CH221 CLASS 16
CHAPTER 9: STEREOCHEMISTRY
Synopsis. This class considers the important topics of optical isomerism, chirality
and chirality centers, starting with simpler molecules with just one center and
then moving on to molecules with two chirality centers. The R/S notation for
chiral molecules is considered, along with descriptions of the terms enantiomers,
diastereoisomers, meso, erythro and threo.
”Mirror, mirror, on the wall…”
Introduction
Stereochemistry is the study of stereoisomerism and its influence on chemical
processes, especially with regard to reactivity, selectivity and physiological
reactions. Conformational isomerism (which involves types of stereoisomers,
called conformers, that are able to interconvert via rotation around bonds) has
been considered already, in classes 7 and 8. Likewise, the cis/trans
stereoisomerism, associated with certain alkenes and cycloalkanes, has been
discussed in classes 6, 8 and11. Now it is time to consider a third type of
stereoisomerism, known historically as optical isomerism and whose best known
examples arise as a natural consequence of the tetrahedral arrangement of
bonds about sp3-hybridized carbon atoms.
Tetrahedral Carbon and Enantiomers
Compare the special arrangement of groups (called configuration) about
successively and unequally substituted methane molecules, all of which are
based upon the tetrahedron.
X
H
C
H
(a)
H
H
C
H
(b)
X
X
H
H
C
H
(c)
Y
H
C
H
Y
Z
(d)
In cases (a) – (c), the molecules possess at least one plane of symmetry (only
one is shown in the above diagrams, for clarity), whereby the molecule is
bisected by the plane into exactly mirrored halves. In contrast, molecule (d) has
no such plane. Furthermore, molecules (a) – (c) are all superimposable with their
mirror images: they have what is known as reflection-rotation symmetry, as
illustrated for (c).
X
reflect in
mirror
C
H
Y
X
Y
H
H
C
H
(c)
identical
mirror plane
X
C
H
Y
H
rotate
(c)
Molecule (d), however, is not superimposable with its mirror image, that is to say
it lacks reflection-rotation symmetry. In the diagram below, (d’) is not the same as
(d) and hence molecules like (d) can exist in two stereoisomeric forms whose
configurations are non-superimposable mirror images.
reflect
in mirror
X
C
H
Y
Z
X
Y
Z
C
H
(d)
X
not identical
C
H
Z
Y
rotate
(d')
In general, mirror image molecules that are not superimposable are called
enantiomers. Alternatively, we can say that enantiomers are stereoisomers
whose configurations are (non-superimposable) mirror images.
Chirality - Handedness in Molecules
Molecules that are not superimposable on their mirror images
and hence exist in two enantiomeric forms are said to be chiral
(from Greek cheir, meaning hand). Molecules that do not have
the above property are called achiral.
The most common cause of chirality in organic chemistry is the presence of an
sp3-hybridized carbon atom that is bonded to four different groups. Such carbons
are called chirality centers, but many alternative names have been used, such as
asymmetric carbon atoms, asymmetric centers and stereogenic centers.
Some examples are given below.
no plane of symmetry
CH3
H
C
CH3
H Propanoic acid
H
COOH
C
OH
2-Hydroxypropanoic acid
(lactic acid)
COOH
plane of
symmetry
Exists as two enantiomeric
forms:
Exists in only one
(achiral) form
HO
OH
C
CH3
COOH
H
CH3
H
CH3
H
Methylcyclohexane
(achiral)
HOOC
H
C
CH3
O
2-Methylcyclohexanone
(chiral)
Some organic chiral molecules, not discussed here, do not actually have a
chirality center, but all chiral molecules lack reflection-rotation symmetry, or more
simply, lack a plane or center of symmetry. However, in determining whether or
not a molecule is chiral, it is useful initially to look for the presence of chirality
centers. Quite often, it will be necessary to look a long way from the chirality
center (which can be indicated with an asterix, *), as illustrated by the example
below.
Br
CH3CH2CH2CH2CH2
C*
CH2CH2CH2CH3
H
5-bromodecane (chiral)
Class Question
Identify the chirality centers in the following molecules. Use *.
Optical Activity
Jean Baptiste Biot was the first to discover that many (but not all) natural
substances have the ability to rotate the plane of plane-polarized light as it
passes through. The angle through which the plane is rotated is called the angle
of rotation, , and is measured using an instrument known as a polarimeter:
Substances that rotate the plane of plane-polarized light to the right (clockwise)
are called dextrorotatory (d) and are given the symbol (+). Those rotate the plane
to the left (anticlockwise) are called levorotatory (l) and are given the symbol (-).
More useful than optical rotation is specific rotation, whose symbol is []tD, where
D is the wavelength of the sodium D-line (589 nm) that is commonly used in
polarimeter experiments and t is the temperature in o C. Specific rotation is
defined below.
See Table 9.1 on p. 281 of the textbook for examples of the specific rotations of
common organic substances.
Louis Pasteur
The great chemist and pioneer biochemist/microbiologist Louis Pasteur was first
to relate rotation of plane-polarized light to molecular structure. Pasteur was able
to isolate mirror image crystals of sodium ammonium tartrate from a
concentrated solution by crystallization below 28 oC. He showed, using
magnification and tweezers, that the right-handed crystals of sodium ammonium
tartrate, when dissolved in water, rotated the plane in one direction, whereas a
solution of equal concentration made from the left-handed crystals rotated the
plane equally in the opposite direction. Through Pasteur’s work, the phenomenon
described above became known as optical isomerism, but it was not until 25
years later that Joseph Le Bel and Jacobus van’t Hoff demonstrated that chiral
molecules were the only molecules capable of showing this phenomenon – i.e.
only chiral molecules are capable of optical activity.
