created by professor william tam & dr. phillis chang ch. 5 - 1 chapter 5 stereochemistry chiral...
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Created byProfessor William Tam & Dr. Phillis
Chang Ch. 5 - 1
Chapter 5Chapter 5
StereochemistryStereochemistryChiral MoleculesChiral Molecules
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Ch. 5 - 2
1. Chirality & Stereochemistry
An object is achiral (not chiral) if the object and its mirror image are identical
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Ch. 5 - 3
A chiral object is one that cannot be superposed on its mirror image
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Ch. 5 - 4
2. Isomerisom: ConstitutionalIsomers & Stereoisomers
Isomers: different compounds that have the same molecular formula●Constitutional isomers:
isomers that have the same molecular formula but different connectivity –their atoms are connected in a different order
2A.2A. Constitutional IsomersConstitutional Isomers
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Ch. 5 - 5
Examples
andButane 2-Methylpropane
MolecularFormula
ClCl
and1-Chloropropane 2-Chloropropane
ConstitutionalIsomers
C4H10
C3H7Cl
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Ch. 5 - 6
Examples
MolecularFormula
and
Butanoic acid Methyl propanoate
OHOCH3
O
O
ConstitutionalIsomers
C2H6O
C4H8O2
OH CH3 O CH3andEthanol Methoxymethane
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Ch. 5 - 7
2B.2B. StereoisomersStereoisomers
Stereoisomers are NOT constitutional isomers
Stereoisomers have their atoms connected in the same sequence but they differ in the arrangement of their atoms in space. The consideration of such spatial aspects of molecular structure is called stereochemistry
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Ch. 5 - 8
2C.2C. Enantiomers & Enantiomers & DiastereomersDiastereomers
Stereoisomers can be subdivided into two general categories:enantiomers & diasteromers●Enantiomers – stereoisomers
whose molecules are nonsuperposable mirror images of each other
●Diastereomers – stereoisomers whose molecules are not mirror images of each other
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Ch. 5 - 9
Geometrical isomers (cis & trans isomers) are:●Diastereomers
e.g.
(trans)Ph
PhPh Ph
(cis)and
Cl
H
Cl
H
H
Cl
Cl
H(trans)(cis)
and
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Ch. 5 - 10
Subdivision of IsomersSubdivision of Isomers
Isomers(different compounds with same
molecular formula)
Constitutional Isomers(isomers whose atoms have a
different connectivity)
Stereoisomers(isomers that have the same
connectivity but differ in spatialarrangement of their atoms)
Enantiomers(stereoisomers that arenonsuperposable mirrorimages of each other)
Diastereomers(stereoisomers that areNOT mirror images of
each other)
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Ch. 5 - 11
3. Enantiomers and Chiral Molecules
Enantiomers occur only with compounds whose molecules are chiral
A chiral molecule is one that is NOT superposable on its mirror image
The relationship between a chiral molecule and its mirror image is one that is enantiomeric. A chiral molecule and its mirror image are said to be enantiomers of each other
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Ch. 5 - 12
OH(2-Butanol)
OHH
(I)
HO H
(II)
(I) and (II) arenonsuperposabl
emirror images
ofeach other
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Ch. 5 - 13
4. A Single Chirality Center Causes a Molecule to Be Chiral
The most common type of chiral compounds that we encounter are molecules that contain a carbon atom bonded to four different groups. Such a carbon atom is called an asymmetric carbon or a chiral center and is usually designated with an asterisk (*)
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Ch. 5 - 14
CH
EtMeCl*
Me Et
ClH
(III)
mirror
MeEt
Cl H
(IV)
(III) and (IV) are nonsuperposable mirror images of each other
Me Et
ClH
(III)
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Ch. 5 - 15
CH
MeMeCl
Me Me
ClH
(V)
mirror
MeMe
Cl H
(VI)
(V) and (VI) are superposable⇒ not enantiomers ⇒ achiral
Me Me
ClH
(V)
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Ch. 5 - 16
4A.4A. Tetrahedral vs. TrigonalTetrahedral vs. TrigonalStereogenic CentersStereogenic Centers
Chirality centers are tetrahedral stereogenic centers
Me Et
OHH
*(A)
mirror
MeEt
HO H
*(B)
Tetrahedral stereogenic center⇒ chiral
(A) & (B) areenantiomers
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Ch. 5 - 17
(C)H
Ph
Ph
H
mirror
(D)Ph
H
H
Ph
Trigonal stereogenic center⇒ achiral (C) & (D) are
identical
Cis and trans alkene isomers contain trigonal stereogenic centers
