1. Isomerism: Constitutional Isomers and Stereoisomers
Constitutional Isomers = same molecular formula, different
connectedness
Stereoisomers = same molecular formula, same connectivity
of atoms but different arrangement of atoms in space
Chapter 5
Stereochemistry: Chiral Molecules
Two types of stereoisomers
Constitutional Isomers - Review
1.
Same molecular formula – different bond connectivities
Examp les of Constitutional Isomers
formu la
OH
CH3CH2CH2OH CH3CHCH3
C4H10
CH3CH2CH2CH3
è Example: cis and trans double bond isomers
constitutional isomers
C3H8O
2.
Enantiomers: stereoisomers whose molecules are
nonsuperposable mirror images
Diastereomers: stereoisomers whose molecules are not
mirror images of each other
CH3CHCH3
CH3
è Example: cis and trans cycloalkane isomers
Always different properties
Very different properties if different functional groups
Enantiomers and Chiral Molecules
Mirror images = handedness
t Chiral molecule - has the property of handedness
l Not superposable on its mirror image
l Can exist as a pair of enantiomers
t Pair of enantiomers
l A chiral molecule and its mirror image
t Achiral molecule
l Superposable on its mirror image
Left hand cannot be superimposed on the right hand
1

2. A chiral molecule: 2-butanol
Mirror image = converts right hand into left
I and II are mirror
images of each other
I and II are not
superposable and so are
enantiomers
2- propanol is not chiral
B is mirror image of A,
but is superimposable by 180 o rotation
Chiral molecules and stereogenic centers
1. A molecule with a single tetrahedral carbon bonded to four
different groups will always be chiral
2. Switching two groups at the tetrahedral center leads to the
enantiomeric molecule
CH3
H
C
3. A molecule with more than one tetrahedral carbon bonded to
CH3
HO
OH
C
CH3
A
four different groups is not always chiral
H
CH3
B
l Stereogenic center (stereo center)
è An atom bearing groups of such nature that an interchange of any two
groups will produce a stereoisomer
è Carbons at a tetrahedral stereogenic center are designated with an
asterisk (*)
l Example: 2-butanol
rotate
Everything has a mirror image, the question is whether it is superimposable
Tests for achirality
Mirror images not superimposable = enantiomers
1. Draw mirror image. Is it superimposable?
2. Does the species have a bisecting plane of symmetry?
2

3. Plane of Symmetry = achiral
2 -chlorobutane: no plane of Symmetry
An imaginary plane that bisects a molecule in such a way that the
two halves of the molecule are mirror images of each other
Cl
A molecule with a plane of symmetry cannot be chiral
*
H Cl
Cl
H
H
2-chloropropane
Compounds with 4 different groups attached to one Carbon must be chiral
unless a meso compound (2 stereocenters)
If any two groups on a C are identical, achiral
Nomenclature of Enantiomers: The R,S System
Many biological processes depend on chirality
Developed as the Cahn-Ingold-Prelog system (1956)
t The binding specificity of a chiral receptor site for a
chiral molecule is usually only favorable in one way
1.
2.
The four groups attached to the stereogenic carbon are
assigned priorities from highest (a) to lowest (d)
Priorities are assigned as follows
è Atoms directly attached to the stereogenic center are compared
è Atoms with higher atomic number are given higher priority
3.
If priority cannot be assigned based on directly
attached atoms, the next layer of atoms is examined
2-butanol
R,S nomenclature, cont.
4.
The molecule is rotated to put the lowest priority group back
è If the groups descend in priority (a,b then c) in clockwise direction the
enantiomer is R (R= rectus, right)
è If the groups descend in priority in counterclockwise direction the
enantiomer is S (S=sinister, left)
R,S nomenclature, cont.
5. Groups with double or triple bonds are assigned
priorities as if their atoms were duplicated or triplicated
3

