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STEREOCHEMISTRY
Stereochemistry deals with the spatial arrangements of atoms or groups in a molecule. Isomers
having the same structure but differ in the spatial arrangements are called stereoisomers (i.e.,
stereoisomers have different configurations) and the phenomenon is called stereoisomerism.
Stereoisomerism can be divided into two classes, optical isomerism and geometrical isomerism. Optical
isomers because of their molecular asymmetry rotate plane of polarization of plane polarized light. Optical
isomers which rotate plane polarized light in equal and opposite amounts are called enantiomers.
Enantiomers have similar physical and chemical properties. Geometrical isomers do not rotate plane
polarized light because of their molecular symmetry. Geometrical isomers have different physical and
chemical properties. Geometrical isomerism is also known as cis-trans isomerism.
Optical Isomerism
All optically active structures have non-superimposable mirror images. Such structures may be
asymmetric or dissymmetric. Asymmetric structures have no elements of symmetry. Dissymmetric
structures possess some elements of symmetry, but they are capable of existing in two forms which are not
superimposable. Optical activity may be due to crystalline or molecular structure. Quartz, sodium chlorate
etc are optically active due to crystalline structure. They are optically active only in the solid state. Such
compounds exist in two crystal forms which are mirror images and rotate the plane polarized light in
opposite directions. Such crystals are called enantiomorphous.
Molecular Chirality
A molecule which is not superimposable on its mirror image is a chiral molecule. If two
stereoisomers are nonsuperimposable mirror images the molecules are enantiomers. Samples containing
only one enantiomer are called enatiomerically pure. Stereoisomers which are not enantiomers are called
diastereoisomers (or diastereomers). In most of the chiral compounds chirality is due to the presence of
chiral centres. Carbon atoms with four different groups attached to it are called chiral carbon atoms or
asymmetric carbon atoms. An asymmetric carbon atom does not possess any symmetry elements. For a
compound to be optically active it need not be asymmetric. But the molecule should not possess plane of
symmetry, centre of symmetry and alternating axis of symmetry in order to show optical isomerism.
Chiral compounds may or may not possess proper axis of symmetry. Only compounds belonging to Cn
and Dn point groups show optical activity.
(B)
(A)
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Compound (A) possesses a centre of symmetry and hence optically inactive. Compound
(B) is also optically inactive due to the presence of an alternating axis of symmetry.
Stereochemical Nomenclature
D and L Nomenclature
Fischer proposed that stereochemical relationships are more important than
actual direction of rotation. He pointed out that the symbols d and l should refer to
stereochemical relationships rather than to the direction of rotation of the compound. He
selected d-glucose as the standard. Natural glucose is dextrorotatory (d-glucose).
Therefore all derivatives of d-glucose were considered to be belonging to d-series. Later
it was found that d-glyceraldehyde is stereochemically related to d-glucose. Therefore
glyceraldehyde was selected as the standard for stereochemical correlation. The symbols
d and l have been replaced by D and L for stereochemical relationships. D(+)glyceraldehyde is drawn with hydrogen atom at the left, hydroxyl group at the right and
the aldehyde group at the top corner by convention. Any compound which can be
prepared from or converted to D(+)-glyceraldehyde belongs to the D-series and any
compound which can be prepared from or converted to L(-)-glyceraldehyde belongs to
the L-series.
CHO
CHO
HO
H
H
OH
CH2OH
CH2OH
L(-)-glyceraldehyde
H
HO
OH
H
CH2OH
CH2OH
L-series
D-series
R and S Nomenclature (The Cahn-Ingold-Prelog System)
In Cahn–Ingold–Prelog system, the four groups on an asymmetric carbon are
ranked according to a set of sequence rules. The important postulates of the sequence rule
are given below.
1. Substituents are listed in order of decreasing atomic number of the atom directly joined
to the carbon.
2. Where two or more of the atoms connected to the asymmetric carbon are the same, the
atomic number of the second atom determines the order. For example, in the molecule
Me2CH-CHBr-CH2OH, the CH2OH group takes precedence over the Me2CH group
because oxygen has a higher atomic number than carbon. Note that this is so although
there are two carbons in Me2CH and only one oxygen in CH2OH. If two or more atoms
connected to the second atom are the same, the third atom determines the precedence, and
so on.
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3. A tritium atom takes precedence over deuterium, which in turn takes precedence over
ordinary hydrogen. Similarly, any higher isotope (e.g., 14C) takes precedence over any
lower one.
4. If double and triple bonds are present then both atoms attached to the multiple bond are
considered to be duplicated (for a double bond) or triplicated (for a triple bond).
