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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5852_Библиотеки_им_академика_М_И_Перельмана.pdf
IX XXI
XII
COOH
COHH
COHH
COOH
Plane of
symmetry
C h a P T E r 3 Stereochemistry
In view of the fact that it has two chiral centres, one may expect the existence of four stereoisomers of
this acid having the congurations IX, X, XI and XII:
Formulae IX and X are nonsuperimposable mirror images of each other and, therefore, represent a pair
of optically active enantiomers.
Formulae XI and XII again have a mirror-image relationship. Close examination of these formulae,
however, shows that one of these structures may be superimposed on the other just by rotating it through
180° within the plane of the paper. These two formulae, therefore, represent two superimposable mirror
image molecules of the same compound. Further examination of formula XI (or XII) reveals that in spite of
two chiral centres in it, the molecule is not chiral. This is because it has a plane of symmetry; one half of its
molecule being mirror image of the other half. As such, the compound represented by formula XI (or XII)
is optically inactive. Such optically inactive compound whose molecules are not chiral even though they
contain two (or more) chiral centres is known as a meso compound. As explained above, the molecules of
such compounds are superimposable on their mirror images.
Thus tartaric acid exists in three forms: (+) tartaric acid (formula IX), (2) tartaric acid (formula X) and
meso-tartaric acid (formula XI or XII).
151
Although optically inactive, the meso-tartaric acid represents a diastereomer of (2) or (1) tartaric acid.
It should be noted that meso compounds are permanently inactive and are said to be internally compensated,
i.e. one half of the molecule cancels the effect of other half.
HO2C
CO
2
H
Rotate LHS Mirror
plane
OH
HO
HO
CO2H
OH
HO2C
152
PharMaCEuTICal OrGanIC ChEMISTry
NOTEWORTHY POINTS
For 1. n chiral centres, the maximum number of stereoisomers is 2n.
a. When n 5 1, 21 5 2. With one stereogenic centre there are always two stereoisomers and they are
enantiomers.
b. When n 5 2, 22 5 4. With two stereogenic centres, the maximum numbers of stereoisomers is
four although sometimes there are fewer than four.
A meso compound is an achiral compound that contains tetrahedral chiral centres and a plane of
2.
symmetry. Meso compounds posses two identical halves due to plane of symmetry.
The chemical and physical properties of two enantiomers are identical except in their interaction with
3.
chiral substances.
If the rotation is clockwise (to the right), the compound is called
4. dextrorotatory. The rotation is labelled
‘d’ or 1.
If the rotation is counterclockwise (to the left), the compound is called
5. laevorotatory. The rotation is
labelled ‘l’ or 2.
Because two enantiomers have identical physical properties, they cannot be separated by common
6.
physical techniques like distillation.
Diastereomers and constitutional isomers have different physical properties, and therefore they can
7.
be separated by common physical techniques.
MEMORY FOCUS
Meso1. compounds contain stereocentres but are still achiral.
Meso compounds have a plane of symmetry with (
2. R) configuration on one side and (S) on the other.
Meso compounds are achiral because they have a plane of symmetry.
3.
3.11 NUMBER OF POSSIBLE STEREOISOMERS IN COMPOUNDS CONTAINING DIFFERENT
NUMBER OF CHIRAL CENTRES
It may be noted that the maximum possible number of stereoisomers of a molecule is 2n where n is the
number of chiral centres in the molecule. Thus the molecules having 1, 2 and 3 chiral carbon atoms exist in
2, 4 and 8 stereoisomeric forms, respectively. The number is, of course, less than the maximum if some of
the isomers exist in meso form.
* *
C h a P T E r 3 Stereochemistry
3.12 RACEMIZATION
We know that when equal quantities of enantiomers are mixed together, it results in the formation of an
optically inactive form called racemic mixture and denoted by using the prex ± before the name of the
compound. The formation of optically inactive racemic mixture is quite understandable because the rotation
caused by the molecules of one isomer is exactly cancelled by equal and opposite rotation caused by the
same number of molecules of the other enantiomer. This is termed as external compensation.
The conversion of an optically active enantiomer into a racemic mixture is known as racemization.
Racemization can be brought about as follows:
1.
By the action of heat: Quite often, an optically active enantiomer changes into a racemic mixture
by the action of heat. For example, when (1) tartaric acid is strongly heated with water, it gets
converted into a mixture of racemic and meso-tartaric acids.
2. By the action of chemical reagents: racemization is also brought about by the presence of foreign
substances (particularly acids and bases) in the solution of an optically active substance. For example,
addition of sodium hydroxide to (1) or (2) lactic acid leads to the formation of a racemic mixture.
