Chapter 4: Stereochemistry - Colby College

1 Chapter 4: StereochemistryIntroduction To StereochemistryConsider two of the compounds we produced while finding all the isomers of C7H16:2-methylhexame is superimposable with its mirror imageCH3CH32-methylhexane3-methylhexaneM eCMe2-methylhexaneMeMeHBuMeMeHBumirrorro tateMeMeHBuHIntroduction To StereochemistryCH3CH32-methylhexane3-met hylhexaneEtMeHPrEtMeHPrmirrorrotateCMe3- methylhexaneHEtMePrHConsider two of the compounds we produced while finding all the isomers of C7H16:2-methylhexame is superimposable with its mirror imageIntroduction To Stereochemistry Compounds that are not superimposable with their mirror image are called chiral (in Greek, chiral means"handed") 3-methylhexane is a chiral molecule. Compounds that are superimposable with their mirror image are called achiral.

2 2-methylhexane is anachiral molecule. An atom (usually carbon) with 4 different substituents is called a stereogenic center or two of the compounds we produced while finding all the isomers of C7H16:EnantiomersTwo compounds that are non-superimposable mirror images (the two "hands") are called To StereochemistryStructural (constitutional) Isomers - Compounds of the same molecular formula with different connectivity(structure, constitution)Conformational Isomers - Compounds of the same structure that differ in rotation around one or moresingle bondsConfigurational Isomers or Stereoisomers - Compounds of the same structure that differ in one or moreaspects of Stereochemistry (how groups are oriented in space - enantiomers or diastereomers)2-methylpentane3-methylpen taneMeHHHHMeMeHHMeHHMeHHMe3-methylhexane 3-methylhexaneWe need a a way to describe the Stereochemistry !

3 The CIP System RevisitedMeHHMe123412341. Rank each substituent attached to the stereocenter according to the CIP priority system (1 = highest, 4 = lowest)2. "View" the compound with the lowest priority substituent pointing away from youEtPrMeH1234 PrEtMeH1234 MeH12343. Draw a circular arrow from connecting substituents 1 3 from highest to lowest priority. If the arrow moves clockwise, the sterocenter is labeled (R) [this stands for rectus]. If the arrow moves counterclockwise, then the stereocenter is labeled (S) [this stands for sinister].EtPrMeH1234 MeHHMePrEtMeH1234 HMe1234counterclockwiseclockwise(S)-3-me thylhexane(R)-3-methylhexaneThe CIP System RevisitedH3 CCH3 BrHH3 CCH3 FHHCH3 OHOCH3HH3 CCH3CH3 The CIP System RevisitedH3 CCH3 BrHH3 CCH3 FHHCH3 OHOCH3HH3 CCH3(R)-2-fluorobutane(S)-4-bromo-2-meth yl-1-pentene(S)-3-tert-butylcyclohexene( R)-2-hydroxy-2-methyl-butanalH3 CCH3FH123412341234CH31234 HCH3H3C1234H3 CProperties of Chiral MoleculesChiral objects can only be "recognized" as chiral by another chiral objectOHOHC arvoneWhich is (S) and which is (R)?

4 [Your nose can tell!]OHOHC arvone12341234(S)(R)Properties of Chiral MoleculesChiral objects can only be "recognized" as chiral by another chiral objectOHOHC arvoneWhich is (S) and which is (R)? [Your nose can tell!]OHOHC arvone12341234(S)(R)Properties of Chiral MoleculesChiral objects can only be "recognized" as chiral by another chiral objectOHOH(R)-carvone [odor of spearmint](S)-carvone [odor of caraway seed]Multiple StereocentersMeHHMe(S)-3-methylhexane(R) -3-methylhexaneMeHMeClClHMeHClHMeHClHMeH ClH3(S), 4(R)-3-chloro-4-methylhexane3(S), 4(S)-3-chloro-4-methylhexane3(R), 4(R)-3-chloro-4-methylhexane3(R), 4(S)-3-chloro-4-methylhexane1 stereocenter: 2 stereoisomers2 stereocenter: 4 stereoisomersMultiple StereocentersStereoisomers that are not enantiomers (non-superimposable mirror images) are called diastereomersMeHClHMeHClHMeHClHMeHClH3(S ), 4(R)-3-chloro-4-methylhexane3(S), 4(S)-3-chloro-4-methylhexane3(R), 4(R)-3-chloro-4-methylhexane3(R), 4(S)-3-chloro-4-methylhexaneWhat about these relationships?

5 EnantiomersenantiomersMultiple Stereocenters8 stereoisomers3 stereocenters(R), (R), (R)(S), (R), (R)(R), (S), (R)(R), (R), (S)(S), (S), (S)(R), (S), (S)(S), (R), (S)(S), (S), (R)For any compound, the maximum number of stereoisomers is 2n where n is the number of stereocenters.!!!BrClCH3 Multiple StereocentersMeMeHow many stereoisomers for 3,4-dimethylhexane?MeHMeHHMeHMeHMeMeHMeH HMeenantiomersThe same compound!(superimposable)MeHMeHHMeHMeMeH HMe(3S,4S)-3,4-dimethylhexaneHMeMeH(3R,4 R)-3,4-dimethylhexane??-3,4-dimethylhexa ne??-3,4-dimethylhexaneMeso CompoundsMeMe3,4-dimethylhexane has 3 stereoisomers!MeHMeHHMeHMeHMeMeHMeHHMeEn antiomers (chiral)A Meso Compound (achiral)MeHMeHHMeHMeMeHHMe(3S,4S)-3,4-d imethylhexaneHMeMeH(3R,4R)-3,4-dimethylh exanemeso-3,4-dimethylhexanemeso-3,4-dim ethylhexaneMeso CompoundsThe best way to identify a meso compound is to prove that it is superimposable with its mirrorimage.