5. Ring systems are treated as branched chains and if double bond is present then the
atoms connected by the double bond are considered to be duplicated.
Once the order is determined, the molecule is held so that the lowest group in the
sequence is pointed away from the viewer. Then if the other groups, in the order listed,
are oriented clockwise, the molecule is designated (R), and if counterclockwise, (S).
Molecules with Chiral Axes
Axial chirality is the chirality resulting from the nonplanar arrangement of four
groups about an axis. The axis is called a chiral axis. Suitably substituted allenes,
biphenyls, alkylidenecycloalkanes and spiranes can possess chiral axis. Some examples
for molecules possessing chiral axes are given below.
R-(+)-2,2’-Diamino-6,6’
-dimethylbiphenyl
In all the above compounds chirality is due to the unsymmetrical distribution of four
groups about an axis. All four groups may not be different from one another, but there
should not be a plane of symmetry present in the molecule.
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In allenes, the central carbon is sp hybridized. The remaining two p orbitals are
perpendicular to each other and each p orbital overlaps with the p orbital of one adjacent
carbon atom. Thus the two groups at one end of the allene lie in plane perpendicular to
the plane containing the two groups at the other end. Allenes are chiral only if both sides
are unsymmetrically substituted.
Possesses plane of symmetry
Possesses plane of symmetry No plane of symmetry
In simple alkenes the four groups lie in one plane and such compounds show cis-trans
isomerism. Similarly if there are odd numbers of cumulative double bonds, then the four
groups at the ends lie in one plane and such compounds show cis-trans isomerism. But if
there are even numbers of cumulative double bonds, the groups at the two ends will be in
perpendicular planes and in such cases optical activity is possible. Similarly spiranes and
compounds with exocyclic double bonds can also show optical activity because of the
presence of chiral axes.
Atropisomerism
Atropisomers are stereoisomers resulting from restricted rotation about single
bonds. In such cases the rotational barrier is high enough for the isolation of isomers.
Certain substituted biphenyls can show atropisomerism. If three of the four ortho
positions in biphenyls are substituted by groups which are large enough to prevent
rotation of the rings about C-C bond, then such compounds can be resolved. In order to
show atropisomerism, both rings should be asymmetrically substituted.
In the above compound, ring A is asymmetrically substituted. But ring B is
symmetrically substituted and the compound has a plane of symmetry. Therefore the
compound is optically inactive. But in the following compound both rings are
asymmetrically substituted and hence no plane of symmetry. The compound can be
resolved.
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In some cases two groups in ortho positions are sufficient for hindered rotation. For
example For example biphenyl,2,2’-bis-sulfonic acid shows atropisomerism.
SO3H
SO3H
1,1’-binapthyl also shows optical activity, since at room temperature rotation about c-c
bond is prevented.
In this case racemisation takes place due to rotation about 1,1’-bond. But this rotation is
resisted due to the van der Waals interaction between the hydrogens.
Specification of Absolute Configuration of biphenyls
Asymmetry of biphenyls is not due to the presence of chiral carbon atoms, the asymmetry
is due to the presence of chiral axis. Absolute configuration of biphenyls can be assigned
by assuming that the chiral axis is derived from a chiral centre (Z).
X
B
A
D
C
Y
The molecule can be viewed from any of he two ends of the chiral axis XY. If the
molecule is viewed from one end of the axis the groups near that end will get precedence
over the groups at the other end. Thus if viewed from the end X, the groups A and B
precede groups C and D. Accordingly the groups are arranged in the priority order.
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Priority of A and B (and C and D) is determined by the normal sequence rule. The
molecule is viewed from the side remote from the least priority group and R and S
notations are assigned as usual.
Some examples are given below.
(i)
X
2
Cl
1
NO2
2
HO2C
O2N
3
1
=
CO2H
4
3
Br
4
(S)-configuration
Y
In this example the molecule is viewed from X. The same result will be obtained if it is
viewed from Y. In that case groups 3 and 4 will become 1 and 2.
(ii)
NH2
1
NH2
2
3
=
two interchanges
=
3
4
CH3
4
CH3
1
2
(R)-configuration
Absolute configurations of compounds other than biphenyls which possess
chiral axis can also be assigned similarly.
1
1
3
H3C
C
H
C
CH3
C
=
two interchanges
=
H
4
2
4
2
3
(R)-configuration
Molecules with Chiral Planes
A chiral plane is a planar unit of a molecule connected to an adjacent part of
the structure through bonds those result in restricted torsion, so that the plane cannot lie
in a symmetry plane. Trans-cyclooctene, monosubstituted paracyclophanes etc. are
examples. Cyclophanes can be resolved if a substituent is present which can restrict the
rotation of the aromatic ring about the larger ring. In the following example (A), the
compound can be resolved if n=10 and X=Br.