3. Autoracemization: In some cases, racemization takes place by merely keeping the substance at room
temperature for some time. This is known as autoracemization. For example, any one of the enantiomers
of dimethyl bromosuccinate changes into a racemic mixture on standing at room temperature.
mechanism of racemization: Racemization is believed to take place through the formation of some intermediate,
which is no longer chiral in nature. Quite often, the achiral intermediate formed is an enol. For example, in an
aldehyde or ketone in which the chiral carbon carries hydrogen and is in position with respect to the carbonyl
group, the given optically active compound changes into an achiral enol by tautomeric change. The enolic form,
being unstable, reverts to the chiral keto form but in doing so it produces (1) and (–) enantiomers in equal
quantities and thus racemization takes place. This is shown below taking example of 3-methyl-2-pentanone.
153
(unstable intermediate)
3.13 INTERNAL AND EXTERNAL COMPENSATION
3.13.1 Internal Compensation
It has been stated above that meso compounds are optically inactive because their molecules are not chiral
even although they contain two (or more) chiral centres. For example, it is clear from the structural formula of
COOH
COHH
COHH
COOH
Plane of
symmetry
Upper half
Lower hal
f
154
PharMaCEuTICal OrGanIC ChEMISTry
meso-tartaric acid that the upper half of the structure is an exact mirror image of the lower half. As such, the
optical activity due to one chiral centre is counterbalanced by the optical activity due to the other chirol centre
and this the compound is optically inactive. The compensation of optical activity due to one half of a molecule
by the other half is known as internal compensation and the molecule is said to be internally compensated.
internally compensated molecule is permanently inactive.
3.13.2 External Compensation
In a racemic mixture, equimolar mixture of two enantiomers, i.e. (1) and (–) lactic acid, are present. This
means that rotation of plane polarized light by each isomer would be equal in magnitude and opposite
in sign, i.e. direction. Therefore, exact cancellation of all rotation would take place and the equimolar
mixture would be optically inactive. The cancellation of rotation of one enantiomer by the other in an
equimolar mixture of the two enantiomers is known as external compensation and the racemic mixture is
said to be externally compensated.
It may be pointed out that if the two enantiomers are not present in equimolar quantities, the rotation
caused by one enantiomer is not exactly cancelled by the other. As such, this mixture still exhibits some
optical activity. The direction of rotation corresponds to that of the enantiomer present in larger quantity
but the specic rotation is lesser. In this way, partial compensation takes place and the mixture formed is
said to be partially racemized.
an
comparison of external and internal compensations
external compensation internal compensation
It is due to the mirror-image relationship between the
structures of the molecules of two enantiomers mixed
together, in equal amount.
In this case, the molecules of one enantiomer cancel the
rotation of the other enantiomer.
The racemate formed is a mixture of two optically active
isomeric compounds.
Complete or partial external compensation of rotation is
possible.
It is a reversible process and the racemic mixture can be
resolved into 1 and – enantiomers.
It is due to the mirror-image relationship between the
structures of two halves of the same molecule.
In this case, one-half of the molecule counterbalances the
rotation of the other half.
Internally compensated compound or meso form represents a
single pure compound.
Partial internal compensation is not possible.
It is a permanent effect and it is not possible to resolve an
internally compensated molecule into optically active forms.
HO2CPh
H
⊕
OMe
(±) or (R)/(S)
racemate
(+) or (R)
(A)
(−)(+)
(A)
(−)(+)
(S)
(−)
(R)
(+)
(B)
(+)(+)
(B)
(+)(+)
Diastereoisomers
Mixture
Separation
HydrolysisHydrolysis
+
HOH
OH
OH
+
O
O
O
Ph
O
O
OMe
O
Ph
OMe
C h a P T E r 3 Stereochemistry
3.14 RESOLUTION OF RACEMIC MODIFICATIONS
When a chiral compound is synthesized from achiral reactants, the product formed is found to be an optically
inactive racemic modication containing equal proportions of enantiomers. The process of separating a
racemic modication into its enantiomers is called resolution.
The main difculty in the process of resolution is that enantiomers have identical physical and chemical
properties. However, the following methods have been introduced for this purpose.
1. mechanical separation: If the enantiomers of a substance exist in well-dened crystalline forms, the
separation can be done by ‘hand picking’ with the help of a magnifying lens and a pair of tweezers.
For example, the enantiomers of sodium ammonium tartarate can be separated by this method.
Limitations: This method has a very limited application as very few enantiomeric substances exist
in the form of mechanically separable crystals. Moreover, the method is very laborious and time
consuming.
REMEMBER
Separation of enantiomers is called ¾
resolution
.
155
Racemic mixture reacts with an optically active compound to form diastereomers. Diastereomers have different physical properties
and hence are separable. On separation they give pure enantiomers.