4. R,S nomenclature, cont.
6.
If lowest priority group is not in back: 3 options
1. Rotate molecule to put lowest priority in back
With isotopes, higher atomic weight gets priority
4
H
2
D
*
3
OH
1
2. Move your eye to sight along bond toward group 4
If lowest priority group is not in back: third option
1. Swap any two groups and then assign the opposite of the
new priority
•
This works because interchanging two groups automatically
generates the enantiomer of the original
H
H3 C
C H3
Name this enantiomer of 3 -chloro-3-methyl -1-pentene
(D)
CH 3
Assign an (R ,S) label to
this stereoisomer:
(B)
C H2 =CH
C (A)
Cl
CH2 CH3
(C )
Step 1: Assign Priorities
Step 2: Visualize along the axi s with the lowest
priority group away from the viewer.
H
*
OH
Swap H and CH3
(B)
OH
-------->
C H=C H2
(D) CH3
R
C
This stereoisomer is (S).
(A)
Cl
CH 2 CH 3
counterclockwise
(C)
therefore: S
Step 3: Trace out the sequence A---->C.
Comparing molecules: Are A and B identical or enantiomers?
Properties of Enantiomers
t Enantiomers have almost all identical physical properties
(melting point, boiling point, density)
Method 1:Rotate B to see if it will become superposable with A
Physical Properties of (R) and (S)-2-But anol
boiling point
(R)
99.5o C
(S)
99.5o C
density (g/mL, 20o C)
0.808
0.808
Method 2: Exchange 2 groups to try to convert B into A
l One exchange of groups leads to the enantiomer of B
l Two exchanges of groups leads back to B
t However enantiomers rotate the plane of plane-polarized light
in equal but opposite directions
4

5. Properties of Enantiomers: Optical Activity
Plane polarized light
t Enantiomers rotate the plane of plane-polarized light in
equal but opposite directions
Oscillation of the electric field of ordinary light occurs in all
possible planes perpendicular to the direction of propagation
Reflected light is largely horizontally polarized
If the light is passed through a polarizer only one plane emerge
s
Plane polarized light
Plane polarized light oscillates in a single plane
Schematic of a Polarimeter
Like a rope thru
a picket fence
Specific Rotation – a property of an enantiomer
An optically active substance (e.g. one pure enantiomer ) will
rotate the plane-polarized light
l The amount the analyzer needs to be turned to permit light through
is called the observed rotation α
l We need to calculate a standard value specific rotation [α ]
Specific rotation of enantiomers
l The specific rotation of the two pure enantiomers of 2-
butanol are equal but opposite
l There is no straightforward correlation between the R,S
l If the analyzer is rotated clockwise the rotation is (+) and the
molecule is dextrorotatory (D)
l If the analyzer is rotated counterclockwise the rotation is ( -) and the
molecule is levorotatory (L)
designation of an enantiomer and the direction [(+) or
(-)]in which it rotates plane polarized light
5

6. An example of specific rotation
A sample of a compound A in chloroform (0.500 g/mL) at 25.0 oC shows
a rotation of +2.5 o in a 1.0 decimeter cell. What is the specific rotation?
[α] ltemp
=
α
LxC
=
+2.5o
1.0 dm x 0.5 (g/mL)
= +5.0o dm-1 (g/mL) -1
Racemic Mixture = A 1:1 mixture of enantiomers
t No net optical rotation
t Often designated as (+)
t Racemic mixture = racemate
Wha t is the o bserv ed ro ta tio n o f A in a 0 .5 dm ce ll?
α = [α]
x L x C = 5.0 o dm-1 (g/mL) -1 x 0.5 d m x 0.5 g/mL = + 1.25o
What is the observed r ot at ion if C = 0.050 g/mL?
α = [α]
x L x C = 5.0 o dm -1 (g/mL)-1 x 1.0 d m x 0.050 g/ mL = +0.25 o
Equal
amounts
of each
Enantiomeric Excess
Enantiomeric Excess
A mixture of enantiomers may be enriched in one enantiomer
We can measure the enantiomeric excess (ee)
ee of 50% = 50% of one enantiomer (+)
50% of racemate (+/-)
t Example : The optical rotation of a sample of 2-butanol is
Equivalently 75% of (+)-enantiomer
25% of (-)-enantiomer
+6.76o . What is the enantiomeric excess?
The Synthesis of Chiral Molecules
Most chemical reactions which produce chiral molecules
generate the racemic mixture (50%R, 50% S)
Enantioselective Synthesis
If all starting materials and reactants are achiral, the products will
be achiral or racemic
If one of the reagents is chiral, as is common in biological
systems, then the products may be chiral
e.g.: picking out the left handed gloves from a racemic mixture of
rights and lefts
H
(achiral)
OH
C
=
O
enzymatic reduction
ClCH2CH2CH2CCH3
alcohol dehydrogenase
5-chloro-2- pentanone
ClCH 2CH 2CH 2
CH 3
(S)-5-chloro-2 -pentanol
( 98% ee)
Top and bottom faces of the ketone bond are different to handed reagents
6