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O
CO2H
CO2H
H2
C
H2C
(CH2)n
(CH2)n
X
C
H2
O
X
B
A
CH2
C
In compound B, if n=10, then, the compound is resolvable. Mono substituted
[2.2]paracyclophane, C can also be resolved. In all these examples optical activity is due
to the hindered rotation of the benzene ring and hence all these are cases of
atropisomerism.
In trans-cyclooctene chiral plane includes the double bond carbon atoms and the four
atoms attached to the double bond.
Racemisation
The process of converting an optically active compound into the racemic
modification is known as racemisation. Most optically active compounds undergo
racemisation under the influence of light, heat or chemical reagents. Ease of racemisation
and the agent required depends on the nature of the compound. Some compounds
racemise so rapidly that they cannot be isolated in optically active form. Some
compounds can be isolated in optically active form but racemise spontaneously. Most of
the compounds can be racemised by using different reagents. A few compounds cannot
be racemised at all.
Mechanism of racemisation depends on the type of compound undergoing
racemisation. Racemisation of (-)-lactic acid in aq.NaOH takes place through keto-enol
tautomerism.
_
OH
O
H3C
H
O
-
OH
-H+
H3C
O
HO
O
C
_
O
-
H3C
C
H+
_
O
H
O
H3C
OH O
-
(+)
(-)
Resolution
Resolution is the process of separation of a racemic modification into its
enantiomers. Resolution procedures may not give complete resolution. There are several
methods for resolution.
1. Conversion to Diastereomers. This is the best of all methods of resolution. If the
racemic mixture to be resolved contains a carboxyl group it is possible to form a salt with
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an optically active base. Since the base used is, say, the (S) form, there will be a mixture
of two salts produced having the configurations (SS) and (RS). Although the acids are
enantiomers, the salts are diastereomers and have different properties. The property most
often used for separation is differential solubility. Naturally occurring optically active
bases are generally used for the resolution of acids. Among the most commonly used are
brucine, ephedrine, strychnine, and morphine. Once the two diastereomers have been
separated, it is easy to convert the salts back to the free acids and the recovered base can
be used again. Racemic bases can be converted to diastereomeric salts with active acids.
Tartaric acid, camphor-β-sulphonic acid etc are mainly used for this purpose. Alcohols
can be converted to diastereomeric esters and aldehydes to diastereomeric hydrazones.
2. Differential Absorption. When a racemic mixture is placed on a chromatographic
column and if the column consists of chiral substances, then the enantiomers should
move along the column at different rates. Separation has been successfully accomplished
with paper, column, thin-layer and gas and liquid chromatography. For example, racemic
mandelic acid has been almost completely resolved by column chromatography on starch.
3. Chiral Recognition. In some cases it is possible for a host to form an inclusion
compound with one enantiomer of a racemic guest, but not the other. This is called chiral
recognition. One enantiomer fits into the chiral host cavity, the other does not. More
often, both diastereomers are formed, but one forms more rapidly than the other, so that if
the guest is removed it is already partially resolved.
4. Biochemical Processes. Certain bacteria and moulds can destroy one enantiomer of
certain racemic modification more rapidly than the other. For example, Pencillium
Glaucum, a mould, when grown in a solution of racemic ammonium tartrate, attacks the
(+)-form and leaves the (-)-form. This method has certain disadvantages. Dilute solutions
should be used and hence the amount obtained will be low. One form is always destroyed
and the other form is also partially destroyed.
5. Mechanical Separation. This method is applicable only if the enantiomers crystallize
separately. Since the appearances of the two types of crystals are different, they can be
separated. Pasteur separated (+) and (-) isomers of sodium ammonium tartrate in this
manner. This method is limited to a few compounds.
6. Kinetic Resolution. Since enantiomers react with chiral compounds at different rates,
it is sometimes possible to effect a partial separation by stopping the reaction before
completion. For example (-)-menthol reacts more slowly with (-) mandelic acid than with
(+)-mandelic acid. If insufficient (-)-menthol is used for the esterification of racemic
mandelic acid, the ester will contain more (+)-mandelate than (-) mandelate. The
unreacted acid will contain more (-)-mandelic acid than (+)-mandelic acid. Thus partial
resolution of mandelic acid can be achieved.
