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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5852_Библиотеки_им_академика_М_И_Перельмана.pdf
D-(+)-Glyceraldehyde
L-(−)-Glyceraldehyde
CHO
COHH
CH
2
OH
CHO
CHHO
CH
2
OH
D-(−)-Lactic acid
L-(+)-Lactic acid
COOH
COHH
CH
3
COOH
CHHO
CH
3
D-(
−
)-Tartaric acid
L-(+)-Tartaric acid
COOH
COHH
CHHO
COOH
COOH
CHHO
COHH
COOH
C h a P T E r 3 Stereochemistry
correct, the assumed conguration of the two enantiomers of glyceraldehyde must also be correct. As such, the
conguration of all other compounds derived by correlation with glyceraldehyde must be correct ones. Thus
the relative conguration assigned to
d-(–)-glyceric acid, l-(–)-lactic acid (discussed earlier), carbohydrates
and a large number of other compounds actually represent their absolute conguration.
The absolute congurations of some simple but stereochemically important compounds are given below
in the planar form:
161
3.16 SPECIFICATION OF CONFIGURATION BY R AND S NOTATIONS
Cahn, Ingold and Prelog suggested a very simple procedure to specify a particular conguration in terms
of prexes R or S. The letter R is taken from the latin word rectus, meaning ‘right’, and S from sinister,
meaning ‘left’. The procedure involves the following two steps:
Step 1: The four atoms or groups of atoms bonded to the chiral centre are assigned a sequence of priorities
in accordance with a set of rules known as sequence rules.
H2CCCH
3
H
OH
H
3
C
H
CO
H
CCH
2
CH
3
CH CH
3
CH
3
CH CH
H
CCH
2
CH
3
CH CH
3
H
CCH
2
C6H
5
i.e.
�
�
�
�
162
The sequence rules are as follows:
1. If all the four atoms directly attached to the chiral centre are different from one another, sequence of
priorities is determined by atomic number. The atom of highest atomic number gets the highest priority
while the one with the lowest atomic number comes last in order of priority. For example, in the compound
1-bromo-1-chloro-ethane, CH
2. If two or more atoms directly attached to the chiral centre have the same atomic number, the relative
priorities may be xed by comparing the next atoms in the groups. If even this does not solve the problem,
the comparison may be extended to the next atom and so on. For example, in sec-butyl alcohol,
PharMaCEuTICal OrGanIC ChEMISTry
CH(Cl) Br, the sequence of priorities will be Br, Cl, C and H.
3
the relative priorities of Ch3 and C2h
chiral centre through the same atom, i.e. carbon. The next atoms in CH
are decided as follows. Each of these groups is linked to the
5
are 3H, while in C2h5 they are
3
C, H and H. Since carbon has a higher atomic number than hydrogen, C2h5 gets higher priority.
3. If a group has an atom X linked to some other atom by double or triple bond, X is considered
equivalent to two or three such atoms. For instance, if we compare the groups,
and –Ch2OH,
the former gets higher priority as the next atoms in it are equivalent to 2O, and H while in CH2Oh
they are O and 2h.
It may be noted, however, that if in a group two or three atoms of X (are separately linked to
some atom through single bonds, such a group would get priority over the group containing doubly
or triply bonded X. For example, let us compare the groups
these groups, the next atoms will be taken as C, C and H. However, in
are actually attached through single bonds while in
through double bond. As such, the group
Similarly
gets priority over –Ch5Ch
gets priority over
, there is only one carbon attached
and
. In both
, the two carbons
.
– which in turn gets priority over
–Ch5Ch2.
Note:
The phenyl group
is considered as if it has one of Kekule structures, that is
C
C
H
H
CH
CH
CH
CH
COOH
H
HO
CH
3
R
COOH
H
OH
H
3
C
S
Cl
H
I
SO
3
H
Clockwise
Cl
H
I
SO
3
H
Anticlockwise
R
S
C h a P T E r 3 Stereochemistry
As such, the atoms next to the carbon attached to chiral centre are treated as C, C and C.
Step 2: After deciding the sequence of priorities, the molecule is imagined to be in a position where the
group of lowest priority is directed away from us. Now, we look at the arrangement of remaining groups in
decreasing order of their priorities. If in doing so, the eye travels in clockwise direction, the conguration
is specied as R (Latin: rectus 5 right). If, on the other hand, the eye travels in anticlockwise direction, the
conguration is specied as S (Latin: sinister 5 left).
Let us illustrate the above rules by considering some specic examples:
1. Lactic acid, ch3ch(oh)cooh: The sequence of priorities is OH, COOH, CH3 and H. Therefore,
the specic conguration may be designated as follows:
163
2. chloroiodomethane sulphonic acid, ch(cl)(i)S3oh: The sequence of priorities is I, Cl, SO3h
and H. Therefore, R and S congurations may be represented as shown below.
