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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5574_Библиотеки_им_академика_М_И_Перельмана.pdf
Mirror
Object
Image
Superimposable
Dotted line represents
plane of symmetry
No plane of
symmetry
Object Image
Nonsuperimposable
C h a P T E r 3 Stereochemistry
Figure 3.3 Chiral structure.
141
The term chiral based upon the Greek word cheir (which means ‘hand’) was rst introduced by Cahn,
Ingold and Prelog in 1964. Thus chirality means ‘handedness’, i.e. the relationship which exists between the
left and right hands. In recent years, the terms chiral and chirality have almost completely replaced the old
terms dissymmetric and dissymmetry, respectively.
Many organic molecules such as lactic acid [CH3CH(OH)COOH] and 2-chlorobutane [CH3ChClCh2Ch3]
represent chiral structures. The substances having chiral structures are said to possess the property of
chirality and these substances are optically active.
Achiral structures
a structure or object which has a plane of symmetry and is superimposable on its mirror image is known
as achiral (or symmetrical). A plane of symmetry is a plane, real or imaginary, which divides a structure
or an object into two equal halves so that one half is the mirror image of the other half. For example, the
letter a represents achiral structures. It can be easily seen that each of these has a plane of symmetry and is
superimposable on its mirror image (Fig. 3.4).
Similarly, many molecules such as those of methane and carbon tetrachloride are symmetrical in nature.
Two objects are said to be superimposable if when placed one upon the other, their corresponding parts
lie on each other. Two objects that are like mirror images of each other may be either superimposable or
nonsuperimposable. For example, two notebooks of the same size having mirror–image relationship are
superimposable.
Figure 3.4 Achiral structure.
aa
bb
e
e
Mirror
dd
H
Chira
l
T
DCCH
3
PharMa CEu TICal OrGanIC ChEMISTry
142
Figure 3.5 Nonsuperimposable mirror image models of chiral C atom.
Chirality in organic compounds
Most of the organic compounds are chiral in nature due to the presence of at least one chiral carbon or chiral
centre in the molecule. Previously a chiral carbon atom was referred to as an asymmetric carbon. a chiral
carbon or chiral centre is a carbon atom that is bonded to four different monovalent atoms or groups such
as C
. There can be two different tetrahedral models for C
abed
which differ in the spatial arrangements of
abed
various groups attached to carbon as shown in Fig. 3.5.
Each of the two model is related to the other like an object to its
mirror image and one cannot be superimposed on the other. Each
of these models, therefore, represents a chiral structure.
Similarly we can have two nonsuperimposable mirror image
structures for any known compound containing a chiral carbon or
chiral centre. For example, lactic acid [CH3*Ch(Oh)COOh] is
a chiral molecule since it contains a chiral carbon marked as (*)
(Fig. 3.6).
Learning Plus
The smallest chiral hydrocarbon ever prepared in
the laboratory has one chiral centre substituted
by the three isotopes of hydrogen [hydrogen
(H), deuterium (D), and tritium (T)] and a methyl
group (
Journal of the American Chemical
Society
, 1997, 119, 1818–1827).
It must be emphasized, however, that certain molecules
may contain more than one chiral centre and still they may be
achiral or nondissymmetric. For instance, 2,3-dichlorobutane,
Ch3–*ChCl–*ChCl–Ch3, which has two chiral centres (those
marked *), exists in many isomeric forms, one of which is not
chiral because it has a plane of symmetry as shown below:
Figure 3.6 Nonsuperimposable mirror images: lactic acid.
COOH
H Ð C * Ð OH
CH
3
COOH
HO Ð C* Ð H
CH
3
CH
3
C*HCl
C*HCl
CH
3
Plane of
symmetry
H
C
H
3
C
CC
H
CH
3
H
C
H
3
C
CC
H
CH
3
C h a P T E r 3 Stereochemistry
On the other hand, we have certain molecules that are chiral even though they do not contain any chiral
carbon. allenes (rCh 5 C 5 Chr) represent a well-known class of such compounds as illustrated
below:
143
Nonsuperimposable mirror image of 2,3-pentadiene
It may be seen by molecular models that chirality in 2,3-pentadiene arises due to the fact that the two
groups singly bound to one of the end carbon atoms of allene system are in a different plane than the two
groups singly bound to the other end carbon of the allene system.
3.7 TYPES OF OPTICAL ISOMERS
It has been observed that optically active compounds always exist in two or more isomeric forms, which
differ with respect to their optical activity. As already stated, the isomers which resemble one another in
their chemical reactions and most of the physical properties but differ in their behaviour towards polarized
light are called optical isomers and the phenomenon is known as optical isomerism.