7. Deracemization. In this type of process, one enantiomer is converted to the other, so
that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one
enantiomer. For this method an outside optically active substance is required. To effect
the deracemization two conditions are necessary: (1) the enantiomers must complex
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differently with the optically active substance; (2) they must interconvert under the
conditions of the experiment. When racemic thioesters were placed in solution with a
specific optically active amide for 28 days, the solution contained 89% of one
enantiomer and 11% of the other.
Stereotopicity
Consider the bromination of propanoic acid to form 2-bromopropanoic acid.
Br2/P
CH3CH2CO2H
CH3CHBrCO2H
The two hydrogen atoms in propanoic acid appear alike. But in this case the two
hydrogens differ in their behaviour towards the reagent. In this reaction the bromine atom
can replace any of the two hydrogen atoms. The two replacements do not produce the
same molecule. Instead, replacement of one hydrogen gives one enantiomer and
replacement of the second hydrogen gives the other enantiomer. The two enantiomers are
formed in equal amounts. The two hydrogen atoms in propanoic acid are called
enatiotopic hydrogens. Two atoms or groups in a molecule are enantiotopic if
replacement of each in turn by some other group lead to a pair of enantiomers. Hydrogen
atoms in propanoic acid are enantiotopic by internal comparison (they are in the same
molecule). Corresponding groups in a pair of enantiomers are enantiotopic by external
comparison (since they are in two different molecules). If separate replacements give the
same molecule the groups are called homotopic.
Consider the bromination of 3-chlorobutanoic acid.
CO2H
CO2H
CO2H
Br2/P
Br2/P
H
Br
H
H
Br
H
H
Cl
CH3
H
Cl
CH3
H
Cl
CH3
In this case the two products are not same, they are not enantiomers either. The products
are diastereomers and they are formed in unequal amounts. The two α-hydrogen atoms in
3-chlorobutanoic acid are called diastereotopic. Two atoms or groups in a molecule are
diastereotopic if replacement of each in turn by some other group leads to a pair of
diastereomers.
Prochirality
If a centre in a molecule bears enantiotopic groups that center is called prochiral
centre. The α-carbon atom in propanoic acid is a prochiral centre. The two enantiotopic
hydrogen atoms in propanoic acid can be designated as pro-S or pro-R hydrogens
depending on whether the replacement of the hydrogen with deuterium gives R or S
isomer.
CO2H
CO2H
CH3
H2
H1
H2
=
D
HO2C
D
two
interchanges
CH3
CH3
H2
(R)9
Thus H1 is pro-R and H2 is pro-S. Prochiral centres on treatment with achiral reagents
gives enantiomers in equal amounts. But on treatment with chiral reagents enantiomers
are formed in unequal amounts.
Faces of double bonds can also be called enantiotopic or prochiral if enantiomers
are produced by addition reactions. The two faces of acetaldehyde are enatiotopic. Attack
of phenyl magnesium bromide from one side gives one enantiomer while attack from the
other side gives the second enantiomer.
OH
CH3
H
Ph
PhMgBr
+
H
CH3
C
H
CH
3
Ph
OH
O
Prochiral faces of double bonds can be designated as si or re according to whether the
three groups makes a right handed pattern (re-face) or left handed pattern (si-face)
H
H3C
CH3
H
C
C
O
O
si-face
re-face
This rule can be applied to ethylenic double bonds also. Each end of the double bond
should be treated separately.
HO2C
CO2H
H
H
C
C
C
C
H
CO H
H
HO C
2
2
re-si
si-re
maleic acid
H
HO2C
CO2H
C
C
C
C
CO2H
H
H
HO2C
H
si-si
re-re
fumaric acid
Enantiomeric Excess
Enantiomeric excess (ee) is the percent excess of an enantiomer over the racemate
in a mixture of the enantiomer and racemate.
RS
ee =
100 = %R or %S
RS
10
In this equation, R and S represent the quantity of the isomers R and S and R+S is the
total quantity. The term enantiomeric excess is widely applied in enantiselective reactions
in order to give the enatiomeric purity of the product.
Non Carbon Chiral Centres
Any molecule containing an atom that has four bonds pointing to the corners of a
tetrahedron will be optically active if the four groups are different. Among atoms in this
category are Si, Ge, Sn and N (in quaternary salts or N-oxides). In sulfones, the sulfur
bonds with a tetrahedral array, but since two of the groups are always oxygen, no
chirality normally results. However, if one oxygen is 16O and the other 18O then the
sulfone can be optically active Optically active chiral phosphates in which two isotopes
of oxygen are present have also been made.
