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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
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