Organic Chemistry Chapter 5 Stereoisomers H. D. Roth 1 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 axial Br equatorial Br B. 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. CH 3 H CH 3 H H CH 3 CH 3 H
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Organic Chemistry Chapter 5 Stereoisomers H. D. Roth
1
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
axial Br equatorial Br B. 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.
CH3H
CH3
H
H
CH3
CH3
H
Organic Chemistry Chapter 5 Stereoisomers H. D. Roth
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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).
H3C CH3
H3C
CH3
HH H
H
cis-2-butene 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 Geometric Isomers
identical composition identical
different connectivity identical
different arrangement in 3D space different
different heat of combustion different
C. 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
Organic Chemistry Chapter 5 Stereoisomers H. D. Roth
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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).
Cl
BrH3C
CH3
Br
BrH3C
CH3
•
Achiral due to plane of symmetry 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.
Organic Chemistry Chapter 5 Stereoisomers H. D. Roth
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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).
C
R2R3
R4
R1C
R2R3
R4
R1
(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.
C*
C*
H
CH3
CH3
H
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 (dotted-
line) 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
Organic Chemistry Chapter 5 Stereoisomers H. D. Roth
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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 HBr
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
F > O > N > C > > > > H
I > Br > Cl > S > O
Rule 2 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).
Organic Chemistry Chapter 5 Stereoisomers H. D. Roth
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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; higher ranking
substituent further away do not matter.
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
Rule 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
Rule 4 isotopes (they really thought of everything )
heavier isotope has priority
D > H
13C > 12C (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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ii) Draw an arrow connecting the substituents in order of decreasing priority:
C
R2
R3
R1
C
R2
R3
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.
H BrH lowest: d
CH3 second lowest: c
Br highest: a
C3H7 second ranking: b
a
c
H Br
b
clockwise – R
The bromopentane shown (with a clockwise arrow) is the R-enantiomer, or R-2-
bromopentane.
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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HBra
cbcounterclockwise – S
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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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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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
Tλ
[α] = l × cα
specific rotation 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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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: