Stereochemistry II
Reading: Wade chapter 5, sections 5-8- 5-16
Study Problems: 5-28, 5-29, 5-30, 5-31, 5-35
Key Concepts and Skills:
•
Draw all stereoisomers of a given structure.
•
Identify enantiomers, diastereomers, and meso compounds; draw correct Fischer
projections of asymmetric carbon atoms.
•
Explain how the physical properties differ for different types of stereoisomers,
and suggest how to separate different types of stereoisomers
Lecture Topics:
I. Conformational isomerism
Consider cis-1,2-dichlorocyclohexane; each chair conformation is chiral, but a ring flip
will convert one stereoisomer to its mirror image. Since chair-chair interconversions are
rapid at room temperature.
A molecule cannot be optically active if its chiral conformations are in rapid
equilibrium with their mirror images.
different
consider only:
Cl
Cl
σ
Cl
Cl
mirror image non-superimposable
on original molecule
ring flip
Cl
Cl
Cl
identical to mirror image:
Cl
Cl
Cl
A correct prediction about whether a molecule is chiral or achiral can be made by
analyzing the most symmetrical conformation (in the case of a cyclic molecule, it is
the “flat” conformation) Note that trans 1,2-dibromo cyclohexane has chiral chair
forms, the mirror images of which cannot be obtained by a ring flip:
different
Cl
Cl
consider only:
Cl
Cl
mirror image non-superimposable
on original molecule
ring flip
Cl
Cl
Cl
Cl
different from
Cl
chiral
Cl
•Some molecules have no asymmetric carbon atoms (no centers of chirality) yet they are
chiral. This is due to locked conformations of a molecule which are chiral and cannot
interconvert because of steric hindrance: “axial chirality”
•An example is 2,2,2,2’-substituted biphenyls, in which the most symmetrical “flat”
conformation cannot be obtained because of a very large degree of steric hindrance to
rotation about the central C-C bond: a very high energy is required to rotate past the point
of planarity. The molecular conformations are thus locked with the two rings
perpendicular to each other. The two conformations are enantiomeric; their mirror images
cannot be superimposed.
CH3
I
Very large degree of steric hindrance
in most symmetrical planar conformation
H3C
I
H3C
CH3
I
I
CH3
H 3C
I
I
locked conformation
non interconvertible conformations
ring planes are perpendicular
chiral conformations
•Allene is a molecule with one sp-hybridized carbon and two sp2-hybridize carbon atoms.
Because of the perpendicular p-orbitals on the central sp-hybridized carbon which
overlap to form the pi orbitals, the pi orbitals are also perpendicular, and thus the end
groups on the molecule are perpendicular. Substituted allenes are thus chiral molecules
with non-superimposable mirror images:
mirror plane
H3C
CH3
H3C
CH3
C
C
H
H
H
H
different compounds
enantiomers
II. Fischer Projections
Fischer Projections are a shorthand method of drawing stereoisomers to facilitate their
comparison when there are multiple asymmetric carbon atoms within a molecule.
• Fischer projections are drawn in cross form with the horizontal bonds coming toward
the viewer and the vertical bonds going away from the viewer. For S-lactic acid:
COOH
COOH
HO
HO
CH3
COOH
HO
H
H
H
CH3
CH3
Fischer projection
•Fischer projections that differ by 180° are the same molecule. A 90° rotation, however,
is not allowed. Fisher projections also my not be flipped over: they must be kept in-plane.
180°
CH3
COOH
COOH
HO
HO
H
H
H
CH3
OH
H
OH
in-plane
COOH
CH3
CH3
COOH
same molecule
COOH
COOH
HO
H
CH3
HO
90°
CH3
OH
H 3C
H
in-plane
non-superimposable
enantiomers
OH
COOH
H
H3C
COOH
H
• A carbon chain must be drawn along the vertical line of the projection and given
IUPAC numbering from top to bottom
• When looking at the mirror image of a Fischer projection, any groups that fail to
superimpose after a 180° turn indicates chirality and the two molecules are enantiomers.
1
CH2OH
H
2
H
CH3
180°
CH2OH
OH
CH3
CH2OH
OH
HO
H
H
3 CH3
in-plane
CH3
OH
CH2OH
non-superimposable: enantiomers
ALSO:
CH3
CH3
Br
Br
H
Br
H
H
Br
CH3
CH3
180°
H
in-plane
Br
H
H
Br
CH3
CH3
not the same molecule! enantiomers
CH3
H
Br
Br
H
H
Br
Br
H
CH3
CH3
180°
CH3
H
in-plane
Br
H
Br
CH3
CH3
SAME MOLECULES: ACHIRAL
Assigning R and S configurations to Fischer Projections
• Same rules apply, but if the low priority group (H) is projecting forward (on a
horizontal bond), a counterclockwise rotation indicates R configuration and a clockwise
rotation indicates S configuration; if the low priority group is projecting backward (on a
vertical bond) the regular Cahn-Ingold Prelog rule applies:
2
2
CHO
CHO
H
1
OH
CHO
H
3
OH
H
CH2OH
HO
CH2OH
CH2OH
1
3
projecting forward
clockwise: R
counterclockwise:
R
3
3
CH2OH
2
Cl
Br
CH2OH
CH2OH
1
Cl
Br
H3C
Br
1
Cl
CH3
CH3
2
clockwise R
clockwise: R
projecting backward
III. Diastereomers
Diastereomers are stereoisomers that are not mirror images; they are geometric isomers
(like cis-trans isomers about a double bond) and usually compounds containing at least
two centers of chirality.
