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 parts. 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;
A.
Conformational isomerism
The conformation can be changed by free rotation about a single bond (or two);
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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Organic Chemistry
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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 the opposite side (trans) of the double bond
(more in chapter 11).
CH3
H3C
H
H
CH3
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 generating isomers. You have long
been familiar with this type of relationship: look at your hands. Your two hands are
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H. D. Roth
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.
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 (not in book; 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 their representations 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.
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
Compounds containing a 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).
R4
R4
C
C
R1
R1
R3
R3
R2
R2
(where R1, R2, R3, R4 are all different)
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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Organic Chemistry
Chapter 5 Stereoisomers
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:
“rank” the four substituents; a (high) – b – c – d (low)
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 1
atomic number of substituent
High atomic number has preference over low
Rule 2
F
>
O
>
N
>
C
>>>>
H
I
>
Br
>
Cl
>
S
>
O
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
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).
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Organic Chemistry
Chapter 5 Stereoisomers
CH2–CH3
>
CH2–H
CH(CH3)2
>
CH2– CH3
C(CH3)2
>
CH–CH2–CH3
H. D. Roth
Note: we don’t “weigh” the entire group, we look for the first difference; higher ranking
substituent further away do not matter.
Rule 3
Rule 4
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
isotopes (they really thought of everything )
heavier isotope has priority
D
13
C
>
H
12
>
C
(not often encountered)
4b)
Once you have ranked the substituents by priority, determine the arrangement
of the four substituents in 3-D space (R or S)
i) Direct (point) the lowest priority group, R4 away from you:
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Organic Chemistry
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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 allow 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?
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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Organic Chemistry
Chapter 5 Stereoisomers
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 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).
iii. Measuring Optical Rotation
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
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 and wavelength 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.
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
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Organic Chemistry
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H. D. Roth
carbon in a symmetrical environment form a racemic mixture. Why? The energies are
identical, so entropy prevails. The conversion of one enantiomer into a racemic mixture is
called racemization.
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
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!).
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
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-3-chlorobutane. First we
draw one isomer and its mirror image:
H Br
Br
H
3
2
H
Cl
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.
Br
H
H Br
3
2
Cl
H
H
2-S,3-R
Cl
2-R,3-S
You can see that these structures are mirror images of each other. But what is
their relationship to the two stereoisomers above? One stereocenter has the same absolute
configuration, but the second one is different. We call such compounds diastereomers.
Note that enantiomers have RR vs. SS or RS vs. SR coformation whereas
diastereomers have RR vs. RS or SR or SS vs RS or SR. We can summarize the
relationship of the four stereoisomers as follows:
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Organic Chemistry
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H. D. Roth
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
different
heat of combustion
identical (enantiomers)
different (diastereomers)
Diastereomers also have different physical and chemical properties so they can be
separated by crystallization or chromatography.
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.
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Organic Chemistry
Chapter 5 Stereoisomers
H Br
Br
3
H
H
Br
2-S,3-S
2-R,3-R
Br
H
2
2-S,3-R
H
enantiomers
2
Br
H Br
3
Br
H. D. Roth
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.
Thus, a compound with two equally substituted carbons has two enantiomers (forming a
racemate) and their one diastereomer, a meso compound.
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.
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Organic Chemistry
Chapter 5 Stereoisomers
CH3
H Br
3
rotate
2
Br
H. D. Roth
H
CH3
Br
C
H
Br
H
H
C
Br
H
Br
CH3
CH3
We will not use the Fischer projection; 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.
11. Ring compounds
Monosubstituted cycloalkanes cannot have an asymmetric carbon in the ring,
because there is a plane of symmetry. Disubstituted cycloalkanes are different; we
consider them on a case-by-case basis, depending on a) the pattern of substitution, b) the
ring size, and c) the particular geometric isomer we are considering with. For the purpose
of evaluating symmetry you may assume that the rings are flat.
i. 1,2-Disubstituted cyclohexanes have two stereocenters; if the substituents are
different, neither of the two geometric (cis- and trans-) isomers has a plane of symmetry.
The trans-isomers are enantiomers of each other; the cis-isomers are enantiomers of each
other; the two cis-stereoisomers are diastereomers of the two trans-isomers. These
features are general for all 1,2-disubstituted cycloalkanes.
H
H
H
H
H3C
Cl
Cl
CH3
CH3
H3C
Cl
Cl
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Organic Chemistry
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H. D. Roth
For 1,2-disubstituted cyclohexanes with two identical substituents, the cis-isomer
is a meso form, whereas the trans-isomer exists as a pair of enantiomers; there are three
stereoisomers (see section 9, above). This feature is general for all 1,2-disubstituted
cycloalkanes.
ii. 1,3-Disubstituted cyclohexanes, with different substituents also have two cisenantiomers and two trans-enantiomers. If the two substituents are identical the cisisomer has a plane of symmetry; it is a meso form and is optically inactive. trans-1,3disubstituted cyclohexanes have two stereo-isomers, they are enantiomers of each other;
they lack a plane of symmetry; each of them shares one stereocenter with the cis-isomer:
both are diastereomers of the cis-isomer. Can you assign the absolute configuration of the
two trans-1,3-dimethylcyclohexanes?
