stereochemistry. · stereo-selective synthesis (kinetic resolution) (2). 20. attilio citterio...
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Stereochemistry.Prof. Attilio Citterio
Dipartimento CMIC “Giulio Natta”
https://iscamapweb.chem.polimi.it/citterio/it/education/course-topics/
Scuola di Ingegneria Industriale e dell’Informazione
Insegnamento di Chimica Generale
083424 - CCS CHI e MAT
Attilio Citterio
Classification of Isomers.2
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 spatial arrangement of their atoms)
Enantiomers(stereoisomers that are
nonsuperimposable mirrorimages of each other)
Diastereomers(stereoisomers that areNOT mirror images of
each other)
Attilio Citterio
Configurational Isomers.3
H
H
H
Cl
H
H
H
H
Cl
H
Different conformations of stereoisomer A
stereoisomer B
C2H5
H
H
H
Cl
H
120°120°
C2H5H5C2
H
H
H
H5C2Cl
H
120°120°
H
H
H
Cl
H
120°
H5C2
No one conformation of A corresponds to B
The two compounds are Configurational Isomers
The two compounds are not two different conformations
stereoisomer A
Attilio Citterio
Two Enantiomers.4
HC2H5
ClH
C2H5Cl
AB
CH3CH3
The two compounds are Specular Images
NOT superimposable
They are defined
ENANTIOMERS
d
ba c
C
d
bac
C
Attilio Citterio
Asymmetric (Chiral) Carbon Atom5
The Carbon atom is hybridized sp3 and is bound to four different substituents
Ca
b
d
c
Attilio Citterio
R,S Cahn-Ingold-Prelog Convention6
The group with lower priority
must be placed
far from the observer
HC
CH3
H5C2
12
3
C3H7
4
CC2H5
CH3
HH7C3
3
21
4
Rectus
“clockwise”
R
Attilio Citterio
Cahn-Ingold-Prelog Convention.
R,S Nomenclature System7
4
1
2
4
31
2
3
RectusR SinisterS
Attilio Citterio
Specific Rotation and R,S –Configuration.
No necessary correlation exists between the (R) and (S) designation and
the direction of rotation of plane-polarized light.
8
Relative vs. Absolute
Configuration (5.15A)(R)-(+)-2-Methyl-1-butanol
25
5.756D
(S)-(−)-2-Methyl-1-butanol
25
5.756D
Same
Configuration
(R)-(+)-3-Methyl-1-butanol (R)-(−)-1-Chloro-3-methylbutane
(R)-(−)-1-Chloro-3-methylbutane (S)-(+)-1-Chloro-3-methylbutane
25
1.64D
25
1.64D
Attilio Citterio
Racemic Forms (Racemate).9
Racemate
CH2CH3
CH3
CH3CH2
H3C
Attilio Citterio
Racemic Forms (Racemate).10
(R)-2-butanol (S)-2-butanol+
.
50:50
Optically inactive
.
.
0 rotation
Racemate = Equimolar mixture of (R) and (S) enantiomer
Attilio Citterio
Physical Properties of Stereoisomers.
Enantiomers also:
• Have the same chemical properties (except
reaction/interactions with chiral substances)
• Show different behavior only when they interact with
other chiral substances (enzymes)
• Rotate plane-polarized light in equally in opposite
directions - this property of enantiomers is called
optical activity
11
Attilio Citterio
Optical Activity.
• The property possessed by chiral substances of rotating
the plane of polarization of plane-polarized light
• 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)
12
Polaroid
lens
Attilio Citterio
Optical Activity and Polarimeter (2).
Polarimeter – instrument to measure optical activity
13
= observed optical
rotation
Attilio Citterio
Optical Activity – Measuring on Polarimeter.14
Attilio Citterio
Optical Activity – Measuring on Polarimeter (2).15
Attilio Citterio
Optical Activity – Measuring on Polarimeter (3).16
(c) Two circularly-polarized beams
counter-rotating at the same velocity
(in phase), and their vector sum.
The net result is like (a).
(d) Two circularly-polarized beams
counter-rotating at the different
velocities, such as after interaction
with a chiral molecule, and their
vector sum. The net result is like (b).
(From Adamson, A Textbook of Physical Chemistry, 3° ed. © 1986 Brooks/Cole, a part of Cengage Learning, Inc.
Attilio Citterio
Optical Activity – Calculating Specific Rotation.17
temperature
wavelength of light
(e.g. D-line of Na
lamp, l = 589.6 nm)concentration of
sample solution
in g/mL
length of cell
in dm (1 dm = 10 cm)
observed
rotation
Attilio Citterio
Enantiomeric Excess (ee).18
Non-equimolar mixture of (R) and (S) enantiomer
Enantiomerically enriched – Optically active
The enantiomeric excess can be calculated from optical rotations:
E.g. a mixture of the 2-butanol enantiomers showed a specific rotation of +6.76°
Pure
..
.
.
.
.
Racemate (50:50)
.
.
