Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
LECTURE POSTING V
Stereoisomerism
A type of isomerism; two compounds are stereoisomers when they differ only in
the spatial relationship of their components. In order to discuss isomerism we use the
following terms (with which you are familiar):
Composition:
the type and number of atoms in a molecule;
Constitution:
the way in which these atoms are connected
(we also call this connectivity);
Configuration:
the arrangement of the atoms in three-dimensional
space;
The term
Conformation:
also describes the arrangement of atoms in 3D
space, when several arrangementsare possible;
A.
Conformational isomerism
The conformation can be changed by free rotation about one or two single bonds;
Br
Br
B.
axial Br
equatorial Br
Configurational isomerism I: cis-trans or geometric isomerism
The configuration cannot be changed; it is “fixed”, by restricting free rotation.
1) Rotation can be restricted if two carbons of an alkane chain are tied up forming
a ring. You have seen examples in the cycloalkanes: substituents can be on the same side
(cis) or on opposite sides (trans) of the ring plane; two examples are shown below.
CH3
H
H
H
CH3
H
CH3
CH3
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H. D. Roth
2) Rotation can be restricted also when two adjacent carbon atoms are connected
by a π bond in addition a σ bond (see chapter 1); the π bond holds the substituents in one
plane; they can be on the same side (cis) or on opposite sides (trans) of the double bond
(more in chapter 11).
CH3
H3C
H
CH3
H
H3C
H
cis-2-butene
H
trans-2-butene
Geometric isomers could be interconverted by breaking and reforming a bond,
either a σ bond of a cycloalkane or π bond of an alkene. These processes do occur, but
they require high energies – therefore the geometric isomers of cycloalkanes and alkenes
are stable at room temperature (unlike conformers, which are readily interconverted).
When we compare structural and geometric isomers we note:
Structural Isomers
C.
Geometric Isomers
identical
composition
identical
different
connectivity
identical
different
arrangement in 3D space
different
different
heat of combustion
different
Configurational isomers, II: compounds with carbon stereocenters
There is another way to arrange atoms in 3D space generating isomers. You have
long been familiar with this type of relationship: look at your hands. Your two hands are
identical in many ways, but they differ in their 3D arrangement: they are related as
mirror images, they are different because they are not superimposable.
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Objects that are different in their 3D arrangement, but related as mirror images,
are called chiral (from Greek χειρ, hand). The difference lies in their “handedness”
(analogy to your left and right hands).
1) We recognize chirality in a molecule by an absence of symmetry. We
examine a molecule for elements of symmetry; objects that have a plane of symmetry
are not chiral (achiral); most compounds that lack a plane of symmetry are chiral. One
exception: compounds with a center of symmetry are achiral (example below).
H 3C
H 3C
Br
Br
CH3
•
Br
Cl
Achiral due to plane of symmetry
CH3
Achiral due to center of symmetry
CAUTION: It is not always easy to recognize symmetry, because molecules are
three-dimensional and the representations we use are two-dimensional.
2) Do we have a positive way to show that a molecule is chiral? An unmistakable,
structural feature identifying chirality: an asymmetrical carbon, or stereocenter. This is
an sp3 hybridized tetrahedral carbon (angle ~ 109.5°), with four different substituents.
Compounds containing an asymmetrical carbon exist in two isomeric forms that
cannot be superimposed; they are "mirror images" of each other. We call such molecules
enantiomers (the left molecule is the enantiomer of the right molecule and vice versa).
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Organic Chemistry
R1
Chapter 5 Stereoisomers
R4
R4
C
C
R1
R3
R3
H. D. Roth
R2
R2
(where R1, R2, R3, R4 are all different)
Enantiomers are identical in just about all properties, except for their
“handedness” (their asymmetry or chirality). If we compare some properties of geometric
isomers with stereo- isomers, we note
Geometric Isomers
Stereo Isomers
identical
composition
identical
identical
connectivity
identical
different
arrangement in 3D space
different
different
heat of combustion
identical (enantiomers)
If that is the case, why do we have to bother with it? As it turns out, the human
body has many “handed” receptors. For example, the two stereoisomers of carvone taste
and smell different, one like spearmint, the other like caraway seed.
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Organic Chemistry
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H. D. Roth
More more important is the difference between the effect of the two stereoisomers
of thalidomide: the (+)-isomer is a sedative without side effects whereas the (–)-isomer is
a teratogen, causing serious birth defects in babies.
O
O
O
H
N
N
O
HN
O
H
O
N
H
O
O
(+)-R a sedative
(–)-S a teratogen
CAUTION: if a compound has two stereocenters that are mirror images of each
other, they are symmetrical and, therefore, achiral.
H
C*
C*
CH3
H
CH3
The starred carbons of cis-1,2-dimethylcyclopentane have four different
substituents: these carbons are stereocenters. However, because the two carbons are
related as mirror images, the molecule is symmetrical, that is, achiral.
3) Drawing chiral molecules requires that you represent this 3-D feature clearly
and unmistakably in two dimensions. You are familiar with the wedge and dash (dottedline) method, which I have used above; this method is usually best for showing the 3-D
relationships in chiral compounds.
For drawing 3-D projections of substituted alkanes, it is convenient to place the
main carbon chain as a horizontal zig zag in the plane of the paper (the book does NOT
always do that). We will use this convention whenever possible. Also, if possible we
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H. D. Roth
place a H on a stereocenter on a dotted line and the other substituent on the wedge. The
projection of the two enantiomers (mirror images) of 2-bromopentane are shown below.
H Br
Br
H
Please, note that the dash and the wedge should always point away from the chain
(this is a consequence of the carbon being tetrahedral).
4) Naming enantiomers - absolute configuration
In order to properly name a stereocenter we have to take two steps:
a) “rank” the four substituents; a (high) –
b
–
c
–
d (low)
b) determine their arrangement in 3-D space as either R (rectus) or S (sinister)
4a) We rank substituents according to a convention by Cahn, Ingold, Prelog,
following these rules:
Rule 1a
atomic number of substituent
High atomic number has preference over low
F
>
O
>
N
>
C
>>>>
H
I
>
Br
>
Cl
>
S
>
O
Rule 1b
isotopes (they really thought of everything )
heavier isotope has priority
D
13
Rule 2
C
>
>
H
12
C
(not often encountered)
For groups with the same atomic number (if there is a tie in the atomic
numbers) break the tie by ranking its substituents to the first point of difference: the
substituent with the first point of difference in priority wins. Since we are dealing with
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H. D. Roth
compounds containing many carbon atoms, there is almost always a tie. For example,
compare methyl (C with 3 H’s) to ethyl (the attached C has 2 H’s and one C), propyl (the
attached C has 2 H’s and one C) and isopropyl (the attached C has one H and two C’s;
the 2 C’s are the point of difference).
CH2–CH3
>
CH2–H
CH(CH3)2
>
CH2– CH3
C(CH3)2
>
CH–CH2–CH3
Note: we don’t “weigh” the entire group, we look for the first difference; a higher
ranking substituent further away does not matter.
Rule 3
CH2-CH(CH3)2
>
CH2-CH2-CH2-CH3
O–CH3
>
O-H
2-methylpropyl
>
butyl
CH2-Cl
>
CH2-CH2-Br
CH2NH2
>
C(t-Bu)3
multiple (double or triple) bonds
H(C = C)
treated as
H(CC2)
C≡C
treated as
CC3
HC=O
treated as
HCO2
HC=S
treated as
HCS2
4b)
Once you have ranked the substituents by priority, determine the arrangement
of the four substituents in 3-D space (R or S) as follows:
i) Direct (point) the lowest priority group, R4 away from you:
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H. D. Roth
ii) Draw an arrow connecting the substituents in order of decreasing priority:
R2
R2
C
R3
R3
C
R1
R1
R Rectus
S
Sinister
The arrow in the example on the left is clockwise – we call this 3D arrangement R
(for Latin rectus); the mirror image (shown on the right) requires a counterclockwise
arrow – we call this S (for Latin sinister).
Let’s look at 2-bromopentane.
Br highest: a
a
H lowest: d H Br
H Br
C3H7 second ranking: b
c
CH3 second lowest: c
b
clockwise – R
The bromopentane shown (with a clockwise arrow) is the R-enantiomer, or R-2bromopentane.
Its enantiomer, which requires a counterclockwise arrow to connect the
substituents in order of decreasing priority, is the S-enantiomer, S-bromopentane.
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
a
Br
H
counterclockwise – S
c
b
5. Detecting stereoisomers
Is there a property, that helps us to distinguish between enantiomers? Enantiomers
are identical in every respect except for their “handedness” (their asymmetry or chirality).
If we compare some properties of geometric isomers with stereo isomers, we note
Geometric Isomers
Stereo Isomers
identical
composition
identical
identical
connectivity
identical
different
arrangement in 3D space
different
different
heat of combustion
identical (enantiomers)
Differences between enantiomers are revealed only by asymmetric probes. The
best-known probe is plane polarized light – therefore stereo isomerism also is called
optical isomerism. How does this work? Glad you asked.