III
H
COOH
CH
3
OH
HO
COOH
CH
3
H
156
PharMaCEuTICal OrGanIC ChEMISTry
2. Biochemical separation: This method involves the use of microorganisms for bringing about
resolution. Certain bacteria, yeasts or moulds are allowed to grow in a dilute solution of a racemic
modication, one of the enantiomers is selectively consumed by the microorganism while the other
is left behind. For example, the mould Penicillium glaucum is allowed to grow in a solution of
racemic ammonium tartarate, the mould completely destroys (1) ammonium tartarate while (2)
tartarate is left practically unaffected.
Limitations: The main disadvantage of the method is that one half of the material is destroyed during
separation. Moreover, as the separation is carried out only in dilute solutions, the process is very
slow and only small amounts of materials can be separated.
3. chemical separation: This is probably the best method of resolution. It involves the conversion of
racemic mixture into a mixture of diastereomers of some other substance by reaction with an optically
active reagent. Since diastereomers have different physical properties, the mixture of diastereomers
can be easily separated through fractional crystallization, fractional distillation, chromatography,
etc. Each of the diastereomers is then suitably treated to generate a pure enantiomer of the original
substance. For example, if a racemic mixture of (1) and (2) lactic acid is treated with a single
enantiomer of an optically active base, say (2) brucine, it would result in the formation of a
mixture of two crystalline salts. The two salts formed would be (2) brucine (1) lactate and (2)
brucine (2) lactate. While brucine part of these salts has the same conguration in both cases, the
acid parts have nonsuperimposable mirror image congurations in the two cases, so that the two
salts represent two diastereomers. As such, the crystals of the two salts differ in their solubilities
and can be separated by fractional crystallization. Once the separation has been achieved, reaction
of each salt with hydrochloric acid would generate a free lactic acid in pure enantiomeric form:
(–) brucine (+) lactate + HCl (+) lactic acid + (–) brucine–HCI
(–) brucine (–) lactate + HCl
(–) lactic acid + (–) brucine–HCl
Apart from the separation of racemic acids or bases by this method, it can also be employed for the
separation of racemic alcohols, aldehydes, etc., by treatment with suitable optically active reagents.
3.15 SPECIFICATION OF CONFIGURATION
The conguration of the two enantiomers of lactic acid are I and II shown below. One of these conguration
represents dextro or (1) lactic acid while the other represents laevo or (–) lactic acid.
IV
D-(+)-Glyceraldehyde
III
L-(−)-Glyceraldehyde
CHO
C
OHH
CH
2
OH
CHO
C
HHO
CH
2
OH
H
OH
CH
2
OH
CHO
H
HO
CH
2
OH
CHO
C h a P T E r 3 Stereochemistry
Specication of conguration means which one of the two enantiomers, (1) or (–), has the
conguration I and which has the conguration II. In other words, we do not know the actual or absolute
conguration of each of the two enantiomers.
In the earlier days, it was not possible to determine the absolute congurations of the compounds.
Fortunately, it is not always necessary to know the absolute conguration of an optically active compound.
On the other hand, we are more interested in knowing the relative congurations of different compounds.
For example, when an optically active compound undergoes a chemical reaction, we are mainly interested
in whether the congurations of the reactant and its product are same or different and not in their actual
congurations.
1.
Relative congurations by d and l notation
It was proposed by Emil Fischer (1885) that a standard reference compound should be chosen to assign relative
congurations to various optically active compounds. The compound chosen as the standard was glyceraldehyde
(Ch2OhChOhChO) and its two enantiomers were designated by the symbols d and l. It must be made clear
that the symbol d and l refer to conguration and are quite different from the prexes d and l (read as ‘dextro’ and
‘laevo’), which refer to the direction of rotation. (1)-Glyceraldehyde was arbitrarily assigned the conguration
III (in which the –Oh group attached to chiral carbon is towards right) and was given the symbol d. The 2
enantiomer was assigned the conguration IV (in which the –OH group attached to chiral carbon is towards
left) and was given the symbol l.
Planar representation
157
three-dimensional representation
D-(+)-Glyceraldehyde D-(+)-Glyceric acid
Oxidation
(Br
2/H2
O)
CHO
COHH
CH
2
OH
COOH
COHH
CH
2
OH
L-(−)-Glyceraldehyde L-(−)-Glyceric acid
P/Br
2
(PBr
3
)Oxidation
(Br
2/H2
O)
CHO
CHHO
CH
2
OH
COOH
CH
HO
CH
2
OH
L-(−)-3-Bromo-
2-hydroxypropanoic acid
L-(−)-Lactic acid
Reduction
– HBr
COOH
CHHO
CH
2
Br
COOH
CHHO
CH
3
158
PharMaCEuTICal OrGanIC ChEMISTry
reasons for selecting glyceraldehyde as the standard: Glyceraldehyde was chosen as the standard mainly
because of the following reasons:
1. It is the simplest carbohydrate and an aldotriose. Its conguration could be easily related to those of
the other important carbohydrates.
