CHAPTER 5: STEREOCHEMISTRY
Identifying Chiral Carbons and Chirality.
Which molecules contain chiral carbons? Mark the chiral carbons with an asterisk.
Cl
Cl Cl
Cl
Cl
Without determining stereochemical configuration (R or S), can you determine which of the
following pairs of molecules are the same, and which are enantiomers?
Br
H
H3C
CN
and
CN
H
H3C
Br
CO2H
H
H3C
and
NH2
Br
CO2H
H
CH3
H2N
H
HO
Br
and
CH2CH3
HO
H3CH2C
H
For molecules that have only one chiral atom, there can only be two possible isomers (below,
left). If you count the number of chiral atoms and solve for 2n, where n = # chiral atoms, this will
tell you how many stereoisomers are possible for any given molecule. For example, 21 = 2.
Cl
A
Cl
and
HO
B
only two possible
only
possiblestereoisomers
stereoisomersare
possible for 3-chlorocyclohexene
O
Identify
chiral carbons
1.How
manythe
isomers
are possible for this structure of vitamin E?
2. How many possible stereoisomers are can you have for this molecule?
Is molecule A optically active? ________
Is molecule B optically active? ________
Can you predict the optical rotation of A or B? _______
If you were to consider an equal mixture (1:1) of both A and B, could you predict the optical
rotation of the mixture? _______
What is the name for this kind of mixture? _________________________
Naming Chiral Centers - The R,S System. Since we cannot
assign D (or +) or L (or -) to an enantiomer simply based on its
structure, another naming system must be used to distinguish
between stereoisomers. After all, we can’t name both these
molecules 2-chloropentane.
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
Cl
Cl
2-chloropentane?
2.8.17 5.1 v3 p1
The Cahn-Ingold-Prelog priority rules are in place to specify an absolute configuration around a
chiral center (carbon, in these examples).
Cahn-Ingold-Prelog Priority Rules
Rule 1:
Look at the four atoms (not group of atoms) directly attached to the chiral atom, and rank
them according to atomic number, where 1 is the highest and 4 is the lowest priority.
With the lowest priority group pointing away, look at the remaining 3 groups in a plane.
From highest to lowest priority, clockwise is designated R, counterclockwise is designated S.
•
•
•
is R
Is th
OH
?
or S
H
Br
CH2CH3
Rule 2:
If the lowest priority group is facing TOWARD you, rather than away from you, continue the
standard method for determining R and S, but REVERSE the ending result. Alternatively,
you can simply put your eye where it needs to be in order for the lowest priority group to be
facing away from you - which is how the middle and right images are drawn, below.
•
is
Is th
Ro
Br
r S?
HO
H
CH2CH3
Assign R or S to the chiral carbons in each example:
H OH
Br H
H2N
OH
•
H OH
CO2H
NH2
If the lowest priority group is neither facing away from you or toward you (like below), adjust
your perspective so it IS pointing away from you.
Assign R or S to the following:
H
Br
Br
HO
CH3
H3C
OH
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
H
2.8.17 5.1 v3 p2
Rule 3:
•
If a decision on priority cannot be reached by ranking the first atoms from the chiral atom,
compare the second, third, or fourth atoms until a priority can be assigned.
Cl
Cl
Which is (R)-2-chloropropane and which is (S)-2-chloropropane?
Rule 4:
•
In most cases, it is safe to presume that atoms with a greater number of bonds are of a
higher priority when compared to the same atom with less bonds, for example:
>
C C H
>
C CH2
H
CH2CH3
Try assigning the configuration of the chiral carbons below:
Cl
Cl
Let’s Practice:
Assign (R) or (S) to the molecules below. Are the pairs the same or are they enantiomers?
Br
NC
H3C
CN
and
H
H
H3C
CO2H
H
Br
H3C
NH2
and
CO2H
H
H2N
CH3
Assign (R) or (S) configurations to the chiral carbons in the following isomer of menthol:
CH3
HO
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
2.8.17 5.1 v3 p3
Assign (R) or (S) configurations to the chiral carbons in the following molecule:
H OH
O
H3C
O
H3CO H
H OH
H OH
H CH3
O
O
H NH2
Molecules With Multiple Chiral Atoms.
1-chloro-2-methylcyclohexane has four possible stereoisomers (22 = 4); they are:
Cl
Cl
Cl
A
CH3
B
CH3
C
CH3
enantiomers
Cl
Cl
D
CH3
CH3
enantiomers
diastereomers
A and B are enantiomers and C and D are enantiomers, but “diastereomer” describes the
relationship of A or B with C or D.
Using IUPAC rules, A is now named (1R,2S)-1-chloro-2-methylcyclohexane. You try naming B
through D.
A: _(1R,2S)_________-1-chloro-2-methylcyclohexane
B: ________________-1-chloro-2-methylcyclohexane
C: ________________-1-chloro-2-methylcyclohexane
D: ________________-1-chloro-2-methylcyclohexane
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
2.8.17 5.1 v3 p4
We predict four stereoisomers for the example below. Draw them, assign (R) and (S) to the
chiral atoms, then determine which are enantiomers and which are diastereomers.