7. Enantioselective Synthesis in the lab
Chiral Drugs and Pharmaceutical Companies
Synthetic chemists are designing chiral catalysts that mimic the
en an tioselectivi ty of en zyme-catalyzed reaction s.
Typically only one enantiomer of a drug is biologically active
Preparation of only the desiredenantiomer saves material, costs, and
possible side effects
O
HO H
H
O
O
(achiral)
+
CH 2=C
(i) chiral catalyst
H
OSi(CH 3) 3
CH3
HO
(ii) acid workup
methyl 5 -phenyl pentan-3-ol-oate
(98% ee) (S)
H
O
O
(R)
(inactive)
(S)
(active)
OCH3
(achiral)
CH 3
HO
Ibuprofen
Molecules with More than One Stereogenic Center
Four stereoisomers of 2,3-dibromopentane
Each new center may generate a potential pair of stereoisomers, so
the theoretical number of possible stereoisomers is 2 n
(May have fewer if symmetry elements are present)
Relationship of 1 and 2 = enantiomers
l Enantiomers = same properties, cannot be separated
How many
stereoisomers?
Relationship of 3 and 4 = enantiomers
1 and 3 (or 1 and 4) = diastereomers
l Diastereomers: stereoisomers not mirror images of each other
l Have different physical properties and can be separated
Four stereoisomers of 2,3-dibromopentane
Meso compounds
Sometimes molecules with 2 or more stereogenic centers
will have less than the maximum amount of stereoisomers
We cannot simply say that 1 is an enantiomer or a diasteromer
Stereoisomerism refers to the relationship between two isomers
7

8. Meso compound are achiral
Meso Compounds and Racemates
t Because superposable on its mirror image
Under achiral conditions, a synthesis of 2,3-dibromobutane may create:
t Despite the presence of stereogenic centers
t Not optically active
t Has a plane of symmetry
è A and B in equal amounts (the racemate)
è C (the meso product)
è Some mixture of racemate (A/B) and meso compound C
+
{_____________}
Definition: a meso compound is a compound that is
achiral despite having stereogenic centers
Fischer Projections
Naming Compounds with More than One Stereogenic Center
Using same rules, assign each stereogenic center separately
meso
racemate
A 2-dimensional representation of chiral molecules
l Vertical lines represent bonds projecting behind the plane of the paper
Example: (2R, 3R)-2,3-dibromobutane
l Horizontal lines represent bonds projecting out of the plane of the
paper
Cannot rotate a
Fischer projection
about either vertical
or horizontal axis
Widely used in carbohydrate chemistry
Relative Configurations: (D)- and (L)-Glyceraldehyde
Relating Configurations of StereogenicCenters
If no bonds to the stereogenic carbon are broken, the reaction
proceeds with retention of configuration
In the la te 19th cent ury , Emil Fischer developed a method for assigning
configurat io ns at stereocenters relativ e t o the enantiomers of
glycera ldehyde. Fo r t he next 50 o r 6 0 years, config ura tions at
stereocenters were la beled rela tive to the stereo centers in the
stereoiso mers of glycera ldehyde.
The St ereoiso mers of
Glycera ldehyde
O
HO
OH
g lyceraldehy de
O
O
CH
CH
H
C
H
OH
CH 2OH
(R)
C
HO
H
CH2OH
( S)
(+)
(-)
(D)
Note change of R
to S despite
retention
( L)
Over 10 0 years ago , Fischer assigned t he dextro rotat ory (+)
st ereoiso mer, the config urat ion we call ( R) , and t he levoro tat ory (-)
st ereoiso mer was a ssigned the (S) co nf ig ura tion .
The la bels Fischer a ssigned were ca lled (D) a nd (L) . These a ssignments
were a g uess.
8