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Ch. 5 - 18
5. More about the BiologicalImportance of Chirality
(+)-Limonene(limonene enantiomer
found in oranges)
(-)-Limonene(limonene enantiomer
found in lemons)
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Ch. 5 - 19
The activity of drugs containing chirality centers can vary between enantiomers, sometimes with serious or even tragic consequences
For several years before 1963 thalidomide was used to alleviate the symptoms of morning sickness in pregnant women
ThalidomideThalidomide
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Ch. 5 - 20
In 1963 it was discovered that thalidomide (sold as a mixture of both enantiomers) was the cause of horrible birth defects in many children born subsequent to the use of the drug
Thalidomide
NNH
O
OO
O
NNH
O
OO
O
enantiomer ofThalidomide
(causes birth defects)(cures morning sickness)
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Ch. 5 - 21
6. How to Test for Chirality:Planes of Symmetry
A molecule will not be chiral if it possesses a plane of symmetry
A plane of symmetry (mirror plane) is an imaginary plane that bisects a molecule such that the two halves of the molecule are mirror images of each other
All molecules with a plane of symmetry in their most symmetric conformation are achiral
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Ch. 5 - 22
Me Me
Cl
H
Me Et
Cl
H
Plane of symmetry
No plane of symmetry
achiral
chiral
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Ch. 5 - 23
7. Naming Enantiomers: R,S-System
Using only the IUPAC naming that we have learned so far, these two enantiomers will have the same name:● 2-Butanol
This is undesirable because each compound must have its own distinct name
OHH
(I)
HO H
(II)
OHRecall:
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Ch. 5 - 24
Rule 1●Assign priorities to the four
different groups on the stereocenter from highest to lowest (priority bases on atomic number, the higher the atomic number, the higher the priority)
7A.7A. How to Assign (R) and (S)How to Assign (R) and (S)ConfigurationsConfigurations
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Ch. 5 - 25
Rule 2●When a priority cannot be
assigned on the basis of the atomic number of the atoms that are directly attached to the chirality center, then the next set of atoms in the unassigned groups is examined. This process is continued until a decision can be made.
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Ch. 5 - 26
Rule 3●Visualize the molecule so that
the lowest priority group is directed away from you, then trace a path from highest to lowest priority. If the path is a clockwise motion, then the configuration at the asymmetric carbon is (R). If the path is a counter-clockwise motion, then the configuration is (S)
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Ch. 5 - 27
CH2
CH3C
O H
Step 2: CH3
Example HO H(2-Butanol)
①
③
④
② or ③ ② or ③CC
O HStep 1:
① ④
②
(H, H, H) (C, H, H)
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Ch. 5 - 28
OH
EtMe
①
④
②③
OH
EtMe
H
OH
EtMe EtMe
HO H
=
OH
EtMe
H
Arrows are clockwise
(R)-2-Butanol
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Ch. 5 - 29
OCH3
H3C CH2CH3Br
Other examples
①
④
②
③
Cl
H CH3HO
Cl
CH3HO
Counter-clockwise
(S)
①
④
②
③
OCH3
CH2CH3Br
Clockwise
(R)
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Ch. 5 - 30
Cl
H OHBr
Cl
Br HHO
Other examples
①
④
②
③
Cl
OHBr
Clockwise
(R)
● Rotate C–Cl bond such that H is pointed to the back
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Ch. 5 - 31
OCH3
H IH3C
H
I OCH3H3C
Other examples
①④
②
③
OCH3
IH3C
● Rotate C–CH3 bond such that H is pointed to the back
Counter-clockwise
(S)
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Ch. 5 - 32
Rule 4●For groups containing double or
triple bonds, assign priorities as if both atoms were duplicated or triplicated
e.g. C O CO
OC
as
C C CC
CC
as
C C CC
CCC
asC
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Ch. 5 - 33
ExampleCH3
H CH=CH2HO①
④ ②
③
(S)
CH3 CH CH2
CH
CCC
HH
CH3
CH CH2
Compare & :
equivalent to
Thus, (H, H, H)
(C, C, H)CH CH2
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Ch. 5 - 34
Other examples
OH
HCl
CH3
O①
④
②
③
(R)
H2C
HCl
CH3
O
OH
①
④②
③
(S)
C (O, O, C)
C (O, H, H)
②
③
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Ch. 5 - 35
8. Properties of Enantiomers:Optical Activity
Enantiomers●Mirror images that are not
superposable
mirror
H3CH2C
*
CH3
H
ClCH2CH3
*
H3C
H
Cl
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Ch. 5 - 36
Enantiomers have identical physical properties (e.g. melting point, boiling point, refractive index, solubility etc.)