Examples:
CH3
CH3
S
H H 3C
H
H
H
H
H3C
H 3C
H
Br
H
Cl
Cl
R
CH3
S
S
CH3
Diastereomers
Br
H
CH3
Diastereomers
Stereoisomers but not
enantiomers
Relationships:
enantiomers
enantiomers
CH3
CH3
CH3
R
S
H
Br
Br
Cl
Cl
H
H
S
R
H
H
Cl
CH3
CH3
2S, 3R
CH3
S
Br
S
R
Br
H
H
CH3
2R, 3S
H
R
Cl
CH3
2S, 3S
2R, 3R
Diastereomers
Diastereomers
Diastereomers
Diastereomers
• If the number of stereogenic carbon atoms in a molecule is n, there are a maximum of 2n
possible stereoisomers. Thus, for two stereogenic carbon atoms, there are a maximum of
22 or 4 possible stereoisomers. There are many cases where less than the maximum
number of stereoisomers may be found, especially in symmetrical molecules.
Example:
Same molecule
enantiomers
CH3
CH3
CH3
H
Br
Br
H
H
H
Br
Br
H
Br
σ
CH3
CH3
"meso-diastereomer"
S
S
CH3
Br
Br
H
H
CH3
2S, 3S
R
R
H
Br
CH3
2R, 3R
(±)-diastereomers
2-stereogenic carbon atoms;
a total of 3 stereoisomers for 2,3-dibromobutane!
•A meso compound is one that is achiral despite having centers of chirality: it usually
has some element of symmetry, like an internal mirror plane
IV. Absolute and Relative Configuration
Absolute configuration is the detailed stereochemical picture of a molecule, specifying
how the atoms are arranged in space through designating R or S configurations at each
chirality center.
Relative configuration is the experimentally determined relationship between the
configuration of two molecules or two stereogenic carbon atoms within a molecule, even
though we may not know the absolute configuration of either.
Example:
O
H 3C
trans 2,4-dimethylcyclohexanone
relative configuration: trans configuration of two methyl groups
determined by NMR
CH3
however, we don't know absolute stereochemistry:
O
O
H3C
R
H3C
S
or
R
S
CH3
CH3
V. Physical Properties of diastereomers
•Diastereomers, unlike enantiomers, have different physical properties: melting points,
boiling points, etc. Diastereomers can thus be separated by ordinary means:
chromatography, distillation, crystallization, etc.
•Enantiomers, which are mirror-image molecules, have virtually identical physical
properties and are thus very difficult to separate..
•Pure enantiomers of optically active compounds are often obtained by isolation from
natural sources. Examples: carbohydrates (D-(+)-glucose) and amino acids (L-(+)alanine)
•Many chemical reactions involve achiral reagents and thus can yield racemic mixtures as
products. How can one separate (resolve) enantiomers of a given molecule?
Resolution of Enantiomers
•Column Chromatography can be employed using a chiral stationary phase as an
adsobent: different enantiomers form diastereomeric complexes with the chiral column
packing and move through the column at different rates. In this way separation can be
achieved without chemical modification of a racemic mixture.
•A racemic mixture can also be resolved by reacting the mixture of enantiomers with a
chiral resolving agent, which generates diasteromers that are easily separated. The pure
enantiomers can then be obtained by hydrolysis of the respective diastereomers.
We illustrate this process for the formation of diastereomeric esters by reaction of a
racemic diacid with a chiral alcohol:
separable
Diastereomers
inseparable
Racemic mixture
Resolving agent
CH3
O
COOH
C
S
H
Br
CH3
Br
2
+
S
H
H+
H
Br
HO
Br
-H2O
COOH
S-phenyl ethanol
H CH3
C
(S,S,S,S)
H
CH3
R
R
O
O
COOH
Br
O
H
2
+
CH3
O
H+
HO
C
O
Br
H
Br
-H2O
COOH
Br
S-phenyl ethanol
H CH3
C
O
O
(S,R,R,S)
hydrolysis:
CH3
O
C
H
O
Br
Br
H CH3
C
O
O
(S,S,S,S)
COOH
H+
S
H
+H2O
Br
Br
S
H
COOH
pure enantiomer
Additional Problems for practice:
1.) Draw a three-dimensional picture that corresponds to each of the
following Fisher projections:
COOH
H
OH
a
b
HO
CHO
COOH
H
HO
H
HO
H
HO
H
HO
H
H
OH
HO
H
c
CH2OH
CH2OH
CH2OH
2.) State the relationship between each of the following pairs of structures
(identical, enantiomers, diasteromers, constitutional (structural) isomers,
or different compounds that are not isomeric)
CH3
CH3
CH3
CH3
OH
OH
OH
OH
a
b
Br
Cl
c
Cl
Br
Cl
Cl
d
Cl
Br
Br
Cl
Cl
Cl
d
Cl
Br
Br
Cl