Ch5 Stereochemistry

8/3/2019 Ch5 Stereochemistry

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StereochemistryStereochemistryChiral MoleculesChiral Molecules

Created byProfessor Will iam Tam & Dr. Phill is Chang

Ch. 5 - 1


2/97

About The AuthorsAbout The Authors

These Powerpoint Lecture Slides were created and prepared by ProfessorWilliam Tam and his wife Dr. Phillis Chang.

Professor William Tam received his B.Sc. at the University of Hong Kong in1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an

University (USA). He joined the Department of Chemistry at the University ofGuelph (Ontario, Canada) in 1998 and is currently a Full Professor and

Associate Chair in the department. Professor Tam has received several awardsn researc an eac ng, an accor ng o ssen a c ence n ca ors , e scurrently ranked as the Top 1% most cited Chemists worldwide. He haspublished four books and over 80 scientific papers in top international journalssuch as J. Am. Chem. Soc. An ew. Chem. Or . Lett. and J. Or . Chem.

Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, herM.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). Sheves n ue p w er us an , am, an e r son, a ew.

Ch. 5 - 2


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1. Chirality & Stereochemistry

An object is achiral(not chiral) if the

object and its mirror image areidentical

Ch. 5 - 3


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Achiralobject is one that cannot be

superpose on s m rror mage

Ch. 5 - 4


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1A.1A. The Biological Significance ofThe Biological Significance of

cannot be superimposable with their

One enantiomer

NNH

Ocauses birth defects,the other cures

Omorning sickness

Ch. 5 - 5

Thalidomide


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HONH

HO

OMe

OMe

One enantiomer is a bronchodilator, the

other inhibits platelet aggregation

Ch. 5 - 6


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66% of all drugs in development are,

enantiomer

Of the $475 billion in world-wide sales of

2008, $205 billion was attributable to

Ch. 5 - 7


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2. Isomerisom: ConstitutionalIsomers tereoisomers

Isomers: different com ounds that

..

have the same molecular formula

that have the same molecular

r u u r v y their atoms are connected in a

Ch. 5 - 8

different order


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Examples

Molecular Constitutional

an

Butane 2-Methylpropane

4 10

ClandC3H7Cl

Ch. 5 - 9

1-Chloropropane 2-Chloropropane


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Examples

Molecular Constitutional

CH O CH2 6 Ethanol Methoxymethane

O

andOH OCH3C4H8O2

Ch. 5 - 10Butanoic acid Methyl propanoate


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2B.2B. StereoisomersStereoisomers

Stereoisomers are NOT constitutional

Stereoisomers have their atoms

connected in the same se uence butthey differ in the arrangement of their

such spatial aspects of molecular

Ch. 5 - 11


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2C.2C. Enantiomers & DiastereomersEnantiomers & Diastereomers

Stereoisomers can be subdivided into

enantiomers&diasteromers

Enantiomers stereoisomers

whose molecules arenonsuperposable mirror images of

Diastereomers stereoisomers

Ch. 5 - 12

images of each other


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Geometrical isomers

c s rans somers are: Diastereomers

e.g. Ph

(trans)(cis)

ClCl HCl

HH ClHand

Ch. 5 - 13

(trans)(cis)


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Subdivision of IsomersSubdivision of Isomers

Isomers(different compounds with same

Constitutional Isomers(isomers whose atoms have a

Stereoisomers

(isomers that have the sameeren connec v y

arrangement of their atoms)

Enantiomers(stereoisomers that are

Diastereomers(stereoisomers that are

Ch. 5 - 14

images of each other)

each other)


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3. Enantiomers and ChiralMo ecu es

whose molecules are chiral

superposable on its mirror image e re at ons p etween a c ra

molecule and its mirror image is one

that is enantiomeric. A chiralm l l n i mirr r im r i

Ch. 5 - 15

to be enantiomers of each other


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OH(2-Butanol)

(I) and (II) are

OHH HO H mirror images of

I II

eac o er

Ch. 5 - 16


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4. A Single Chirality Center

auses a Mo ecu e to Be ira

compounds that we encounter aremo ecu es a con a n a car on a om

bonded to four different groups. Sucha carbon atom is called an asymmetriccarbonor a chiral centerand isusually designated with an asterisk (*)