CH3
H3 C
H3 C
CH3
H3 C
CH3
iii. 1,4-disubstituted cyclohexanes have two geometric isomers; both are optically
inactive (achiral) because of a plane of symmetry that bisects C-1 and C-4 and their
substituents.
OH
Br
OH
Br
This feature is generally found for even-numbered cycloalkanes substituted in
opposite positions, for example, 1,3-disubstituted cyclobutanes or 1,5-disubstituted
cyclooctanes.
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
12. Reactions of Compounds with Asymmetric Carbons
We need to consider two cases:
A. No bonds of the C* are broken in the reaction; the relative configuration of the
four substituents at the stereocenter is maintained, but the absolute configuration (the R,S
designation) may change because the priority of the substituents may change.
B. One or more bonds at the asymmetric carbon are broken and new bonds are
formed. The stereochemical outcome depends on the mechanism of the reaction; it may
either be specific or unspecific (random).
a) Some reactions, such as a free radical halogenation, proceed through a planar
intermediate. Even if the product has a stereocenter, it will be a racemic mixture. Such
reactions are said to be stereorandom.
b) Other reactions have stereospecific mechanisms, meaning a given stereoisomer
forms another given stereoisomer; the spatial relations of all the participants in the
reaction are specified (and predictable) without options. We will see examples of such a
reaction in Chapter 6. Stereospecific reactions can occur in two ways: i) in the same
position as the bond being broken; ii) the new bond is formed from the opposite side.
H Y
same side
H X
Y H
opposite side
replacement
replacement
C) Examples
We illustrate both cases with a free-radical chlorination, a reaction you have
already studied; first we consider chlorination of an achiral substrate, butane; then, to
make things more interesting , we look at a chiral substrate, S-2-bromobutane. Since
chlorine atoms are not very selective, we expect chlorination to occur at all four centers.
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Organic Chemistry
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H. D. Roth
Chlorination of butane
The reaction of butane with Cl• generates a primary and a secondary free radical;
abstraction of Cl by the primary free radical forms 1-chlorobutane, an achiral product.
Simple. The case of the secondary free radical is more interesting because its reaction
generates a new stereocenter. The intermediate is planar; both sides are equally
accessible; both sides abstract Cl with the same probability: we obtain 2-chlorobutane as
a racemic mixture.
Cl•
•
Cl•
•
H Cl
Cl
H
enantiomers
Cl
S-
R-
Chlorination of S-2-bromobutane
• Chlorination at C-4 leaves the chiral center unaffected (case A, above); the
priority of the substituents remains unchanged; we have formed S-3-bromo-1chlorobutane.
• Reaction at C-1 also leaves the chiral center unchanged (case A), but the priority
of the groups is changed: in the starting material CH3 is the third-ranking substituent, in
the product CH3Cl ranks second. We have generated R-2-bromo-1-chloro-butane.
Br
H
Br
H
Br
Cl
Cl
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Organic Chemistry
Chapter 5 Stereoisomers
H. D. Roth
• Reaction at C-3 also leaves the chiral center unchanged (case A), but we are
facing two problems. First, substituting an H at C-3 will create a new stereocenter,
resulting in a pair of diastereomers. Because we start with the S-enantiomer the product is
a mixture of (2-S,3-S)- and (2-S,3-R)-2bromo-3-chlorobutane. We call a pair of
hydrogens that give rise to diastereomers upon replacement of one or the other
diastereotopic. Please, verify the assignment (see also Figure 5.14).
Second, the free radical generated by hydrogen abstraction has two different faces
with different steric hindrance. For this reason, the two products will be formed in
unequal
yields.
and
a
reaction
giving
diastereomers
in
unequal
amounts
diastereoselective.
H3C
Br
H
Br
H
H-Cl
H
Br
Cl•
•
H
CH3
Br
H
Cl
Br
H
diastereomers
H
H
Cl
• Chlorination at C-2 is an example of case B: hydrogen abstraction from C-2
produces an achiral free radical (C–2 is planar); reaction of the two faces forms two
different enantiomers: they are said to be enantiotopic. The planar intermediate (only
one conformation is shown below) allows each face to react equally likely with Cl2.
Therefore chlorine abstraction by the intermediate produces a 50:50 mixture of the two
enantiomers, a racemate; the product is optically inactive.
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H. D. Roth
H3C
Br
H
Br
H
H3C
Cl•
•
•
H-Cl
H Br
Br
Cl
Cl
Br
enantiomers
The above reaction is an example of a mechanism that is not stereospecific. Even
though the product, 2-bromo-2-chlorobutane, has an asymmetric carbon, it is formed as a
racemic mixture (see also Figure 5.13 and pg 196).
Effect of enantiomers on living creatures can be very different; thalidomide was
used as a sedative; the (+)-isomer has no side effects whereas the (–)-isomer is a
teratogen, causing serious birth defects in babies.
O
N
O
O
N
H
O
Do you recognize the stereocenter in this molecule?
O
O
H
H
N
N
O
O
N
H
O
O
O
20
N
H
O