9. A n Example : Re lating (-)-Lac tic A cid to (+)-Glyc eraldeh yde
Absolute Configurati onal Assignments
O
CH
H C* OH
O
O
HgO
oxidation
COH
H C* OH
Retention
CH 2OH
(+ )-glyceraldeh yde
HNO 2
H 2O
Retention
CH 2 OH
(-)-glyceric acid
COH
H C* OH
CH2NH2
(+ )-isoserine
O
This transformation shows that (+ )-isoserine has
the same absolute con figuration as (+)-glyceraldehyde.
O
The series of chemical reactions involv ing retention of
configuratio n at the stereo centers configurationally link
(+)-glyceraldehyde and (-)-lactic acid .
H C* OH
COH
CH3
(-)-lactic acid
Zn, H +
Retention
CH2Br
(-)-3-bromo-2-h ydroxypropanoic acid
CH 3
(-)-lactic acid
Before 1951 the absolute configurations were not known.
Only these relative configurations were known from carefully
designed chemical transformations linking the assignments to the
configurations of the glyceraldehydes assumed by Emil Fis cher.
1951, X-ray crystal structure of (+) tartaric acid showed Fischer made the right guess!
Stereoisomerism of Cyclic Compounds
Stereoisomerism of Cyclic Compounds
l 1,4-dimethylcyclohexane
Consider 1,2-dimethylcyclopropane
è Neither the cis not trans isomers is optically active
è Each has a plane of symmetry
Two stereogenic centers
I
COH
H C* OH
COH
H C* OH
This transformation shows that (+)-isoserine has
the same absolute configuration as (-)-lactic acid.
CH 3
configurationally
the same
CH 2OH
(+)-gly ceraldehyde
O
H C* OH
O
CH
HNO2
HBr
Retention
CH3
II
CH 3
III
CH3
trans
Trans isomer has two enantiomers
R,R and S,S
H3C CH3
cis
Cis isomer is a
meso compound
Separation of enantiomers = resolution
t 1,3-dimethylcyclohexane
l The trans and cis compounds each have two
stereogenic centers
l The cis compound has a plane of symmetry and is meso
Cannot be separated directly Why not?
Can be separated by chiral reagent which creates diastereomeric relationship
l The trans compound exists as a pair of enantiomers
R
S
R
R
reaction
Racemic Form
(ide nt ical propert ies)
R
R
+
S R
R R
- R
S
R
pure forms
separate
R
Dia stereo mers
(different pro perties)
- R
S
is a resolving agent. It is a single enant iomer
(such as R) of a chiral compound.
Ring flip of (a) produces another (a), not the mirror image (b)
9

10. General Approach to Resolution
Resolution of a Carboxylic Acid
Often use organic acids or based which are found optically pure in nature
Can form acid-base salts which usually assures a high melting point and
the potential to separate by selective crystallization
HO
H
(+)(-)-Salt
+ (-)-alkaloid
(-)(-)-Sal t
(basic)
diastereomer s
(+,- )-2-phenylpro panoic acid
( ra cemic form)
Easily regenerate starting acid or base
CH 3O
CH 3
C6 H *
5CCOOH
H
separate by
fractional
cryst allization
H
N
(+)(-)-S alt
(-)(-)-Salt
H3O+
H3O+
wate r phase
organic phase
CH 3
(-)-alkaloid as
(+ )- C6 H5*
CCOOH
ammonium salt
H
organic phase water phase
CH 3
(-)-alkaloid as
*
(-)- C 6H 5 CCOOH ammonium salt
H
N
quinine
(primary alkaloid from various
spec ie s of Cinchona)
Chiral Molecules without a tetrahedral carbon
l Atropoisomer: conformational isomers that are stable
R1
R1
R4
Chirality without tetrahedral atoms
R4
+ R2
R2
Si
N
R3
R3
silane
quaterna ry ammonium io n
Chir al Molecules withou t a Stereoce nter : Molec ular C hirality
Some molecules begin a helical chirality by restricted rotation
l Allenes: contain two consecutive double bonds
A
A
A
B
A
A
B
A
B
B
B
B
10