Ch. 5 - 17


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Cl

C

H

EtMe

Me Et

ClH

MeEt

Cl H

Me Et

ClH

(III) (IV)(III)

m rror

Ch. 5 - 18

mirror images of each other


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Cl

C

H

MeMe

Me Me

ClH

MeMe

Cl H

Me Me

ClH

(V) (VI)(V)

m rror

Ch. 5 - 19

not enantiomers achiral


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4A.4A. Tetrahedral vs. TrigonalTetrahedral vs. Trigonal

stereogeniccenters

OHH HO HMe Et*

A

MeEt *

B

mirroretrahedral

stereogenic (A) & (B) are

Ch. 5 - 20

r

chiral

enan omers


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Cisand transalkene isomers containtrigonal stereogenic centers

Ph H H Ph

H Ph Ph H(C)

mirror

(D)Trigonalstereogenic

center achiral (C) & (D) are identical

Ch. 5 - 21


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4A.4A. Tetrahedral vs. TrigonalTetrahedral vs. Trigonal

stereogeniccenters

Cisand transalkene isomers containtrigonal stereogenic centers

Ch. 5 - 22


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5. More about the B iological

Importance o ira ity

- - -(limonene enantiomer (limonene enantiomer

Ch. 5 - 23


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ThalidomideThalidomide

The activity of drugs containingc ra y cen ers can vary e weenenantiomers, sometimes with seriousor even tragic consequences

For several years before 1963

symptoms of morning sickness in

Ch. 5 - 24

pregnan women


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In 1963 it was discovered that thalidomide

the cause of horrible birth defects in many

drug

N

NH

O N

NH

O

O O

Thalidomide enantiomer ofThalidomidecures mornin sickness

Ch. 5 - 25

(causes birth defects)


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Plane of symmetry

Me Me

H

ac ra

Cl

Me Et

Ch. 5 - 27No plane of symmetry chiral


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7. Naming Enantiomers: R,S-System

OHH HO HOH

(I) (II)Recall:

Using only the IUPAC naming that we havelearned so far, these two enantiomers willhave the same name:

2-Butanol This is undesirable because each compound

Ch. 5 - 28

must have its own distinct name


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7A.7A. How to Assign (R) and (S)How to Assign (R) and (S)

Assign priorities to the four differentr u r r r

highest to lowest (priority bases onatomic number, the higher theatomic number the hi her the

priority)

Ch. 5 - 29


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When a priority cannot be assigned

of the atoms that are directlyattac e to t e c ira ity center, t en

the next set of atoms in theunassigned groups is examined.

decision can be made.

Ch. 5 - 30


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Visualize the molecule so that the

away from you, then trace a pathrom ig est to owest priority. I

the path is a clockwise motion, thenthe configuration at the asymmetric

counter-clockwise motion, then the

Ch. 5 - 31


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Example HO H (2-Butanol)

H

CCStep 1:

or or

O H

CC

H3CStep 2: CH3

Ch. 5 - 32

2

(H, H, H) (C, H, H)


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OH

H

e EtMe

OH HO H

OH

EtMeEtMe

=

Et

H

MeArrows are clockwise

Ch. 5 - 33

R- -Butano


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Other examples

Cl Cl Counter-

HCH CHHO

HO

OCH3

OCH3

Clockwise

H3C (R)

Ch. 5 - 34

Br


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Other examples

Rotate CCl bond such that H is pointedto the back

ClCl

H

OH

Br

H

Clockwise

Ch. 5 - 35

OHBr (R)


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Other examples

Rotate CCH3 bond such that H isointed to the back

OCH3H

H

I

I

OCH3

33

-3

Ch. 5 - 36

IH3C


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Rule 4

or groups con a n ng ou e ortriple bonds, assign priorities as if

both atoms were duplicated ortri licated

e.g. C O C Oas O C

C C

C C

Ch. 5 - 37

C C C

C

C

C

as


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Other examples

OH

HCl

3

H2C

H CH3 C (O, O, C)

Ch. 5 - 39

C (O, H, H)


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8. Properties of Enantiomers:

v y

Mirror images that are notsuperposa e

* *

H3CH2CCH3

CH2CH3H3C

Ch. 5 - 40mirror


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Enantiomers have identical physical

proper es e.g. me ng po n , o ngpoint, refractive index, solubility etc.)