2. Since glyceraldehyde contains very reactive functional groups, it could be converted into many other
types of compounds. In this way, it could be congurationally related to a large number of compounds.
Correlation of conguration: Many other compounds were then assigned relative congurations by
relating their conguration to that of d- or l-glyceraldehyde. For this purpose, either the compound under
examination is converted into d- or l-glyceraldehyde or it is converted into the given compound by means
of reactions which do not involve breaking of bonds to a chiral centre. The general principle involved in
correlating the congurations of two compounds is that if a reaction does not involve the breaking of a
bond about a chiral centre, the conguration about that chiral centre remains unchanged. Some important
examples of the correlations of the congurations are given below:
a. Conguration of (2) glyceric acid: (2) Glyceric acid can be obtained by the oxidation of d-(1)-
glyceraldehyde as shown below. Since this reaction does not involve breaking of bonds about the
chiral centre, (2)-glyceric acid must have the same conguration as that of glyceraldehyde taken,
i.e. d conguration.
b. Conguration of (1) lactic acid: The conguration of (1) lactic acid was established to be similar
to that of l-(–)-glyceraldehyde by the following reactions:
D-(+)-Glyceraldehyde
(Two configurations possible around
new chiral centre marked *)
HCN
CHO
COHH
CH
2
OH
VIV
meso-Tartaric acid
D-(−)-Tartaric acid
Hydrolysis Ba(OH)
2
COOH
Oxidation (HNO
3
)
COOH
C
∗
CN
HHO
C
CH2OH
OHH
C*
HHO
C
CH2OH
OHH
C
∗
HHO
C
COOH
OHH
Hydrolysis
Oxidation
Ba(OH)
2
COOH
(HNO
3
)
COOH
C
∗
CN
OHH
C
CH2OH
OHH
C
∗
OHH
C
CH2OH
OHH
C
∗
OHH
C
COOH
OHH
C h a P T E r 3 Stereochemistry
c. Conguration of tartaric acid: When d-(1)-glyceraldehyde was converted into tartaric acid by
the series of reactions shown below, a mixture of two products was obtained. These two products
differed from each other in their conguration around newly created chiral centre (marked *). One
of the products was the inactive or meso-tartaric acid (V). The other was the optically active tartaric
acid, which rotated the plane of light towards left, i.e. it was
d-glyceraldehyde by reactions, which did not involve breaking of bonds around the original
from
chiral centre, it was assigned
d-conguration, i.e. the same as that of starting glyceraldehyde.
d-(–)-tartaric acid. Since it was obtained
159
VIIVI
D-(−)-Tartaric acid L-(+)-Tartaric acid
COOH
COOH
COH
H
H
HO C
COOH
COOH
CH
OH
HO
HC
D-(+)-Glyceraldehyde
D-(
−
)-Glyceric acid
CHO
COHH
CH
2
OH
COOH
COHH
CH
2
OH
D-(+)-Glyceraldehyde L-(+)-Lactic acid
CHO
COHH
CH
2
OH
COOH
CHHO
CH
2
OH
160
PharMaCEuTICal OrGanIC ChEMISTry
Since d-(–)-tartaric acid was assigned conguration VI. l-(1)-tartaric acid would naturally have the
mirror image conguration, i.e. VII.
It must be emphasized that there is no direct relationship between absolute conguration and direction
of rotation of polarized light. Two substances may have similar relative congurations and yet may rotate
the plane of light in different directions. For example, d-(1)-glyceraldehyde and d-(–)-glyceric acid have
similar conguration even though the former is dextrorotatory while the latter is laevorotatory.
Similarly two compounds may have different congurations and even then they may rotate the plane
of light in the same direction. For example, d-(1)-glyceraldehyde and l-(1)-lactic acid have opposite
congurations but the same sign of rotation.
2. Absolute conguration
Bijvoet (1951) was able to determine the absolute conguration of a compound by using X-ray diffraction
studies. The actual arrangement in space of the atoms or groups constituting a particular stereoisomer
is called absolute conguration. The rst compound whose absolute conguration was determined was
sodium rubidium salt of (1)-tartaric acid. Bijvoet conrmed that (1)-tartaric acid actually has the same
conguration, which was previously assumed to have on the basis of congurational relationship between
glyceraldehyde and tartaric acid (as described earlier). If the assumed conguration of (1)-tartaric acid was