There are two main types of optical isomerism. These are as follows:
1. Enantiomerism
2. Diastereomerism
3.7.1 Enantiomerism
In 1948, Pasteur observed that an aqueous solution of sodium ammonium tartarate was found to be optically
active. he separated two distinct types of crystals from the solution of this compound and found that each
Mirror
H
Br
Cl
H
H
Br
Cl
H
Mirror
H
CH
3
C2H
5
HOH2C
H
CH
3
C2H
5
CH2OH
144
PharMaCEuTICal OrGanIC ChEMISTry
Nonsuperimposable mirror images: 2-Methyl-1-butanol
Figure 3.7 Enantiomeric forms of 2-methyl-1-butanol.
crystal possessed optical activity equal in magnitude but opposite in its sign. The shape of the two types of
crystals was found to be different and they were nonsuperimposable.
Such isomers whose molecular structures are nonsuperimposable mirror images of each other and
which rotate the plane polarized light equally but in opposite directions are known as enantiomers or
enantiomorphs. The phenomenon of object and its mirror-image isomerism is called enantiomerism. Since
the object and its mirror-image isomers differ only in the spatial arrangement of atoms, enantiomerism is
only a particular type of stereoisomerism.
The existence of object and its mirror-image isomers was justied by van’t Hoff on the basis of tetrahedral
concept of carbon atom. Tetrahedral models of an imaginary compound of the type C
has already been shown
abed
and that of lactic acid has been shown in Fig. 3.6. These models represent two enantiomers of the compound.
Similarly, we can construct models of enantiomeric forms of 2-methyl-1-butanol [C2h5Ch(Ch3)Ch2Oh]
(Fig. 3.7), which is also known to exhibit enantiomerism.
We nd that it is possible to construct two models which are nonsuperimposable mirror images of each
other and as such they represent the different enantiomers.
It may be pointed out, however, that the molecules of most of the compounds containing a tetrahedral
carbon atom are superimposable on their mirror images as illustrated below with the help of models of
bromochloromethane Ch2ClBr. Such compounds do not exhibit enantiomerism because all their structure
are of the same type.
C h a P T E r 3 Stereochemistry
3.7.2 Essential Condition for Enantiomerism
Enantiomeric molecules are always nonsuperimposable mirror images of each other. The nonsuperimposability of mirror images invariably arises due to chiral nature of the molecules. a molecule is termed as
chiral if it has no plane of symmetry and is, therefore, nonsuperimposable on its mirror image.
Chirality in most of the enantiomeric molecules is itself due to the presence of at least one chiral carbon
in the molecule. For example, lactic acid [CH
*CH(OH)COOH] and 2-methyl-1-butanol [C2h5*Ch(Ch3)
3
Ch2Oh] contain one chiral carbon each (the one marked *) and therefore exist in enantiomeric forms as
shown already. On the other hand, there can be molecules such as 2,3-pentadiene, which do not contain any
chiral carbon but they still possess the property of chirality and thus exhibit enantiomerism.
It may be concluded, therefore, that chirality (i.e. the property of existing as nonsuperimposable mirror
images) is the fundamental and only condition of enantiomerism.
3.7.3 Characteristics of Enantiomers
The important characteristics of the enantiomers of a given substance are described below:
1. They have identical physical properties such as melting points, boiling points, densities, solubilities,
refractive indices. The only difference lies in the direction of rotation of plane polarized light,
although the magnitude of specic rotation is same.
2. They have identical chemical properties except in reactions with other optically active compounds.
For example, the ordinary chemical reactions of (1) lactic acid are exactly like those of (–) lactic
acid. There may be a difference, however, in the rates of reactions at which two enantiomers react
with some other optically active compound. For instance, the rate of esterication of (1) lactic acid
with (1) sec-butyl alcohol [CH3Ch2Ch(Oh)Ch3] would be different from the rate of esterication
of (–) lactic acid with the same alcohol.
3. They have different biological properties. In contrast to physical and usual chemical properties,
enantiomers are quite different in their biological properties. For example, (1) sugar plays an
important role in animal metabolism whereas (–) sugar is not metabolized at all. Similarly, (1)
tartaric acid is readily consumed by the mould Penicillium glaucum while (–) tartaric acid is
not.
4. When equal quantities of enantiomers are mixed together, it results in the formation of an optically
inactive form called racemic modication or racemic mixture or racemate. The racemic modication
is distinguished by using the prex ± before the name of the compound. For example, if equal
quantities of (1) lactic acid and (–) lactic acid are mixed with each other, we get racemic or (±) lactic
acid, which is optically inactive.