CH2CH3
H3C
The levorotatory isomer of epinephrine, below, has profound effects on the cardiovascular
system.
Draw (+)-epinephrine (remember, enantiomers have exactly the opposite
stereochemistry).
NHCH3
OH
(-)-Epinephrine
What can you say with certainty about the optical rotation of (+)-epinephrine?
What can you say with certainty about the biological properties of (+)-epinephrine?
Meso Compounds. Some molecules that have chiral carbons do not obey the “2n” rule. For
example, consider the following four structures of 1,2-dimethylcyclohexane
CH3
CH3
CH3
CH3
A
B
CH3
C
CH3
CH3
CH3
D
CH3
CH3
Although C and D are enantiomers, A and B are the same; hence, although trans-1,2dimethylcyclohexane is chiral, cis-1,2-dimethylcyclohexane is not - and it carries a unique name:
meso. A molecule that is meso has more than one chiral carbon, but is not chiral. So ultimately,
1,2-dimethylcyclohexane only has three different stereoisomers; A is meso, and is a
diastereomer of C and D, while C and D are enantiomers of each other.
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
2.8.17 5.1 v3 p5
Can you identify which of the following are meso compounds? Look for symmetry.
Are the molecules within each set, below, identical, enantiomers or diastereomers?
If you find these difficult by simply looking at the molecules and comparing their shape, start by
assigning (R) and (S) to the chiral atoms - this may simplify the task.
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
2.8.17 5.1 v3 p6
Fischer Projections. Molecules depicted this way are all drawn with the assumption that the
horizontal bonds are coming toward you and the vertical bonds are going away from you - like
this:
CO2H
H
NH2
H
OH
CH3
same as
CO2H
H
NH2
H
OH
CH3
Fischer Projection
If that representation is still a little foreign, you can convert this to a molecular representation
you might recognize by pretending that you’re looking at the underside of a dog. The horizontal
bonds are the four legs, and are coming toward you, and the vertical bonds are the head and
tail, going away from you. Simply pick up the dog and put it on its feet. No joke - it works!
CO2H
H
NH2
H
OH
CH3
same as
CO2H
H
NH2
H
OH
CH3
same as
HO2C
H
CH3
same as
HO2C
CH3
H
H2N H OH
H2N H OH
To assign chirality to atoms in molecules that are drawn in a Fischer projection, you can either
simply imagine the horizontal/vertical bonds forward/back (the easier way to do it) or stand the
dog up on its feet. Which ever method works for you - give it a try. Assign (R) or (S) to the
chiral carbons in the following molecule:
CO2H
H
H3C
H
OH
NH2
Prochirality. Some molecules that are NOT chiral can have prochiral atoms if adding a fourth
atom can create asymmetry. Re and Se are used to describe the face of a planar molecule such
as this ketone to indicate the rotation from highest to lowest priority (left). From the perspective
of viewing the alkene (right) in the plane of the paper, each of the two prochiral carbons can be
labeled Re or Se - give it a try:
HO2C C C H
H
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
CO2H
2.8.17 5.1 v3 p7
Prochirality can also describe hydrogen atoms attached to achiral carbons. In the following
example, if the pro-R hydrogen was replaced with a higher priority atom, the resulting absolute
configuration would be (R). You try:
Br H
pro-S
pro-R
pro-S
H H
pro-R
Br H
(R)
(R)
H Br
H Br
H H
(S)
(S)
H HH H
- COCO
2 2
H
C
3
H3C
+
3N H
+H N HH
3
Question 5.61 from text: One of the steps in fatty-acid biosynthesis is the dehydration of (R)-3hydroxybutyryl ACP to give trans-crotnyl ACP. Does the reaction remove the pro-R or pro-S
hydrogen from C2?
Question 5.70 from the text: (S)-1-Chloro-2-methylpentane undergoes light-induced reaction
with Cl2 to yield a mixture of products, among which are 1,4-dichloro-2-methylbutane and 1,2dichloro-2-methylbutane.
(a) Write the reaction, showing the correct stereochemistry of the reactant
(b) One of the products is optically active, but the other is optically inactive. Which is which?
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
2.8.17 5.1 v3 p8
Question 5.76 from the text: Ketones reaction with sodium acetylide to give alcohols.
example, the reaction of sodium acetylide with 2-butanone yields 3-methyl-1-pentyn-3-ol.
H3C
O
C
1. Na+
CH2CH3
C CH
2. H3O+
H3C
HC
C
For
OH
C
CH2CH3
(a) Is the product chiral?
(b) Assuming that the reaction takes place with equal likelihood from the Re and Si faces of the
carbonyl group, is the product optically active? Explain.
Most chiral nitrogens are unstable and readily interconvert their stereochemistry spontaneously
to form racemic mixtures. This process can be slowed to maintain the stereochemistry of the
nitrogen atom in which of the following ways?
(a)
(b)
(c)
(d)
Increasing the pH of the solution
Decreasing the size of the functional groups on the nitrogen
Increasing the temperature of the solution
Increasing the steric hinderance of the functional groups on the nitrogen
Organic Chemistry I, CHM 223
Winter 2017 - Dr. Turk
2.8.17 5.1 v3 p9