6 However, a quick test is to see if it contains a plane of symmetry:Compounds containing a planeof symmetry are achiral!No plane of symmetry(3S,4S)-3,4-dimethylhexane(3R,4R )-3,4-dimethylhexanemeso-3,4-dimethylhex aneMeHMeHplane of symmetryHMeMeHMeHHMeThe Isomers of C3H4Cl2, RevisitedCH3 ClCH2 ClClClClClClClCH3 ClClClClClClClClClClClClThe Isomers of C3H4Cl2, RevisitedCH3 ClCH2 ClClClClClClClCH3 ClClClClClClClClClClClClClClRacemic MixturesA 50:50 mixture of 2 enantiomers is called a racemic mixture or a (E)-2-buteneHBr2-bromobutaneachiralchira lBut do we get (R) or (S)?We get both!CH3H3C50%(S)-2-bromobutane(R)-2-bro mobutaneHBrCH3H3 CBrH50%addition reactionCH3 HHH3 CCH3 HHHBrRacemic Mixtures In MedicineCH3CH3CH3 OHOCH3CH3CH3 OHO(R)-ibuprofen(inactive)(S)-ibuprofen( active)NNHOOOOHNNHOOOOH(S)-Thalidomide(t eratogenic)(R)-Thalidomide(analgesic)Pre scribed worldwide from 1957-1961 for morning sickness and as a sleep aidOptical Rotation and PolarimetryChiral molecules will rotate polarized light.

7 Monochromatic light sourcerandomly oriented lightoptical polarizer - only allows "vertical" light to pass throughoptical polarizer - only allows "horizontal" light to pass throughNo light emittedmonochromatic light sourcerandomly oriented lightoptical polarizer - only allows "vertical" light to pass throughoptical polarizer - only allows "horizontal" light to pass throughchiral materialdetectormonochromatic light sourcerandomly oriented lightoptical polarizer - only allows "vertical" light to pass throughoptical polarizer - only allows "horizontal" light to pass throughchiral materialdetectormonochromatic light sourcerandomly oriented lightoptical polarizer - only allows "vertical" light to pass throughoptical polarizerchiral materialdetectorThe maximum signal will be optained if the second polarizer is rotated to match the light rotation:maximum signalOptical Rotation and Polarimetrymonochromatic light sourcerandomly oriented lightoptical polarizer - only allows "vertical" light to pass throughoptical polarizerchiral materialdetectormaximum signalThe amount (in degrees) that a chiral material will rotate light is called the optical rotation.

8 Different chiralmolecules will have optical rotations that vary in direction and size of the optical rotation. Enantiomers willalways have equal optical rotations but in opposite optical purity of a substance can be measured by comparing the optical rotation of the sample to theknown optical rotation of a single entantiomer of that compound. Optical purity is usually reported in percententantiomeric excess (%ee).Enantiomeric excess is the % of the sample that is non-racemic. For example, 80% ee means that there is90% of one enantiomer and 10% of the =single enantiomer rotationsample rotationX 100 Optical Rotation and PolarimetryVocabulary (R) or (S): identifies the configuration of a stereocenter using the CIP priority system d- or (+): indicates that a (chiral) compound rotates light in a clockwise direction (thishas no correlation with S or R) l or (-): indicates that a (chiral) compound rotates light in a counterclockwise direction(this has no correlation with S or R) dl or (+/-) or rac-: indicates a racemateResolution of Enantiomers(R)-compound X(S)-compound Xreact or somehow associate with.

9 (R)-compound Y(R)-compound X(R)-compound Y(R)-compound Y(S)-compound XSeparate by some technique (chromatography, crystallization, distillation, etc.)(R)-compound X(R)-compound Y(R)-compound Y(S)-compound Xsomehow remove compound Y(R)-compound X(S)-compound Xracemic mixture of enantiomersSingle enantiomermixture of 2 diastereomerssingle diastereomersingle diastereomersingle enantiomersingle enantiomerReaction Using Diastereomers to Separate EnantiomersOOHClMeOOHClMethis hydrogen is acidic(S)-2-chloroproprionic acid(R)-2-chloroproprionic acidH2 NMe(R)-!-methylbenzylaminethis hydrogen is acidicH3 NMeOOClMeOOClMeH3 NMethis nitrogen lone pair is basic(R)-!-methylbenzylamineThe R,S-diastereomer of the saltThe R,R-diastereomer of the saltseparateOOHClMeH2 NMethis nitrogen lone pair is basicOOClMeH3 NMeacidify(R)-2-chloroproprionic acidH3 NMeOOClMeacidifyOOHClMe(S)-2-chloropropr ionic acidResolution of EnantiomersChiral Compounds Without Stereogenic CentersHHHH mirror planeNO2 MeO2 NMemirror planeO2 NMeNO2 Memirror planeThere is hindered rotation around this bond!

10 Chirality Without StereocentersChirality Without StereocentersCMeMeHHWhy is 1,3-dimethylallane (1,3-dimethyl-2,3-pentadiene) chiral?