyme-CatalyzedReacFons

EnanFotopicHydrogens,DiastereotopicHydrogens,andProchiralCarbons

OtherSourcesofChirality

C C CCO2H

HHO2C

HCCC

HO2C

H CO2H

H

Allenedicarboxylicacid

OO

1,7-dioxaspiro[5.5]undecane

trans-cyclooctene

HH

HH

(R) "M" (S) "P"

OOO

O

(R) "M" (S) "P"

atropisomerism

A

BB

AA

BB

A

(R) "M" (S) "P"

41

ChiralSwitchesS-AMLODIPINE Anti-hypertensive S-METOPROLOL Anti-hypertensive S-PANTOPRAZOLE PPI R-ONDANSETRON Anti-emetic DEXRABEPRAZOLE PPI ESZOPICLONE Non-barbiturate Hypnotic DEXIBUPROFEN NSAID DEXKETOPROFEN NSAID R-SIBUTRAMINE Anti-obesity S-ETODOLAC NSAID ARMODAFINIL Narcolepsy

Naturalproductsarethemoleculesofnature

Adrenalineisahumanhormone.Itisproducedinmomentsofstressandincreasesourbloodpressureandheartratereadyfor‘fightorflight’.You’vegottositanexamtomorrow—surgeofadrenaline.

ThemoleculeinhemlockthatkilledSocrates

Thetoxininabsinthethatkilledthenineteenth-centuryarFstsinParis

Causesinnumerabledeathsthroughheartdiseasebutwhichisavitalcomponentofcellwalls

Onedropofwhichwouldinstantaneouslyclotallthebloodinyourbodybutwithoutwhichyouwouldbleedtodeathifyoucutyourself

Picrotin E.J.Corey

Monensin W.Clark-Still

Amphotericin K.C.Nicolaou

Lasalacid R.E.Ireland

Some complex molecules synthesised by chemists

Viagra citrate

Nobel1990

•  Brevetoxin,awonderfulanddeadlymolecule.•  AlternaFngoxygenatomsonthetopandboYomfacesof

alternaterings•  Rings—six-,seven-,andeight-membered,eachwithonlyone

oxygenatom.•  ConFnuouscarbonchainrunningfromthelactonecarbonyl

groupintheboYomle]-handcornertothealdehydecarbonylinthetopright,nobranching.

•  22stereogeniccentres,thisisabeauFfulpieceofmoleculararchitecture.

Palitaxin,themostcomplexnaturalproduct,fromfishwassynthesisedbyKishiatHarvard

R.B.Woodward

Synthesis of most complex natural products

Nobel Prize 1965

Emil Fischer

Synthesis of D-glucose, 1890, First total, chiral synthesis

Robert Robinson

Natural Products Synthesis, 1917, Tropinone synthesis by reterosynthetic analysis

We stand on their shoulders…

C.Ingold

Physical organic chemistry

B.Merrifield SolidphasesynthesisNobel Prize 1984