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Transcript of Ch5 Stereochemistry
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StereochemistryStereochemistryChiral MoleculesChiral Molecules
Created byProfessor Will iam Tam & Dr. Phill is Chang
Ch. 5 - 1
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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
1,3-Dimethylcyclohexane
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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
1,3-Dimethylcyclohexane
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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
1,2-Dimethylcyclohexane
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H H
MeMe
MeMe
H H
enantiomers
trans-1,2-Dimethylcyclohexane
Ch. 5 - 82
exists as a pair o enantiomers
1,2-Dimethylcyclohexane
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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