Compound bp (oC) mp (oC)(R)-2-Butanol 99.5(S)-2-Butanol 99.5(+)-(R,R)-Tartaric Acid
168 – 170
(–)-(S,S)-Tartaric Acid
168 – 170
(+/–)-Tartaric Acid 210 – 212
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Ch. 5 - 37
Enantiomers●Have the same chemical
properties (except reaction/interactions with chiral substances)
●Show different behavior only when they interact with other chiral substances
●Turn plane-polarized light on opposite direction
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Ch. 5 - 38
Optical activity●The property possessed by
chiral substances of rotating the plane of polarization of plane-polarized light
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Ch. 5 - 39
The electric field (like the magnetic field) of light is oscillating in all possible planes
When this light passes through a polarizer (Polaroid lens), we get plane-polarized light (oscillating in only one plane)
Polaroidlens
8A.8A. Plane-Polarized LightPlane-Polarized Light
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Ch. 5 - 40
A device for measuring the optical activity of a chiral compound
8B.8B. The PolarimeterThe Polarimeter
= observed optical rotation
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Ch. 5 - 41
8C.8C. Specific RotationSpecific Rotation
D[] =
25 c x
temperatureobserved rotation
wavelength of light(e.g. D-line of Na lamp,=589.6 nm)
concentration of sample solutionin g/mL
length of cellin dm (1 dm = 10 cm)
ℓ
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Ch. 5 - 42
The value of depends on the particular experiment (since there are different concentrations with each run) ●But specific rotation [] should
be the same regardless of the concentration
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Ch. 5 - 43
Two enantiomers should have the same value of specific rotation, but the signs are opposite
mirror
HO
*
CH2CH3
CH3
H
[] = + 13.5o25
D
OH
*
H3CH2C
CH3
H
[] = 13.5o25
D
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Ch. 5 - 44
9. The Origin of Optical Activity
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Ch. 5 - 45
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Ch. 5 - 46
Two circularly-polarized beams counter-rotating at the same velocity (in phase), and their vector sum
Two circularly-polarized beams counter-rotating at different velocities, such as after interactionwith a chiral molecule, and their vector sum
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Ch. 5 - 47
An equimolar mixture of two enantiomers is called a racemic mixture (or racemate or racemic form)
A racemic mixture causes no net rotation of plane-polarized light
9A.9A. Racemic FormsRacemic Forms
HC2H5
CH3
OH
(R)-2-Butanol
HC2H5
H3C
HO
(S)-2-Butanol(if present)
rotation
equal & opposite rotation by the enantiomer
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Ch. 5 - 48
A sample of an optically active substance that consists of a single enantiomer is said to be enantiomerically pure or to have an enantiomeric excess of 100%
9B.9B. Racemic Forms and EnantiomericRacemic Forms and EnantiomericExcessExcess
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Ch. 5 - 49
An enantiomerically pure sample of (S)-(+)-2-butanol shows a specific rotation of +13.52
D[] = +13.52
25
A sample of (S)-(+)-2-butanol that contains less than an equimolar amount of (R)-(–)-2-butanol will show a specific rotation that is less than 13.52 but greater than zero