R/S Notation for Chiral Molecules
Following the work of Le Bel and van’t Hoff, the need quickly arose for a chiral
nomenclature – a naming system that unambiguously tells us the configurations
of chiral molecules. At the end of the 19th century, Emil Fischer proposed the D/L
notation. By assuming that D-(+)-glyceraldehyde has the following configuration,
CHO
C
HOCH2
OH
H
,
he and others were able to notate the configuration with the sign of rotation of a
large number of molecules, but it was not until 1951 that Bijvoet, using X-ray
crystallography, proved (luckily) that Fischer was correct. However the D/L
notation has been partly superceded by the less ambiguous R/S notation, based
upon the Cahn-Ingold-Prelog sequence rules that are also used for the Z/E
notation for ‘geometric isomerism’.
To name a chiral configuration according to the R/S notation, carry out the
following steps.
1. Assign priority labels (1, 2, 3, 4 or a, b, c, d) to each of the four groups
attached to the chirality center, according to the Cahn-Ingold-Prelog rules
described for E/Z notation.
E.g. (+)-lactic acid
2. View the molecule from the side remote from the lowest priority group (number
4, here, H).
E.g.
3. Name R (Latin rectus, for right-handed) if the sequence (1) (2) (3) is
clockwise (right-handed) or S (Latin sinister, for left-handed) if anti-clockwise
(left-handed).
1
2
E.g. in the above example,
C
anticlockwise
3
,
The sequence is anticlockwise and hence the configuration of (+)-lactic acid is S:
its full name is (S)-(+)-lactic acid.
Class Question.
Determine the configurations of the following compounds, according to the R/S
notation.
CHO
H
(a) (+)-Glyceraldehyde
(b) (-)-alanine
C
C
CH2OH
COOH
H
H2N
OH
CH
3
Stereoisomerism of Molecules Possessing Two Chirality Centers
So far, we have considered molecules with only one chirality center – now it is
time to study molecules with two chirality centers. Two specific cases will be
dealt with here: firstly, when the two sets of groups attached to the chirality
centers are different and secondly, when there are identical sets of groups
attached to the two chirality centers.
The important stereochemical terms enantiomers, diastereoisomers, internal
symmetry, meso, erythro and threo are introduced and defined, although the
first term has already been mentioned earlier in the course.
Two Chirality Centers Possessing Non-identical Sets of Groups
Consider the ALDOTETROSE sugars (2,3,4-trihydroxybutanal,
OHC.CH(OH).CH(OH).CH2OH). The FOUR POSSIBLE stereoisomers are
represented below.
CHO
CHO
H
C
H
C
R
R
OH
HO
C
OH
HO
C
S
S
CHO
H
H
C
H
HO
C
R
S
CHO
OH
H
HO
C
H
C
S
R
H
OH
CH2OH
CH2OH
CH2OH
CH2OH
1
2
3
4
OH
OH
H
H
HO
HO
CHO
CH2OH
H
HO
H
H
OH
H
HO
H
CHO
CH2OH
CHO
CH2OH
H OH
CHO
CH2OH
Newman Formulas
There are no internal mirror planes and so each structure represents an
individual stereoisomer. In fact, 1 and 2 are (-)- and (+)-erythrose, respectively; 3
and 4 are (+)- and (-)-threose, respectively. ERYTHRO and THREO are terms
used for configurations as follows:
a
C
b
a
C
b
a
C
b
b
C
a
Erythro
Threo
A look at the four structures above reveals that there are two kinds of isomers
here. Firstly, there are those whose configurations are related by MIRROR
REFLECTION: these are 1 and 2, and also 3 and 4. They are called
ENANTIOMERS. Secondly, there are isomers whose configurations are not
related by mirror reflection: these 1 and 3, 2 and 3, 1 and 4, and 2 and 4. They
are called DIASTEREOISOMERS.
Two Chirality Centers with Identical Sets of Groups
Consider TARTARIC ACID (2,3-dihydroxybutanedioic acid,
HOOC.CH(OH).CH(OH).COOH). The FOUR POSSIBLE stereoisomers are
represented below.
Newman Formulas
It can be seen that isomers 1 and 2 are IDENTICAL - they are superimposible.
This is because both structures possess INTERNAL SYMMETRY (an internal
mirror plane (imp), .......). Both 1 and 2 represent the achiral MESO-TARTARIC
ACID, which is not found in nature. Isomers 3 and 4 are CHIRAL (they are
enantiomeric) and represent (+)- and (-)-TARTARIC ACID, respectively. Thus, an
important general situation exists for molecules of the type xyzC-Cxyz – only
three stereoisomers exist (out of a possible four), one meso isomer which is
optically inactive and a pair of enantiomers.
Class Question
Does cis-1,2-dimethylcyclobutane have any chirality centers? Is it chiral?
cis-1,2-Dimethylcyclobutane
CH3
CH3
H
H
Yes, the molecule has two chirality centers (*), but is
achiral, because it possesses a plane of symmetry ( ):
*
CH3
H
*
CH3
H