6. Optical Rotation
Light is electromagnetic radiation with an electric and a magnetic component
perpendicular to one another. Light has a dual nature, two different ways how light
manifests itself: a) a quantized nature (light = photons, hν); you learned about this nature
of light in the initiation step of free radical halogenation); b) light has wave character (we
use this concept here).
i. Ordinary light vectors oscillate randomly (in all directions); it is symmetrical.
When ordinary light is passed through a Nicol prism (polarizer), only light whose
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H. D. Roth
electric and magnetic vectors oscillate in one specific direction (plane) can pass: the light
becomes plane polarized light (only one vector shown; electric and magnetic vectors are
still ⊥).
ii. When plane polarized light passes through a solution of chiral molecules the
plane of polarization is rotated by a certain angle in a certain direction, either clockwise
or counterclockwise (that’s why chiral compounds are said to be optically active).
Compounds that rotates light clockwise are called dextrorotatory (dexter is Greek
for right); they are designated by (+) or d in front of their names. Compounds that rotate
light to the left are called levorotatory (Greek for left); they are designated by a (–) or
letter l in front of their names. Please, note that there is no direct connection between the
direction of rotation (d or l) and the absolute configuration (R and S).
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Organic Chemistry
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H. D. Roth
iii. Measuring Optical Rotation
We can measure optical rotation, the direction and the degree (angle) of rotation,
using an instrument called a polarimeter. The measured angle of rotation, α, depends on
several factors, including the type of molecule and the number of molecules in the light
path; this quantity is given by concentration, c, of the chiral substance and the distance
light travels through the solution, the cell length, d. Other factors include the temperature
and wavelength of the polarized light.
We combine these factors in defining the specific rotation, [α], which is
measured in a solution of concentration, c = 1.0g/mL, and a path length, l = 1.0 dm. The
specific rotation is calculated from the measured rotation, α, by
observed rotation
[α] T
λ
specific rotation
α
=
l × c
length concentration
The temperature (T) and wavelength (λ) are indicated by superscripts and
subscripts, respectively.
iv. Absence of Optical Activity.
When we detect optical activity, we can be sure that a chiral compound is present.
But, failure to observe optical activity does not mean that no chiral compound is present.
Each compound with an asymmetric C atom has two enantiomers, each rotating light
with the same magnitude of specific rotation, but rotating light in opposite directions,
one to the right (+) and one to the left (–). If we have a 50-50 mixture of the pair of
enantiomers, we observe NO rotation at all, because the two rotations, equal in magnitude
but opposite in direction, cancel each other.
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We call a 50-50 mixture of two enantiomers a racemic mixture or a racemate,
represented by (±). Racemic mixtures are found very often: reactions generating a chiral
carbon in a symmetrical environment form a racemic mixture. Why? The energies are
identical, so entropy prevails, resulting in random attack. For example, the catalytic
hydrogenation of 2-butanone (Figure 5.16) can occur either from “top” or from “bottom”;
because both sides are equivalent, attack is equally likely: a racemate is formed.
The conversion of one enantiomer into a racemic mixture is called racemization.
For example, the (+)-isomer of thalidomide (see p. 5) racemizes in the human body,
converting a sedative into a teratogen.
7. Optical purity
In addition to 50-50 (racemic) mixtures of two enantiomers we may have
mixtures that are not racemic. This may happen if an environment is not completely
asymmetric or because racemization was stopped before completion. In such cases the
observed rotation is due to the excess of one enantiomer over the other. We can
determine the composition of the mixture (if we know the specific rotation of the
enantiomers) by comparing the rotation observed for the mixture to the rotation of the
pure enantiomers. We define the optical purity of the mixture as:
% optical purity =
[α] observed × 100%
–––––––––––––––––––
[α] for pure enantiomer
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Organic Chemistry
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H. D. Roth
Assume that the optical purity is 60%; this means that 60% is one pure
enantiomer and that the remaining 40% is a racemic (50:50) mixture. 40% racemate
means that one half of this (= 20%) is the same as the dominant enantiomer; we have a
total of 60% + 20% = 80% of the dominant isomer in the nonracemic mixture.
8. Compounds with more than one asymmetric carbon
If there are no other factors, the maximum number of stereoisomers for a
n
compound with n asymmetric carbons is 2 . This means that for 2, 3, 4 asymmetric
carbons there are 4, 9, 16 stereoisomers (this is getting out of hand fast!).
Let’s begin with the case where n =2 and two adjacent asymmetric atoms in a
chain, bearing two different substituents. We consider 2-bromo-3chlorobutane. First we
draw one isomer and its mirror image:
H Br
Br
H
3
2
Cl
H
H
2-R,3-R
Cl
2-S,3-S
By applying our “rank/assign3D” procedure we determine that these isomers are
the 2-R,3-R (left) and 2-S,3-S (right) stereoisomers; they are enantiomers.
If we exchange H and Br in these stereoisomers we change (invert) the absolute
configuration at that carbon, but we do not change the other carbon. The structures we
have drawn are the 2-S,3-R (left) and 2-S,3-R (right) stereoisomers. You can see that
these structures are mirror images of each other. But what is their relationship to the two
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H. D. Roth
stereoisomers above? One stereocenter has the same absolute configuration, but the
second one is different. We call such compounds diastereomers.
Br
H
H Br
3
2
H
Cl
H
2-S,3-R
Cl
2-R,3-S
We have learned above that pairs of enantiomers have identical energies. In
contrast, diastereomers have different energies. So if we compare the different features
of stereoisomers, as we did above, we have to make one significant amendment:
Geometric Isomers
Stereo Isomers
identical
composition
identical
identical
connectivity
identical
different
arrangement in 3D space
different
identical (for enantiomers)
different
heat of combustion
different (for diastereomers)
Diastereomers also have different physical and chemical properties so they can be
separated by crystallization or chromatography through a column that is packed with
some chiral material.
Note that enantiomers have RR vs. SS or RS vs. SR conformations whereas
diastereomers have RR vs. RS or SR or SS vs RS or SR conformations. We can
summarize the relationship of the four stereoisomers as follows:
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Organic Chemistry
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H. D. Roth
9. Compounds with two identically substituted stereocenters
A compound with two equally substituted carbons has three stereoisomers. We
consider 2,3-dibromobutane, related to the 2-bromo-3-chlorobutane discussed above.
H Br
Br
3
enantiomers
2
Br
H
H
Br
2-S,3-S
2-R,3-R
Br
H
2
2-S,3-R
H
H Br
3
Br
identical
H
2
H
H
rotate
C-2 by
180°
Br
2-S,3-R
Br H Br
2
internal mirror plane
The R,R- and S,S- stereoisomers clearly are enantiomers (mirror images); in
contrast, the presumed diastereomers, S,R- and R,S- are actually identical. You can verify
this by rotating one of the stereocenters by 180°, as shown. The resulting structure has an
internal mirror plane: it is symmetrical. We call this stereoisomer a meso compound.
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
Thus, a compound with two equally substituted carbons has two enantiomers (forming a
racemate) and their one diastereomer, a meso compound.
The two geometric isomers of 1,2-dimethylcyclopentane are diastereomers; the
cis-isomer is a meso compound.
CH3
H
H
H
CH3
H
CH3
CH3
We also consider the two geometric isomers of 2-butene diastereomers, because
they are non-superimposable.
CH3
H3C
H
CH3
H
H3C
H
H
The two compounds shown below are achiral for different reasons. 1-Bromo-3chloro-2,4-dimethylcyclobutane isomer on the left has a plane of symmetry; that means
the two carbons bearing the methyl groups are chiral and the compound is a meso
compound. The 1,3-dibromo-3,4-dimethylcyclobutane on the right has identical pairs of
bromine-bearing and methyl-bearing carbons. Accordingly, none of the carbons is chiral.
H 3C
H 3C
Br
Br
CH3
•
Br
Cl
Achiral due to plane of symmetry
CH3
Achiral due to center of symmetry
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Organic Chemistry
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H. D. Roth
10) Fischer projection
The German chemist Emil Fischer was a pioneer of the chemistry of
carbohydrates (sugars) that contain multiple –OH functions and stereocenters. In order to
visualize these compounds Fischer used a dash and wedge projection without actually
showing the dashes and wedges. The projection consists of intersecting perpendicular
lines representing the four bonds of an asymmetric carbon located at their intersection.
By convention, the two vertical lines are dotted, the two horizontal lines are wedges; the
main carbon chain is oriented vertically with the lowest numbered carbon at the top. This
means that all substituents are eclipsed. We can derive the Fischer projection of R,R-2,3dibromobutane in two steps as shown below.
CH3
H Br
3
rotate
2
Br
H
CH3
Br
C
H
Br
H
H
C
Br
H
Br
CH3
CH3
We will not use the Fischer projection in this class, but note that an in plane
rotation of a Fischer projection by 180° will leave the absolute configuration unchanged,
whereas a rotation by 90° will convert S to R or R to S, because all substituents change
(by definition) from “above the plane” to “below the plane” and by “below the plane” to
“above the plane”.
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