Such a sample is said to have an enantiomeric excess less than 100%
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Ch. 5 - 50
Enantiomeric excess (ee) ●Also known as the optical
purity
% enantiomericexcess
mole of oneenantiomer
moles of otherenantiomer
total moles of both enantiomers= x 100
% enantiomericexcess *
observed specific rotation
specific rotation of thepure enantiomers
= x 100
●Can be calculated from optical rotations
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Ch. 5 - 51
Example●A mixture of the 2-butanol
enantiomers showed a specific rotation of +6.76. The enantiomeric excess of the (S)-(+)-2-butanol is 50%
% enantiomericexcess *
+6.76+13.52
= x 100 = 50%
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Ch. 5 - 52
10. The Synthesis of Chiral Molecules
10A.10A. Racemic FormsRacemic Forms
O
CH3CH2CCH3 H H ( )-CH3CH2CHCH3
OH
+Ni
Butanone(achiral
molecules)
Hydrogen(achiral
molecules)
( )-2-Butanol(chiral
molecules; but50:50 mixture
(R) & (S))
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Ch. 5 - 53
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Ch. 5 - 54
10B.10B. Stereoselective SynthesesStereoselective Syntheses Stereoselective reactions are
reactions that lead to a preferential formation of one stereoisomer over other stereoisomers that could possibly be formed● enantioselective – if a reaction
produces preferentially one enantiomer over its mirror image
● diastereoselective – if a reaction leads preferentially to one diastereomer over others that are possible
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Ch. 5 - 55
OEt
O
FOH
O
F
+ EtOHH+, H2O
heat
racemate ( ) racemate ( )
OEt
O
FOH
O
F
+ EtOH
H2Olipase
racemate ( ) ( )(> 69% ee)
OEt
O
F(+)
(> 99% ee)
+
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Ch. 5 - 56
12. Molecules with More than OneChirality Center
Diastereomers●Stereoisomers that are not
enantiomers
●Unlike enantiomers, diastereomers usually have substantially different chemical and physical properties
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Ch. 5 - 57
C H
C HCH3
Cl
Br
HOCH
CHCH3
Cl
Br
OH(I) (II )
C H
C HHO
Cl
Br
CH3
CH
CHOH
Cl
Br
CH3(III ) (IV)
Note: In compounds with n tetrahedral stereocenters, the maximum number of stereoisomers is 2n.
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Ch. 5 - 58
C H
C HCH3
Cl
Br
HOCH
CHCH3
Cl
Br
OH(I) (II )
C H
C HHO
Cl
Br
CH3
CH
CHOH
Cl
Br
CH3(III ) (IV)
(I) & (II) are enantiomers to each other
(III) & (IV) are enantiomers to each other
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Ch. 5 - 59
C H
C HCH3
Cl
Br
HOCH
CHCH3
Cl
Br
OH(I) (II )
C H
C HHO
Cl
Br
CH3
CH
CHOH
Cl
Br
CH3(III ) (IV)
Diastereomers to each other:●(I) & (III), (I) & (IV), (II) & (III),
(II) & (IV)
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Ch. 5 - 60
12A.12A. Meso CompoundsMeso Compounds
Compounds with two stereocenters do not always have four stereoisomers (22 = 4) since some molecules are achiral (not chiral), even though they contain stereocenters
For example, 2,3-dichlorobutane has two stereocenters, but only has 3 stereoisomers (not 4)
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Ch. 5 - 61
C Br
C BrH
CH3
H
CH3
CBr
CBrH
CH3
H
CH3(I) (II )
C Br
C BrCH3
CH3
H
HCBr
CBrCH3
CH3
H
H(III ) (IV)
Note: (III) contains a plane of symmetry, is a meso compound, and is achiral ([] = 0o).