Cl
H
CH
2
CH
First
interchange
Second
interchange
HOH
CH
3
CH2CH
3
HO H
CH
3
CH2CH
3
HO CH2CH
3
CH
3
H
First
interchange
Second
interchange
CH
3
H
CHO
NH
2
CH
3
NH
2
CHO
H
NH
2
CH
3
CHO
H
164
PharMaCEuTICal OrGanIC ChEMISTry
3.16.1 Configuration on the Basis of Projection Formulae
While assigning conguration to a stereoisomer on the basis of projection formula, the procedure is
essentially the same as in case of three-dimensional formulae. However, if the group of lowest priority
is pointing towards us (i.e. bonded horizontally), an additional step is required. In such cases, the given
formula is converted into another projection formula by making two interchanges so that the group or atom
of lowest priority is placed vertically downwards or upwards. Then the conguration is assigned following
the usual procedure:
1.
2.
3.
3.16.2 Configuration of Compounds Containing More Than One Chiral Centre
In such cases, the conguration about each chiral centre is ascertained separately. The specication of each
atom along with its number is then prexed before the name of the compounds as illustrated below:
The sequence of priorities is Cl,
,
Ch 5 Ch2 and H. Therefore, conguration is S.
The sequence of priorities is OH, CH2Ch3, CH3 and H. Therefore, conguration is S.
The sequence of priorities is NH
, CHO, CH3 and H. Therefore, conguration is R.
2
∗
CHOHCOOH
∗
CHOHCOOH
COOH
C
C
COOH
H
OH
OH
H
CH
3
2
C
3
C
CH
3
H
H
Cl
Cl
CH
3
2
C
CHClCH
3
HCl
H
2
CCl CH
3
(After two
interchanges)
Configuration = S
CHClCH
3
COOH
COOH
H
OH
HO
H
C h a P T E r 3 Stereochemistry
1. let use consider one of the forms of tartaric acid
Each chiral centre in this molecule has the same set of four groups attached to it. The sequence of
priorities of these groups is OH, COOH, CHOH–COOH and H. Following this sequence of priorities,
the congurations around each of the chiral centres is S so that the compound may be designated as
(2S,3S)-tartaric acid.
165
2. Let us now assign conguration to the compound
priorities of groups is Cl, CHClCH3, CH3 and h.
Conguration at
Each of carbon atoms 2 and 3 has the groups Ch3, H, Cl and CHClCH3 attached to it. The order of
2
C can be known as follows:
Learning Plus
For compounds with two chiral centres, the maximum
number of configurational isomers possible is four, based
on the 2n rule. Since each chiral centre may have an R- or
S-configuration, the isomers possible include RR, SS, RS
and SR. The RS and SR isomers are nonsuperimposable
mirror images and hence are enantiomers. The same
relationship exists for the RR and SS isomers. The
relationship between each member of an enantiomeric
pair and each member of the other enantiomeric pair
is diastereomeric; they are nonsuperimposable mirror
images. Thus the RS isomer is a diastereomer of the RR
and SS isomers, and the SS isomer is a diastereomer of
the RS and SR isomers.
(After two
interchanges)
CHClCH
3
3
C
CH
3
HCl
3
C
CH
3
H
Cl
Configuration = R
CHClCH
3
PharMa CEu TICal OrGanIC ChEMISTry
166
Conguration at 3C can be obtained as follows:
Hence, the conguration of the above compound is (2S,3R).
3.17 GEOMETRICAL ISOMERISM
Geometrical isomerism is a general phenomenon and is shown by any molecule which can assume rigid
conguration due to hindered rotation in a portion of the molecule. The hindered rotation may be about a
double bond or a single bond in part of the molecule.
3.17.1 Geometrical Isomerism or Carbon–Carbon Double Bond
This isomerism is mostly shown by such compounds that contain at least one carbon–carbon double bond and
in which each of the doubly bonded carbon atoms have same or different sets of two unlike atoms or groups.
Thus compounds of the type abC 5 Cab or abC 5 Cxy show
geometrical isomerism.
The relative positions of the atoms or groups attached to the
doubly bonded carbon atoms get xed up because of hindered
rotation about a double band. This is explained as follows:
The carbon–carbon double bond consists of one sigma and one
pi bond. The (p) bond is formed by the sideways overlapping of
unhybridized p-orbitals of two carbon atoms above and below
the plane of the bond. Because of this type of overlapping,
Learning Plus
Geometric isomerism was first defined by
Wislicenus in 1887. This isomerism occur in only
those compounds where rotation is restricted by
double bonds or ring systems. Geometric isomers
are not optically active and hence do not rotate the
plane of polarized light even if they also contain a
chiral centre.
rotation around carbon–carbon double bond is strongly hindered
as explained below.
