INTRODUCTION TO STEREOCHEMISTRY

Isomers are compounds with the same molecular formula but not identical structures



Constitutional isomers are isomers which have the same molecular formula but differ
in the way their atoms are connected
Constitutional Isomers






















Constitutional isomers are isomers which have the same molecular formula but differ
in the way their atoms are connected



Stereoisomers have the same molecular formula, maintain the same connectivity, but
differ in the way their atoms are arranged in space



Conformational isomers (or conformers or rotational isomers or rotamers) are
stereoisomers produced by rotation about single bonds, and are often rapidly
interconverting at room temperature




Conformations of Alkanes and Cycloalkanes





















Conformations of Ethane
ethane
Staggered
conformation of
ethane
Eclipsed
conformation of
ethane
Sawhorse
Representation
Sawhorse
Representation
Newman
Projection
Newman
Projection





















ethane
Staggered
conformation of
ethane
Eclipsed
conformation of
ethane
Sawhorse
Representation
Sawhorse
Representation
Newman
Projection
Newman
Projection



Configurational Isomers are stereoisomers that do not readily interconvert at room
temperature and can (in principle at least) be separated.



Geometric isomers are configurational isomers that differ in the spatial position
around a bond with restricted rotation (e.g. a double bond):



Geometric (Cis and Trans) Isomers
Geometric (Cis and Trans) Isomers result from restriction rotation

Compounds with double bonds
cis isomer have same substituents on the same side of the double bond (= Z
with more complex molecules having high priority groups on the same side)
trans isomer have the same substituents on the opposite side of the double
bond (= E with more complex molecules having high priority groups on opposite
sides)

Compounds with bonds in a ring:
cis isomer have the same substituents on the same side of the ring
trans isomer - have the same substituents on the opposite side of the ring













Cis-trans (Geometric) isomerism in Alkenes
cis-1,2-dichloroethene trans-1,2-dichloroethene
(E)-1,2-dichloroethene (Z)-1,2-dichloroethene
Cis-trans (Geometric) isomerism in Alkenes








1,1-dichloroethene
*If one of the two carbon atoms of the double bond has two identical substituents,
there are no cis-trans isomers for that molecule










Identifying cis and trans isomers of Alkenes
Example 11.3
Two isomers of 2-butene are shown below. Which is the
cis isomer and which is the trans isomer

cis-2-butene trans-2-butene










Naming cis and trans compounds
Example 11.4
Name the following geometric isomers.

trans-3,4-dichloro-3-heptene cis-3,4-dimethyl-3-octene















Identifying Geometric Isomers
Example 11.5
Determine whether each of the following molecules can
exist as cis-trans isomers:
(1) 1-pentene
(2) 3-ethyl-3-hexene
(3) 3-methyl-2-pentene
1-pentene 3-ethyl-3-hexene
cis-3-methyl-2-pentene trans-3-methyl-2-pentene





















cis-9-octadecenoic acid
Cis and Trans Fatty Acids
trans-9-octadecenoic acid














Cis-trans (Geometric) isomerism in Cycloalkanes
Cis-trans isomers are molecules having the same arrangement of atoms but differ in
the spatial orientation of their substituents.
cis-1,2-dichlorocyclohexane trans-1,2-dichlorocyclohexane

















Naming cis-trans Isomers of Substituted Cycloalkanes
Example 10.6
Determine whether the following susbstituted
cycloalkanes are cis or trans isomers.

trans-1,2-dimethylcyclopentane cis-1,2-dimethylcyclopentane
Conformations of Alkanes and Cycloalkanes





















Conformations of Cyclohexane
cyclohexane
Chair
conformation of
cyclohexane
Boat
conformation of
cyclohexane





















Chair
conformation of
cyclohexane
Boat
conformation of
cyclohexane
Chair-Chair Interconversion



Optical isomers are configurational isomers that differ in the 3D relationship of the
substituents about one or more atoms.








Diastereomers are optical isomers (stereoisomers) that are not enantiomers.










Enantiomers are optical isomers that are non-superimposable mirror images.