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Ch. 5 - 62
C Br
C BrH
CH3
H
CH3
CBr
CBrH
CH3
H
CH3(I) (II )
C Br
C BrCH3
CH3
H
HCBr
CBrCH3
CH3
H
H(III ) (IV)
(I) & (II) are enantiomers to each other and chiral
(III) & (IV) are identical and achiral
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Ch. 5 - 63
C Br
C BrH
CH3
H
CH3
CBr
CBrH
CH3
H
CH3(I) (II )
C Br
C BrCH3
CH3
H
HCBr
CBrCH3
CH3
H
H(III ) (IV)
(I) & (III), (II) & (III) are diastereomers
Only 3 stereoisomers:●(I) & (II) {enantiomers}, (III)
{meso}
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Ch. 5 - 64
12B. 12B. How to Name Compounds withHow to Name Compounds with More than One Chirality CenterMore than One Chirality Center
2,3-Dibromobutane
●Look through C2–Ha bond
HbBrHa Br
1
2 3
4
C C
Br Ha
12
3
(H, H, H) (Br, C, H)
①④
②③C2: (R) configuration
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Ch. 5 - 65
C C
Br Hb
23
4
(H, H, H) (Br, C, H)
●Look through C3–Hb bond
CH3
HaHbBr
CH3
Br1
23 4
①④
②③
C3: (R) configuration
●Full name: (2R, 3R)-2,3-Dibromobutane
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Ch. 5 - 66
13. Fischer Projection Formulas
13A. 13A. How To How To Draw and Use Fischer Draw and Use Fischer ProjectionsProjections
H3C
Ph
COOH
HOEt Br
Et OH
Br Ph
CH3
COOH
Et OH
Br Ph
CH3
COOH
FischerProjection
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Ch. 5 - 67
Ph
H
COOH
HMe OH
Me H
HO H
Ph
COOH
Me H
HO H
Ph
COOH
FischerProjection
PhCOOH
H Me
OHH
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Ch. 5 - 68
H3C
Cl
CH3
HCl H
(I)(2S, 3S)-Dichlorobutane
Cl H
H Cl
CH3
CH3
CH3
Cl
H3C
HClH
(II)(2R, 3R)-Dichlorobutane
H Cl
Cl H
CH3
CH3
mirror
enantiomers
(I) and (II) are both chiral and they are enantiomers with each other
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Ch. 5 - 69
H3C
Cl
CH3
ClH H
(III)(2S, 3R)-Dichlorobutane
H Cl
H Cl
CH3
CH3
(III) is achiral (a meso compound) (III) and (I) are diastereomers to
each other
Plane ofsymmetry
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Ch. 5 - 70
14.Stereoisomerism of CyclicCompounds
Me
H Me
H Me
H Me
H
mirror
enantiomers
H
Me Me
H
Plane ofsymmetry
a meso compoundachiral
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Ch. 5 - 71
14A. 14A. Cyclohexane DerivativesCyclohexane Derivatives
Me
Me
Me
Me
1,4-Dimethylcyclohexane
Plane ofsymmetry
H
Me
Me
H
H
Me
H
Me
cis-1,4-dimethylcyclohexane
trans-1,4-dimethylcyclohexane
• Both cis- & trans-1,4-dimethylcyclo-hexanes are achiral and optically inactive
• The cis & trans forms are diastereomers
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Ch. 5 - 72
Me Me**
cis-1,3-dimethylcyclohexane
1,3-DimethylcyclohexanePlane of
symmetry
(meso)
H
Me
H
Me
●cis-1,3-Dimethylcyclohexane has a plane of symmetry and is a meso compound
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Ch. 5 - 73
Me Me**
trans-1,3-dimethylcyclohexane
1,3-Dimethylcyclohexane
NO plane of symmetry
enantiomers
H
Me
Me
HH
Me
Me
H
●trans-1,3-Dimethylcyclohexane exists as a pair of enantiomers
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Ch. 5 - 74
1,3-Dimethylcyclohexane●Has two chirality centers but
only three stereoisomers
(meso)
H
Me
H
Me
cis-1,3-dimethylcyclohexane
enantiomers
H
Me
Me
HH
Me
Me
H
trans-1,3-dimethylcyclohexane
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Ch. 5 - 75
1,2-Dimethylcyclohexane
enantiomers
H
H
MeMe
H
H
MeMe
●trans-1,2-Dimethylcyclohexane exists as a pair of enantiomers
mirror