If the doubly bonded carbon atoms are rotated with respect to each other, sideways overlapping of
p-orbitals will not be possible and thus molecular orbitals get destroyed. We know that 260 kJ of energy is
required for the cleavage of bond, which is not available under ordinary conditions. Thus rotation around
double bond gets hindered. Therefore, hindered rotation of carbon atoms about double bond is the essential
and sufcient criterion for geometric isomerism.
Due to hindered rotation around carbon–carbon double bond, the relative positions of the atoms or groups
attached to the doubly bonded carbon atom gets xed in space giving rise to two distinct isomeric forms.
For example, 2-butene, H3ChC5ChCh3 can exist in the following two isomeric forms:
CH
3
C
CH
3
H
H
CH
3
C
CC
H
H
3
C
H
cis-2-Butene trans-2-Butene
cis-form
Maleic acid (m.p. = 130°C)
trans-form
Fumaric acid (m.p. = 302°C)
C
H
CC COOHH C COOH
H
C COOH
HOOC H
(cis-isomer)
2-Butene (b.p. = 4°C)
(trans-isomer)
2-Butene (b.p. = 1°C)
CH
3
HC
CH
3
HC
CH
3
HC
H
CH
3
C
C h a P T E r 3 Stereochemistry
Isomers in which similar atoms or groups lie on the same side of double bond are called the cis-isomers
(latin cis 5 on same side), and the isomers in which the similar atoms or groups lie on the opposite sides
of double bond are called trans-isomers (latin trans 5 across).
Such isomers which have the same molecular formula, same structural formula but differ in the relative
spatial arrangement of atoms or groups about the double bond are called geometrical isomers and the
phenomenon is known as geometrical isomerism or cis–trans isomerism.
Maleic acid and fumaric acid are important examples of unsaturated dicarboxylic acids, which exhibit
geometrical isomerism. These two isomers are shown below:
167
Both these isomers differ not only in physical but also in chemical properties. For example, maleic acid
readily forms an anhydride but fumaric acid does not. Maleic acid may be converted into fumaric acid, when
its aqueous solution is heated with a small amount of hydrochloric acid. Fumaric acid may be converted
into maleic acid by irradiation with ultraviolet light. The greater ease of anhydride formation indicates that
maleic acid is the cis-isomer. anhydride formation is not possible in fumaric acid (trans-isomer) as the two
carboxylic groups are too far apart. The melting point of maleic acid is 130°C while fumaric acid melts at
302°C. The dipole moment of maleic acid is quite high while that of fumaric acid is zero.
Geometrical isomerism is commonly found in ethylene derivative in which each of the doubly bonded
carbon atom is linked with two different groups. Some more examples are given below:
1.
(cis-isomer)
Dichloroethene (b.p. = 60°C)
(trans-isomer)
Dichloroethene (b.p. = 48°C)
H
CIC
H CIC
H ClC
Cl HC
(cis-isomer)
Allocinnamic acid (b.p. = 68°C)
(trans-isomer)
Cinnamic acid (b.p. = 133°C)
C6H5C COOH
H
HOOC C
C6H5C COOH
COOH
HC
(cis-isomer)
Iso-crotonic acid (b.p. = 168–169°C)
(trans-isomer)
Crotonic acid (b.p. = 185°C)
CH
3
CH
HOOC CH
CH3CH
HCCOOH
168
PharMaCEuTICal OrGanIC ChEMISTry
2.
3.
4.
3.17.2 Configuration of Geometrical Isomers on the Bases of Properties
Geometrical isomers have different physical properties such as melting points, boiling points, solubilities,
dipole moments, etc. Like other diastereomers, geometrical isomers have similar but not essentially identical
chemical properties. These properties are employed in determining the conguration of these isomers.
There are no general methods to ascertain the conguration of geometrical isomers. The methods
employed depend on the nature of compound under consideration. These facts are used to ascertain the
conguration of the isomers. The following methods are employed to determine whether a given compound
is a cis- or a trans-isomer.
By studying their physical properties: It has been found that generally a cis-isomer has low melting
1.
point, high boiling point, higher density, greater solubility in organic solvents, higher heat of combustion
and hydrogenation, higher refractive index, higher viscosity and higher dissociation constant (if an acid)
than a trans-isomer. Some of these important physical properties and their applications in ascertaining the
congurations are discussed below.
a. Melting points: The trans-isomer, in general, has a higher melting point than the corresponding cis-
isomer. This is due to the fact that cis-isomer is unsymmetrical and does not show close packing in
the crystal lattice. On the other hand, trans-isomer is more symmetrical as the two similar atoms or
groups lie on the other side of the double bond. Therefore, these molecules pack well in the crystal
lattice. As a result, the intermolecular forces of attraction of trans-isomer are much stronger than
those holding the cis-isomer. Hence, the melting point of trans-isomer is higher than that of the
corresponding cis-isomer. For example, maleic acid (cis-isomer) has a m.p. of 130°C while fumaric
acid (trans-isomer) melts at 302°C.