Chirality
Chiral objects are objects with left-handed and right-handed forms
Achiral objects - objects that have superimposable mirror images
Nonsuperimposable mirror images - a mirror image that is not the same as the image
itself - chiral objects have nonsuperimposable mirror images
Assymetric Center
Chirality is not reserved just for objects - molecules can be chiral
Chiral molecules - generally molecules containing an asymmetric center
Asymmetric (chiral) center - tetrahedral atom bonded to four different groups -
indicated with an asterisk (*)











Enantiomers
nonsuperimposible mirror images
OH
CH
3
HO
2
C
H
OH
CO
2
H
CH
3
H
mirror
plane
(S)(+) lactic acid (R)(-) lactic acid
from muscle tissue from milk
[o] = +13.5 [ o] = -13.5
o
o
Enantiomeric Excess
(Optical Purity)

actually 94.3% (+)
11.4% racemic
88.6% (+)
= 88.6% e.e.
x 100
123.0
109.0
e.e. =
o
observed rotation = +109
from oranges
o
[o] = +123.0
H
from lemons
o
[o| = 123.0
(S)-(-) Limonene (R)(+) Limonene
H
x 100 = enantiomeric excess(e.e.)
rotation of pure enantiomer
observed rotation
Biological Activity
(R)(+) Thalidomide (S)(-) Thalidomide
N
N
O
O
O
O
H
H
a sedative and hypnotic a teratogen
N
N
O
O
O
O
H
H
SSRI Efficacy depends on
Stereochemistry
O
N(CH
3
)
2
F
NC
*
(+/-) Celexa
(-) Lexapro
Chiral Molecules with One Asymmetric Center
Molecules with one chiral center would have 2 enantiomers
*Chiral molecules would have 2
n
enantiomers (where n is the number of chiral centers)






















Chiral vs Achiral














































































































How to Represent Enantiomers: Perspective Formulas
Perspective Formulas - shows two bonds of the asymmetric center as lines in the plane of
the paper, another bond as a solid wedge protruding forward out of the paper, and the
fourth bond as a hatched wedge extending behind the paper























Fischer Projections
Fisher Projection - representation of an asymmetric center as the point of intersection of
two perpendicular lines
Horizontal lines represent bonds that project out of the plane of the paper
Vertical lines represent bonds that extend back from the plane of the paper away from the
viewer
Fischer Projections




























































Naming Enantiomers -R,S System
STEP 1. Rank the groups/atoms bonded to the asymmetric center in order of priority.
- rank in terms of atomic mass. Higher atomic mass, higher priority.
- lets have 1-chloro-1-ethanol as an example.

1. Chlorine = 36 amu
2. Oxygen = 16 amu
3. Carbon = 12 amu
4. Hydrogen = 1 amu

STEP 2. Rotate the molecule so that the lowest priority group is pointing away from the
reader.









Naming Enantiomers -R,S System
Step 3. Trace your finger around the three highest priority groups in order of the
priority.

- If the circle is moving counterclockwise the CIP designation is S. If the circle
is moving clockwise the CIP designation is R.











Step 4. Name the enantiomer in terms of its R or S configuration.
- the name for this isomer is (S)-1-chloro-1-ethanol
Naming Enantiomers -R,S System
Assigning Priorities to Groups

1. Oxygen (from CH
2
OH) = 16
2. Carbon (from CH
2
CH
3
) = attached to carbon
3. Carbon (from CH
3
) = attached to hydrogen
4. Hydrogen = 1







Naming Enantiomers -R,S System
Lactic Acid
(S) (R)
4
3
2
1
4
3
2
1
OH
CH
3
CO
2
H
H
OH
CH
3
HO
2
C
H












































Plane-Polarized Light

Plane-Polarized Light through an
Achiral Compound
Plane-Polarized Light through a Chiral
Compound
Polarimeter Measures
Optical Rotation
Specific Rotation, []

[] = / cl
o = observed rotation
c = concentration in g/mL
l = length of tube in dm