(R)
(R)-2-butanol
(+13.52°)
(R
(+6.72°)
(S)
(-6.72°)(R
(+6.72°)(R)
(+3.36°)
(S)
(+3.36°)
% Enantiomeric excess =moles of one enantiomer - moles of other enantiomer
total moles of both enantiomers 100
% Enantiomeric excess * =specific rotation of the pure enantiomer
observed specific rotation 100
6.76Enantiomeric excess 100 50%
13.52
Attilio Citterio
Stereo-selective Synthesis (Kinetic Resolution).19
>99% ee >99% ee
Attilio Citterio
Stereo-selective Synthesis (Kinetic Resolution) (2).20
Attilio Citterio
Chiral Drugs (for Chiral Receptor).21
OH
O
OH
O
H Me H Me
Ibuprofen (Isobutyl phenyl pripionic
acid)
(S)
Active anti-inflamatory agent
(R)
No anti-inflamatory activity
H
N
OHO
Acetaminophen (Tylenol)
OH
O
NH2HO
HO
Me
OH
O
Me NH2
(R)
No activity
HO
HO
(S)
Methyldopa (Aldomet)
Anti-hypertensivedrug
OH
O
NH2
HO
HO
H
L-DOPA
H3CO
OH
O
(S)-Naproxene
H Me
(S)-BINAP-Ru(Ac)2
H3CO
OH
OH H
OH
O
SH H NH2
(R)
Penicillamine
N
S
Penicillin G
CH3
H CO2H
CH3
H H H N
O
Therapeutic agent
for primary chronic arthritisHighly toxic
O
Me
MeOH
OMe
Me
SH H NH2
(S)
Attilio Citterio
Molecules with Multi-Stereogenic Centers.22
.
.
enantiomers
enantiomers
diastereomers
.
.
diastereomers
.
.
diastereomers
Diastereomers have different physical properties: different
m.p. and b.p., different solubilities, and so forth.
Total number of stereoisomers will not exceed 2n, where n
is equal to the number of tetrahedral stereogenic centers.
Attilio Citterio
Naming Molecules with Multi-Stereogenic Centers.23
.
.
enantiomers
enantiomers
diastereomers
.
.
diastereomers
.
.
diastereomers
Diastereomers have different physical properties: different m.p.
and b.p., different solubilities, and so forth.
Total number of stereoisomers will not exceed 2n, where n
is equal to the number of tetrahedral stereogenic centers.
(2R,3R)-2,3-dibromobutane
Attilio Citterio
Molecules with Multi-Stereogenic Centers
Meso Compounds.24
enantiomers
enantiomers
..
.
(superimposable)
Attilio Citterio
Molecules with Multi-Stereogenic Centers
Meso Compounds (2).25
enantiomers
Meso Compound
.
Total number of stereoisomers will not exceed 2n, where n is equal
to the number of tetrahedral stereogenic centers.
diastereomers
Attilio Citterio
Molecules with Multi-Stereogenic Centers
Fisher Projection Formula.26
.
Vertical lines represent bonds that project behind the plane of the paper (or that lie
in it). Horizontal lines represent bonds that project out of the plane of the paper.
Attilio Citterio
Molecules with Multi-Stereogenic Centers
Fisher Projection Formula (2).27
.
Vertical lines represent bonds that project behind the plane of the paper (or that lie
in it). Horizontal lines represent bonds that project out of the plane of the paper.
Attilio Citterio
Stereoisomerism of Cyclic Compounds.28
.
.
.
.
.
.
Mirror plane
trans-1,3-dimethylcyclohexane
cis-1,3-dimethylcyclohexane
Attilio Citterio
1,2-Dimethylcyclohexane.29
trans-1,2-dimethylcyclohexane
.
.
.
.
H
Me
H
Me
H
Me
H
Me
Enantiomers
H
Me
Me
H
H
Me
Me
H
Enantiomers
1,2-dimethylcyclohexane
cis-1,2-dimethylcyclohexane
Attilio Citterio
1,2-Dimethylcyclohexane.30
trans-1,2-dimethylcyclohexane
.
.
.
H
Me
H
Me
.
H
Me
H
Me
Enantiomers
H
Me
Me
H
H
Me
Me
H
Enantiomers
1,2-dimethylcyclohexane
cis-1,2-dimethylcyclohexane
.
.
diastereomers
.
Attilio Citterio
1,2-Dimethylcyclohexane.31
1,2-dimethylcyclohexane
trans-1,2-dimethylcyclohexane
.
.
.
.
H
Me
H
Me
H
Me
H
Me
Enantiomers
H
Me
Me
H
H
Me
Me
H
Enantiomers
.
.
diastereomers
.
Identical
HH
HH
Me Enantiomers MeMeMe
cis-1,2-dimethylcyclohexane
Attilio Citterio
1,2-Dimethylcyclohexane.32
1,2-dimethylcyclohexane
trans-1,2-dimethylcyclohexane
.
.
.
.
H
Me
H
Me
H
Me
H
Me
Enantiomers
H
Me
Me
H
H
Me
Me
H
Enantiomers
.
.
diastereomers
.
Enantiomers
Identical
HH
HH
MeMeMe
Me
cis-1,2-dimethylcyclohexane
Attilio Citterio
Compounds with Stereogenic Centers Other
than Carbon or No Stereogenic Centers.33
H
Me
H
Me
Mirror
(S)-Naproxene
Attilio Citterio
Other Chirality in Organic Chemistry.34
Attilio Citterio
Other Chirality in Organic Chemistry.35
enantiomers
Attilio Citterio
Other Chirality in Organic Chemistry.36
mirror
enantiomers
allene