Compound bp (oC) mp (oC)

(R)-2-Butanol 99.5

- -

(+)-(R,R)-Tartaric Acid 168 170

()-(S,S)-Tartaric Acid 168 170

Ch. 5 - 41


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Have the same chemical properties

chiral substances) ow erent e av or on y w en

they interact with other chiralsubstances

-opposite direction

Ch. 5 - 42


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The property possessed by chiral

polarization of plane-polarized light

Ch. 5 - 43

8A8A PlPl P l i d Li htP l i d Li ht


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8A.8A. PlanePlane--Polarized LightPolarized Light

he electric field (like the magneticfield of li ht is oscillatin in all

possible planes

polarizer (Polaroid lens), we get plane-po ar ze g osc a ng n on y oneplane)

Polaroid

Ch. 5 - 44

ens

8B8B Th P l i tTh P l i t


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8B.8B. The PolarimeterThe Polarimeter

A device for measuring the optical

= rvoptical rotation

Ch. 5 - 45

8C8C S ifi R t tiS ifi R t ti


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8C.8C. Specific RotationSpecific Rotation

temperatureo serverotation

=25 D c x

wavelen thof light

e. . D-lineof sample in dm

of Na lamp,=589.6 nm

in g/mL =

Ch. 5 - 46


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The value of depends on the

different concentrations with each run)

the same regardless of theconcen ra on

Ch. 5 - 47

Two enantiomers should have the


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Two enantiomers should have the

same va ue o spec c ro a on, u esigns are opposite

CH3 CH3

*

CH CHH

*

H CH CH

HO OH

mirror[] = + 13.5o

D[] = 13.5o

D

Ch. 5 - 48

9 The Origin of Optical Activity


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9. The Origin of Optical Activity

Ch. 5 - 49


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Ch. 5 - 50


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wo circularl - wo circularl - olarizedpolarized beamscounter-rotatin at

beams counter-rotatingat different velocities

the same velocityin hase and

such as after interactionwith a chiral molecule

Ch. 5 - 51

their vector sum and their vector sum

9A9A Racemic FormsRacemic Forms


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9A.9A. Racemic FormsRacemic Forms

n equ mo ar m x ure o woenantiomers is called a racemic mixture

(or racemateor racemic form)A r mi mix r n nrotation of plane-polarized light

equal & opposite

rotationrotation by theenantiomer

H

C2H5

3

OH H

C2H5

3

HO

Ch. 5 - 52

(R)-2-Butanol (S)-2-Butanol

(if present)

9B9B Racemic Forms and EnantiomericRacemic Forms and Enantiomeric


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9B.9B. Racemic Forms and EnantiomericRacemic Forms and Enantiomeric

substance that consists of a singleenan omer s sa o e

enantiomerically pure or to have anenantiomeric excess of 100%

Ch. 5 - 53

An enantiomerically pure sample of (S)-(+)-


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An enantiomerically pure sample of (S) (+)

-+13.52

25

D

= +13.52

A sample of (S)-(+)-2-butanol that containsless than an equimolar amount of (R)-()-2-butanol will show a specific rotation that is

ess t an 13.52 ut greater t an zero Such a sample is said to have an

Ch. 5 - 54

enantiomeric excessless than 100%

Enantiomeric excess (ee)


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Enantiomeric excess (ee)

so nown as e op ca pur y

% enantiomericexcess

enantiomer enantiomertotal moles of both enantiomers

= x 100

rotations

% enantiomericexcess *

observed specific rotation

specific rotation of the= x 100

Ch. 5 - 55

pure enantiomers

Example


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Example

m x ure o e - u anoenantiomers showed a specificrotation of +6.76. Theenantiomeric excess of the S - + -2-butanol is 50%

% enantiomeric +6.76= x 100 = 50%

excess +13.52

Ch. 5 - 56

10. The Synthesis of Chiral Molecules


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10. The Synthesis of Chiral Molecules

10A.10A. Racemic FormsRacemic Forms

CH3CH2CCH3 H H ( )-CH3CH2CHCH3+Ni

O OH

Butanone(achiral

Hydrogen(achiral

( )-2-Butanol(chiral

mo ecu es mo ecu es mo ecu es; ut50:50 mixture

Ch. 5 - 57


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Ch. 5 - 58

10B.10B. Stereoselective SynthesesStereoselective Syntheses


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10B.10B. Stereoselective SynthesesStereoselective Syntheses

Stereoselective reactions are reactionsthat lead to a preferential formation of onestereoisomer over other stereoisomers thatcould possibly be formed

enantioselective if a reaction

roduces referentiall one enantiomerover its mirror image

diastereoselective if a reaction

leads preferentially to one diastereomerover others that are ossible

Ch. 5 - 59

O OH

+, H2O


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+ EtOHH , H2O

F Fea

racemate ( ) racemate ( )