145
3.8 PLANAR REPRESENTATION OF THREE-DIMENSIONAL FORMULAE: FISCHER
PROJECTION FORMULAE
It is not very convenient to represent the formulae of stereocompounds on paper. a simple method was
introduced by Emil Fischer (1891) for projecting three-dimensional formulae of chiral molecules on the
planar surface. The planar representations are called Fischer projection formulae.
146
PharMaCEuTICal OrGanIC ChEMISTry
NOTEWORTHY POINTS
With no chiral centres, a molecule generally is not chiral.1. H2O and CH2BrCl have no chiral centres and
are achiral molecules.
With one tetrahedral chiral centre, a molecule is always chiral. CHBrCIF is a chiral molecule
2.
containing one chiral centre.
With two or more chiral centres, a molecule may or may not be chiral.
3.
When trying to distinguish between chiral and achiral compounds, keep in mind the following:4.
a. A plane of symmetry is a mirror plane that cuts a molecule in half, so that one half of the molecule
is a reflection of the other half.
b. Achiral molecules usually contain a plane of symmetry but chiral molecules do not.
c. The achiral molecule CH2BrCl has a plane of symmetry, but the chiral molecules do not.
The basic principles of chirality:
5.
a. Everything has a mirror image. The fundamental question is whether a molecule and its mirror
image are superimposable.
b. If a molecule and its mirror image are not superimposable, the molecule and its mirror image
are chiral.
c. The presence of a plane of symmetry makes a molecule achiral.
Any molecule with one tetrahedral chiral centre is a chiral compound and exists as a pair of 6.
enantiomers.
MEMORY FOCUS
Enantiomers have identical chemical and physical properties.1.
They differ only in rotating plane polarized light and interaction with other chiral molecules.2.
A pair of enantiomers rotates the plane of polarized light by equal amounts in opposite directions.3.
A 1:1 mixture of enantiomers does not rotate light and is called a 4. racemates or racemic mixture.
5. dextrorotatory ‘d’ or
If the plane polarized light is rotated towards right, the compound is called
(1) form.
6. laevorotatory ‘l’ or (–) form.
If the plane polarized light is rotated towards left, the compound is called
7.
Because two enantiomers have identical physical properties, they cannot be separated by common
physical techniques like distillation.
The following procedure is adopted for writing the projection formulae:
1. The chiral molecule is considered to be so held that two groups attached to chiral carbon lie
horizontally and point towards the observer while the other two groups lie vertically and point away
from the observer.
2. The various groups attached to the chiral carbon are then projected to the plane of the paper so that
horizontal lines represent bonds pointing towards the observer while vertical lines represent the
bonds pointing away from the observer. In case the chiral molecule contains two or more chiral
carbons, each carbon is considered separately as described above.
(R)-Bromochlorofluoromethane (S)-Bromochlorofluoromethane
Br
H
F
Cl
Br
H
F
Cl
H
C
COOH
CH
3
OH HO
C
COOH
CH
3
H
(R)-Lactic acid (S)-Lactic acid
H
C
COOH
CH
3
OH
Rotation
through 180°
I (+) Lactic acid
II (−) Lactic acid
COOH
H
CH
3
HOH HO
COOH
CH
3
C h a P T E r 3 Stereochemistry
3. The vertical part of the projection formula should represent, so far as possible, the longest chain of
carbon atoms in the molecule with the carbon atom to be numbered as written at the top according
to IuPaC system.
For instance, the projection formulae of the two enantiomers of bromochlorouoromethane and
lactic acid may be represented as shown below.
147
4. Very often the chiral carbon atom is not written at all while writing the projection formulae. It is
taken for granted that the chiral carbon is located where the lines showing the horizontal and vertical
bonds cross as shown below.
REMEMBER
In determining chirality in substituted cycloalkanes,
always draw the rings as at polygons. This is
especially true for cyclohexane derivatives, where
having two chair forms that interconvert can make
analysis especially difficult.
5. If necessary planar formula may be imagined to be rotated from end to end but without lifting it from
the plane of the paper. rotation by 180° in the plane of the paper does not bring about any change of
conguration. For example:
(No change in conguration: I and II represent the same compound.)