Acetylene dibromide (cis-isomer)
Dipole moment 1.35 D (b.p. = 110°C)
Acetylene dibromide (trans-isomer)
Dipole moment zero (b.p. = 108°C)
HCBr
HCBr
(cis-isomer)
Dipole moment 1.85 D (b.p. = 60°C)
(trans-isomer)
Dipole moment zero (b.p. = 48°C)
HCCI
HCCI
HCCI
Cl CH
C h a P T E r 3 Stereochemistry
b. Solubility: As discussed above, molecules of cis-isomer are less closely packed and thus have
weak intermolecular forces of attraction in the crystal lattice than the corresponding trans-isomer.
Therefore, cis-isomers should have higher solubilities than those of the corresponding trans-isomers.
This is evident from the solubilities (in water at 20°C) of maleic acid (79.0 g/100 ml) and fumaric
acid (0.7 g/100 ml).
c. Dipole moments: It has been found that generally cis-isomers have higher dipole moments as compared
to trans-isomers, which have zero or nearly zero dipole moments. This is due to the orientations of the
two dipoles of cis-isomer at some angle and thereby having a denite dipole moment. On the other hand,
the dipoles of trans-isomer are in the opposite directions and thus cancels out. As a result, cis-isomer will
have some nite value of dipole moments but trans-isomer will have zero dipole moments.
It is evident from the dipole moment of acetylene dibromide that trans-isomer has zero dipole
moment as compared to cis-isomer, which has a dipole moment of 1.35 D.
d. Boiling points: In general, the boiling point of a cis-isomer is higher than that of the corresponding
trans-isomer. It is due to the more polar nature (due to higher dipole moments) of cis-isomer than
the corresponding trans-isomer.
As a result, dipole–dipole interactions are comparatively stronger in case of cis-isomer than
the corresponding trans-isomer. Consequently, the cis-isomer has a higher boiling point than the
corresponding trans-isomer. For example, cis-dichloroethene boils at 60°C whereas trans-isomer boils
at 48°C.
169
e. Studying their X-ray diffraction pattern: This method depends upon the fact that the diffraction of
X-rays by a crystalline substance produces a pattern on a photographic plate, which can be used to
calculate the relative positions of atoms in a molecule.
2. By studying their chemical properties: Chemical properties of the cis- and trans-isomers are related
to the relative positions of the two groups, each of the two doubly bonded atoms. These provide more
dependable methods than those provided by physical properties.
a. By cyclization method: Crystallization occurs easily if the two reacting groups are close together.
Since in cis-isomers, the reacting groups are quite near to each other, they result in the formation
of a cyclic compound. But in trans-isomer, the two reacting groups are far apart and, therefore, are
heat
O + H
2
O
Maleic acid (cis-isomer) Maleic anhydride
HC
COOH
HCCOOH
C
CO
H
HCOC
heat
Fumaric acid (trans-isomers)
No anhydride formation
HCCOOH
HOOC CCH
Fumaric acid
(trans)
H
2
O
Trichloro crotonic
acid (trans)
Zn + HCl
Crotonic acid
(trans)
HCCOOH
HOOC CH
HCCCl
3
HOOC CH
HCCH
3
HOOC CH
Zn + HCl
No fumaric acid
H
2
O
Trichloro crotonic acid
(cis)
Isocrotonic acid
(cis)
HCCCI
3
HCCOOH
HCCH
3
HCCOOH
170
PharMaCEuTICal OrGanIC ChEMISTry
unable to react mutually to form a cyclic derivative. This fact is utilized to assign conguration to
cis–trans isomers. For example, when maleic acid is heated, it forms maleic anhydride. Anhydride
formation does not take place with fumaric acid.
b. By converting into compounds of known conguration: In some cases, a geometrical isomer can
be changed into a compound of known conguration. It is presumed that during such a change,
there is no isomerization. For example, trichloro crotonic acid can be converted into fumaric acid
on hydrolysis. Hence, the trichloro crotonic acid must be a trans-isomer. It further gives crotonic
acid on reduction. The other isomer of trichloro crotonic acid does not give fumaric acid and on
reduction it gives isocrotonic acid. Hence, it is cis-isomer.
c. From the formation of the type of optical isomer: Both the forms of ethylene dicarboxylic acid,
maleic and fumaric acid on hydroxylation give an optically inactive form of tartaric acid. One
obtained from maleic acid (cis-isomer) is meso-tartaric acid and while the other obtained from
fumaric acid (trans) is racemic (±) tartaric acid.