O OH O

OEt

F

OH

Flipase

(> 69% ee)

O

+ EtOHOEt

F

+

Ch. 5 - 60

(+)

(> 99% ee)

11. Chiral Drugs


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g

Of the $475 billion in world-wide sales of

2008, $205 billion was attributable to single

NC HO

NHNMe2 HO H

CO2

F

Escitalpram(anti-depressant )

-(treatment for Parkinson's)

Ch. 5 - 61

Naproxen


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-

CH3

MeO

NaO2CHO

CH3

3

S

Ch. 5 - 62

(asthma and allergy treatment)

12. Molecules w ith More than One


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r y r

Stereoisomers that are notr

Unlike enantiomers, diastereomersusuall have substantiall different

chemical and physical properties

Ch. 5 - 63

C HBr

CHBr


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C H CH

C HHO CH OH

Br BrC HCl CH Cl

H(III) (IV)

HO OH

ote: n compoun s w t ntetra e rastereocenters, the maximum number of

Ch. 5 - 64

stereoisomers is 2n.

C HBr

CHBr


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C H CH

C HHO CH OH

Br BrC HCl CH Cl

H

(III) (IV)

HO OH

(I) & (II) are enantiomers to each other

Ch. 5 - 65

other

C HBr

CHBr


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C H CH

C HHO CH OH

Br BrC HCl CH Cl

H

(III) (IV)

HO OH

Diastereomers to each other:

Ch. 5 - 66

, , ,

(II) & (IV)

12A.12A. Meso CompoundsMeso Compounds


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Compounds with two stereocenters do

(22

= 4) since some molecules are,

contain stereocenters

or examp e, , - c oro u ane astwo stereocenters, but only has 3

stereoisomers (not 4)

Ch. 5 - 67

C BrH

CBrH


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C Br CBr

C BrCH3 CBr CH3

H HC BrCH3

H

CBr CH3

H

(III) (IV)

CH3 CH3

ote: conta ns a p ane o symmetry,is a meso compound, and is achiral ([]

Ch. 5 - 68

= 0o).

C BrH

CBrH


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C Br CBr

C BrCH3 CBr CH3

H HC BrCH3

H

CBr CH3

H

(III) (IV)

CH3 CH3

(I) & (II) are enantiomers to each

Ch. 5 - 69

(III) & (IV) are identical and achiral


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12B.12B. How to Name Compounds w ithHow to Name Compounds w ith


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r r y rr r y r

- Ha

Br,HBr

2 3

Look through C2H

a

bond

1 4

Br Ha

C C12

3

C2: (R)configuration

Ch. 5 - 71

(H, H, H) (Br, C, H)

Look through C3Hb bond


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Br Hb

aH

bBr

C C23

4CH3Br 23 4

(H, H, H) (Br, C, H)CH31

u name: 2R, 3R -2 3-Dibromobutane

Ch. 5 - 72

13. Fischer Projection Formulas


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13A.13A. How ToHow To Draw andDraw and Use FischerUse FischerProjectionsProjections

Projection

Et BrCOOH COOH

Et OH

r r

H3C COOH CH3 CH3

Ch. 5 - 73


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Me OHCOOHH Me

Ph HPh COOHOH

COOHCOOH

Me HFischer

Ch. 5 - 74PhPh

ro ec on

ClHCl H

Cl HClH


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H3C CH3(I)

CH3H3C(II)

(2S, 3S)-Dichlorobutane (2R, 3R)-Dichlorobutane

H Cl

CH3

Cl H

CH3

Cl H H Clenantiomers

CH3

3

mirror

Ch. 5 - 75

an are o c ra an ey are

enantiomers with each other


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14. Stereoisomerism of Cyclic


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ompoun s

mirror

achiral

H Me H Me Me Me

Me H Me H H H

enantiomers

Ch. 5 - 77

symmetry

14A.14A. Cyclohexane DerivativesCyclohexane Derivatives


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, - met y cyc o exane Both cis- &trans-