III (+) Lactic acid (R) IV (+) Lactic acid (S)
Rotation
through 90°
COOH
H
CH
3
COOH
H
OH
OH
CH
3
V (–) Lactic acid
COOH
H
R
S
R
OH
CH
3
COOH
H
CH
3
VI (+) Lactic acid
(Inversion of configuration)
VII (–) Lactic acid
(Configuration same as
that of I)
First
interchange
HO
COOH
H
CH
3
HO
Second
interchange
∗∗
CH CHCH
2
CH
3
CH
3
Cl Cl
148
PharMaCEuTICal OrGanIC ChEMISTry
But rotation by 90° or 270° leads to inversion of conguration (i.e. changes one conguration
into its mirror image) so that the new conguration represents the enantiomer of the original
compound.
(Inversion of configuration)
6. If positions of two groups or atoms about the chiral carbon are interchanged, it also leads to
inversion of conguration. But if we carry out two such interchanges, the conguration remains
unaltered:
It is quite evident from above that one interchange is equivalent to rotation by 90° or 270° while
two interchanges are equivalent to rotation by 180°.
3.9 DIASTEREOMERISM: COMPOUNDS HAVING MORE THAN ONE CHIRAL CARBON
We have learnt that a compound containing one chiral centre exists in two stereoisomeric forms, which are
known as enantiomers of each other. But compounds containing more than one chiral centre can exist in more
than two stereoisomeric forms. To illustrate this statement, let us consider the case of 2,3-dichloropentane
which contains two chiral centres. Since the four different groups attached to one chiral centre are not the same
as those attached to the other, the two chiral carbon atoms are dissimilar from one another. There are as many
as four stereoisomers (I, II, III and IV) possible for this compound.
III III
IV
I III
Same
configuration
Mirror image
configuration
CH
3
C2ClH
C
3
HCl
C
2H5
CH
3
C2ClH
C
3
ClH
C
2H5
VVI VII VIII
C h a P T E r 3 Stereochemistry
Examination of formulae I and II reveals that they are nonsuperimposable mirror images of each other
and hence represent a pair of enantiomers. Similarly, III and IV are also nonsuperimposable mirror images
of each other and as such represent another pair of enantiomers.
let us now compare the formula I with formula III.
149
It becomes immediately clear that the two formulae have identical congurations about one chiral carbon
(C2) and mirror image congurations about the other chiral carbon (C3). The net result is that the two forms
are neither identical nor mirror images of each other. Such stereoisomers of a substance that are not mirror
images of each other are known as diastereomers. In addition to formulae I and III, formulae I and IV, II
and III, and II and IV also represent pairs of diastereomers.
3-Chloro-2-butanol affords another example of a compound having two dissimilar chiral carbon atoms
and can exist in four stereoisomeric forms as given below:
It may be seen that structures V and VII, V and VIII, VI and VII, and VI and VIII represent pairs of
diastereomers.
∗
CHOHCOOH
∗
CHOHCOOH
150
PharMaCEuTICal OrGanIC ChEMISTry
characteristics of diastereomers
The important characteristics of diastereomers are as follows:
1. They show similar, but nonidentical, chemical properties. In the reactions of two diastereomers with
a given reagent, the rates of reactions are generally different.
2. They have different physical properties, such as melting points, boiling points, densities, solubilities
and refractive indices. Even specic rotations are different: this does not, of course, apply to
diastereomers which are geometrical isomers since such diastereomers are not optically active.
3. On account of differences in physical properties, they can be rather easily separated through fractional
crystallization, fractional distillation, chromatography, etc.
MEMORY FOCUS
Cyclic compounds can also exist as diastereomers.1.
Diastereomers have different spatial arrangement of atoms.2.
These have different physical properties.3.
If a molecule has three stereocentres, then it has potentially eight stereoisomers (4. four diastereoisomers
and their enantiomers).
If a molecule has 5. n stereocentres, then it can have 2n stereoisomers. But if a molecule has a plane of
symmetry, there will be less number of stereoisomers.
comparison of enantiomers and diastereomers
They have a mirror-image relationship. They do not have a mirror-image relationship.
They have similar physical properties, such as melting point,
boiling point, solubility in a given solvent, density, etc.
They cannot be separated by methods. They can be separated by fractional distillation, fractional
They have optical rotation in opposite direction but to the
same extent.
They have identical chemical properties except with other
optically active compounds.
3.10 MESO COMPOUNDS
let us now consider a compound containing two similar chiral centres, i.e. having the same set of four
different groups attached to each of the chiral carbon atoms. a typical sample of such a compound is provided
by tartaric acid:
enantiomers Diastereomers
They have different physical properties such as melting
point, boiling point, solubility in a given solvent, density,
etc.
crystallization and adsorption chromatography.
They may have optical rotation in the same or opposite
directions but to a different extent.
They have identical chemical properties but differ in the
rate of reactions with optically active compounds.