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Ch. 5 - 76
1,2-Dimethylcyclohexane●With cis-1,2-
dimethylcyclohexane the situation is quite complicated
Me
H
MeH
Me
H
MeH
(I) (II)
●(I) and (II) are enantiomers to each other
mirror
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Ch. 5 - 77
●However, (II) can rapidly be interconverted to (III) by a ring flip
Me
H
MeH
12
Me
H
MeH
(I) (II)
1'
2'
mirror
H
Me 12
Me
H(III)
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Ch. 5 - 78
●Rotation of (III) along the vertical axis gives (I)
Me
H
MeH
12
H
Me12
Me
H
Me
H
MeH
(I) (II)
(III)
1'
2'
C1 of (II) and (III) become C2’ of (I) & C2 of (II) and (III) become C1’ of (I)
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Ch. 5 - 79
Me
H
MeH
12
H
Me12
Me
H
Me
H
MeH
(I) (II)
(III)
1'
2'
Although (I) and (II) are enantiomers to each other, they can interconvert rapidly (I) and (II) are achiral
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Ch. 5 - 80
15. Relating Configurations throughReactions in Which No Bonds tothe Chirality Center Are Broken
If a reaction takes place in a way so that no bonds to the chirality center are broken, the product will of necessity have the same general configuration of groups around the chirality center as the reactant
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Ch. 5 - 81
H
O
Me H
HOH
Me HH
NaBH4
MeOH
Ph Br
NaCN
DMSO
Me H
Ph CN
Me H
Same configuration
Same configuration
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Ch. 5 - 82
15A. 15A. Relative and Absolute ConfigurationsRelative and Absolute Configurations Chirality centers in different molecules
have the same relative configuration if they share three groups in common and if these groups with the central carbon can be superposed in a pyramidal arrangement
Y
AB
CX
AB
C
The chirality centersin I and II have thesame relativeconfiguration. Theircommon groups andcentral carbon canbe superposed.
I
II
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Ch. 5 - 83
The absolute configuration of a chirality center is its (R) or (S) designation, which can only be specified by knowledge of the actual arrangement of groups in space at the chirality center(R)-2-Butanol (S)-2-Butanol
HO H H OH
enantiomers
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Ch. 5 - 84
16.Separation of Enantiomers:Resolution
e.g.R R'
OH
*(racemic)
ClOMe
O
Ph CF3
(Mosher acidchloride)
R R'
O
OOMe
PhCF3
R R'
O
OOMe
PhCF3+
( 1 : 1 )
diastereomers
usually separable either by flash column
chromatography or recrystallization etc.
Resolution – separation of two enantiomers
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Ch. 5 - 85
Kinetic Resolution
R2
R1R
OH
*R2
R1R
OH
*R2
R1R
OH
*O
+
(racemic)
●One enantiomer reacts “fast” and another enantiomer reacts “slow”
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Ch. 5 - 86
e.g.Me3Si
C5H11
OH*
(racemic)
tBuOOH, Ti(OiPr)4
(-)-DET
Me3Si
C5H11
OH
Me3Si
C5H11
OHO+
42%(99%ee)
43%(99%ee)
Me3Si
OHR'
H
Me3Si
OHH
R'
S R
* stop reaction at 50%* maximum yield = 50%
(-)-DET:COOEt
COOEtHO
HO
(D)-(-)-Diethyl Tartrate
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Ch. 5 - 87
18.Chiral Molecules That Do NotPossess a Chirality Center
P(Ph)2
P(Ph)2
(Ph)2P
(Ph)2P
(S)-BINAP (R)-BINAP
enantiomers
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Ch. 5 - 88
enantiomers
C C
Cl
H
CCl
HCC
Cl
H
CCl
H
mirror
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Ch. 5 - 89
END OF CHAPTER 5