Me Me

symmetry1,4-dimethylcyclo-hexanes areachiraland

o ticall inactiveMe H The cis&trans

HMe

H

HMe

Me diastereomers

Ch. 5 - 78

cis-1,4-dimethyl

cyclohexane

trans-1,4-dimethyl

cyclohexane

1,3-Dimethylcyclohexane


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Plane ofsymmetry

Me Me Me

cis-1,3-dimethyl HMe

(meso)

cis-1,3-Dimethylcyclohexane has a

Ch. 5 - 79

compound



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NOplane of symmetry

Me Me** Me Me

HMe

HMe

trans-1,3-dimethylcyclohexane enantiomers

trans-1,3-Dimethylcyclohexane

Ch. 5 - 80

exists as a pair o enantiomers



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as wo c ra y cen ers u on ythreestereoisomers

cis-1,3-dimethyl trans-1,3-dimethylcyclohexane cyclohexane

Me H H

H Me Me

Ch. 5 - 81

(meso) enantiomers



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H H

MeMe

MeMe

H H

enantiomers

trans-1,2-Dimethylcyclohexane

Ch. 5 - 82

exists as a pair o enantiomers



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c s- , - me y cyc o exanethe situation is quite complicated

mirror

H H

H

e

H

e

I II

(I) and (II) are enantiomers to each

Ch. 5 - 83

ot er

However, (II) can rapidly be


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n erconver e o y a r ng pmirror

e

H 2

e

H2'

H

Me

H

Me

(I) (II)

2Me

Ch. 5 - 84H

H(III)

Rotation of (III) along the vertical


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ax s g vesMeMe

H 12H1'

2'

HH(I) (II)

C1 of (II) and (III)

Me12

Me(III)become C2 of (I) &C2 of (II) and (III)

Ch. 5 - 85

HHbecome C1 of (I)

MeMe2'


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Me 1Me1'

MeAlthough (I) and (II)

Me 2

H

each other, they cann erconver rap y (I) and (II) are

Ch. 5 - 86

achiral

15. Relating Configurations through


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the Chirality Center Are Broken

I f a reaction takes place in a wayr y

center are broken, the product willof necessity have the same generalconfi uration of rou s around the

chirality center as the reactant

Ch. 5 - 87

Same configuration


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O OH

H

Me H Me H HMeOH

NaCNMe H Me H

Ch. 5 - 88Same configuration

15A.15A. Relative and Absolute ConfigurationsRelative and Absolute Configurations


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ra y cen ers n eren mo ecu es avethe same relative configuration if theys are ree groups n common an ese

groups with the central carbon can besuperpose n a pyram a arrangemen

Y

AB

CXin I and II have thesame relative

A B C configuration. Theircommon groups andI

Ch. 5 - 89

central carbon can

be superposed.

The absolute configuration of a chirality,


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can only be specified by knowledge of the

the chirality center

(R)-2-Butanol (S)-2-Butanol

HO H H OH

Ch. 5 - 90

enantiomers

16. Separation of Enantiomers:

R ti


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Reso ution

OHO OMe O OMe

. .

R R'*(racemic) OMe

OR R'

O

PhCF3

R R'

O

PhCF3+

Ph CF3

(Mosher acid

( 1 : 1 )

diastereomersc or e usually separable

either by flash column

Ch. 5 - 91

recrystallization etc.

Kinetic Resolution

OH OH OH


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R1R

OH

*R1

R

OH

*R1

R

OH

*+

R2 R2 R2O

(racemic)

another enantiomer reacts slow

Ch. 5 - 92

e.g.Me Si Me Si

BuOOH Ti(OPr)4 OH OHO+


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OH*BuOOH, Ti(OPr)4

(-)-DET OH OHO+

5 11

(racemic)

5 11 5 11

42% 43%(-)-DET:

COOEt

COOEtHO

HO

- - - e y ar ra e

Me3Si Me3Si

R'

H

H

R'

S R

Ch. 5 - 93

* stop reaction at 50%

* maximum yield = 50%

17. Compounds w ith Chirality

enters t er t an ar on


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enters t er t an ar on

R4 R3 H R3

R1 R2 R1 R2

R4 R3 R2 R1

R1 R2 O

Ch. 5 - 94

18. Chiral Molecules That Do Not

Possess a ira ity enter


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Possess a ira ity enter

P(Ph)2 (Ph)2P

2

- -

Ch. 5 - 95enantiomers

i


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mirror

H H HHC C C

ClCCC

Cl

enantiomers

Ch. 5 - 96


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END OF CHAPTER 5

Ch. 5 - 97

Ch5 Stereochemistry

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