Dextrorotary designated as d or (+), clockwise
rotation
Levorotary designated as l or (-), counter- clockwise
rotation
Specific Rotations of some Common
Organic Compounds
Compound [o] #
*
centers
Penicillin V +233.0 3
Sucrose +66.5 10
Camphor +44.3 2
MSG +25.5 1
Cholesterol -31.3 8
Morphine -132.0 5
Diastereomers
Stereoisomers That Are Not Mirror Images
3
3
2
2
opposite stereochemistry at C
3
same stereochemistry at C
2
(S)
CO
2
H
OH H
Br H
CO
2
H
OH
H
Br
H
(2S,3S) (2S,3R)
Fischer Projections with 2 Chiral
Centers
CO
2
H
CH
3
H OH
Br H H Br
H OH
CO
2
H
CH
3
(2S,3S) (2S,3R)
2
3
2
3
Identical, Enantiomers or
Diastereomers?
H
H
CH
3
CH
3
&
CH
3
CH
3
H
H
C C
a)
CH
2
CH
3
CH
3
H
H
Br
Br
CH
2
CH
3
CH
3
&
b)
OH
HO
NH
2
NH
2
Tartaric Acids
CO
2
H
CO
2
H
H OH
HO H
H OH
HO H
CO
2
H
CO
2
H
CO
2
H
CO
2
H
H OH
H OH
HO H
HO H
CO
2
H
CO
2
H
R,R S,S
R,S S,R
Racemic Mixture
o
(g/mL) 1.7598 1.7598 1.7723
m.p. C 168-170 168-170 210-212
[o] (degrees) - 12 + 12 0
(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid
Racemic Mixture (Racemate): 50/50 mixture of enantiomers
CO
2
H
CO
2
H
H OH
HO H
H OH
HO H
CO
2
H
CO
2
H
R,R S,S
Meso Compound
Internal Plane of Symmetry
Optically Inactive
o
rotate 180
superimposible
CO
2
H
CO
2
H
H OH
H OH
HO H
HO H
CO
2
H
CO
2
H
R,S S,R
mirror
plane
2,3,4-trichlorohexane
How many stereoisomers?
Cl
Cl
Cl
3 asymmetric centers
8 stereoisomers
*
*
*
2
n
, n= # asymmetric centers (3)
n = 3; 2
n
= 8
CH
3
CH
2
CH
3
H Cl
Cl H
H Cl
Cl H
H Cl
Cl H
CH
3
CH
2
CH
3
CH
3
CH
2
CH
3
Cl H
H Cl
H Cl Cl H
Cl H
H Cl
CH
3
CH
2
CH
3
H Cl
H Cl
H Cl
CH
3
CH
2
CH
3
Cl H
Cl H
Cl H
CH
3
CH
2
CH
3
Cl H
H Cl
H Cl
CH
3
CH
2
CH
3
H Cl
Cl H
Cl H
CH
3
CH
2
CH
3
S
S
R
R
R
S
A Carbohydrate
CHO
CH
2
OH
H OH
HO H
H OH
H OH
(+) D-Glucose
R
S
R
R
Internal Planes of Symmetry
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
Both are Meso
Asymmetric Centers on Rings
Br
Br
Br
Br
1(R),2(S) cis 1,2-dibromocyclohexane
nonsuperimposible but A flips into B
A B
Br Br
Meso
Bromination
Trans is formed exclusively
No Meso is formed (cis)
racemic mixture
S S
R R
Br
Br
Br
Br
Br
2
Preparation of (L)-Dopa
for Treatment of Parkinsons
HO
HO
CH
2
C
CO
2
H
NH
2
H
l-(-) Dopa
HO
HO
CH
2
CH
2
NH
2
Dopamine
cannot cross blood-brain
barrier
C=C
NH
2
CO
2
H H
HO
HO
H
2
Rh(DIOP)Cl
2
enz.
Relevance of Stereochemistry
(S,S)
(R, S)
useful decongenstants
d-pseudoephedrine and l-ephedrine
4 stereoisomers
*
*
2 asymmetric centers
EPHEDRA from Ma Huong
NHCH
3
CH
3
OH
One-step synthesis
Pseudophed
*
d-(S)- "Meth"
l-(R) - Vicks
(methamphetamine)
"desoxyephedrine"
NHCH
3
CH
3
o-(p-isobutylphenyl)propionic acid
CH
3
CO
2
H
H
(S)(+) ibuprofen (R)(-) ibuprofen
CH
3
HO
2
C
H
anti-inflammatory 80-90% metabolized to (S)(+)
Model of Thalidomide
How Sweet it is!
Sucrose
O
HO
OH
O
CH
2
OH
O
CH
2
OH
CH
2
OH
HO
HO
OH
Sucralose or Splenda
O
Cl
HO
OH
O
CH
2
OH
O
CH
2
Cl
CH
2
Cl
HO
HO
Sucralose is 600 times sweeter and does not
get metabolized.
Sildenafil (Viagra) and Caffeine
N
N
N
N
CH
3
H
O
CH
3
CH
2
O
S
N
N
CH
3
O
O
N
N
N
N
CH
3
O
O
CH
3
CH
3
Radiosensitizer of Choice Until 2004
Okadaic acid
17 asymmetric centers
O
OH
HOOC
OH
O
H
O
O
H
H
O
OH
H
OH
O
O