Atoms with pyramidal bonding might be expected to give rise to optical activity if
the atom is connected to three different groups, since the unshared pair of electrons is
analogous to a fourth group. For example, a secondary or tertiary amine where X, Y, and
Z are different would be expected to be chiral and thus resolvable. Many attempts have
been made to resolve such compounds, but until 1968 all of them failed because of
pyramidal inversion, which is a rapid oscillation of the unshared pair from one side of the
XYZ plane to the other, thus converting the molecule into its enantiomer.For ammonia,
there are 2 X1011 inversions every second. The inversion is less rapid in substituted
ammonia derivatives (amines, amides, etc.). Two types of nitrogen atom invert
particularly slowly, namely, a nitrogen atom in a three-membered ring and a nitrogen
atom connected to another atom bearing an unshared pair. Even in such compounds
pyramidal inversion is rapid. Optically active compounds could be prepared only when
both features were combined. For example the enantiomers of 1-chloro-2-methylaziridine
were separated.
In molecules in which the nitrogen atom is at a bridgehead, pyramidal inversion is
course prevented. Such molecules, if chiral, can be resolved. For example, Troger’s base
is optically active.
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Phosphorus inverts more slowly and arsenic still more slowly. Nonbridgehead
phosphorus, arsenic, and antimony compounds have also been resolved. Sulfur exhibits
pyramidal bonding in sulfoxides, sulfinic esters, sulfonium salts, and sulfites. Many
optically active compounds of these types are known.
The Cause of Optical Activity
The reason why a chiral molecule rotates the plane of plane polarized light is
explained below. Whenever any light hits any molecule in a transparent material, the
light is slowed because of interaction with the molecule. This is responsible for the
refraction of light and the decrease in velocity is proportional to the refractive index of
the material. The extent of interaction depends on the polarizability of the molecule.
Plane-polarized light may be regarded as being made up of two kinds of circularly
polarized light. Circularly polarized light has the appearance of a helix propagating
around the axis of light motion, and one kind is a left- and the other is a right-handed
helix. As long as the plane-polarized light is passing through a symmetrical region, the
two circularly polarized components travel at the same speed. However, a chiral molecule
has a different polarizability depending on whether it is approached from the left or the
right. One circularly polarized component on approaching the molecule sees a different
polarizability (hence a different refractive index) than the other and is slowed to a
different extent. This would seem to mean that the left- and right-handed circularly
polarized components travel at different velocities, since each has been slowed to a
different extent. However, it is not possible for two components of the same light to be
traveling at different velocities. Actually the faster component ‘‘pulls’’ the other towards
it, resulting in rotation of the plane.
In liquids and gases, the molecules are randomly oriented. An optically inactive
molecule which has a plane of symmetry will show no optical rotation when the plane of
the polarized light coincides with the plane of symmetry. But all other orientations rotate
the plane, even though the molecules are achiral. There is no net rotation because, there
will always be another molecule later on in the path of the light that is oriented exactly
opposite and will rotate the plane back again. Even although nearly all molecules rotate
the plane individually, the total rotation is zero. For chiral molecules, however (if there is
no racemic mixture), no opposite orientation is present and there is a net rotation.
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Dependence of Rotation on Conditions of Measurement
The amount of rotation α is not a constant for a given enantiomer; it depends on the
length of the sample vessel, the temperature, the solvent and concentration (for
solutions), the pressure (for gases), and the wavelength of light. The length of the vessel
and the concentration or pressure determine the number of molecules in the path of the
beam and a is linear with this. Therefore, a number is defined, called the specific rotation
[α], which is
where α is the observed rotation, l is the cell length in decimeters, c is the concentration
in grams per milliliter, and d is the density in the same units. The specific rotation is
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usually given along with the temperature and wavelength, in this manner: [α] 546
. The
expression [α]D means that the rotation was measured with sodium D light; that is, λ =
589 nm. The molar rotation [M] t is the specific rotation times the molecular weight
divided by 100.
Chiroptical Properties
Chiroptical properties are properties of chiral compounds which arise as a result
of their non-destructive interaction with anisotropic radiation (polarized light). These
properties can differentiate the two enantiomers of a chiral compound. Optical activity,
optical rotatory dispersion (ORD), circular dichroism (CD) etc. are examples for
chiroptical properties.
Optical Rotatory Dispersion (ORD)
The measurement of optical rotation as a function of wavelength is called optical
rotatory dispersion. ORD measurements are valuable only for chiral compounds. ORD
arises because of the different refractive indices of the left and right circularly polarized
light in a chiral compound. The value of specific rotation increases as the wavelength
decreases. In order to get valuable information optical rotation should be measured
around the region of absorption band. The most widely studied compounds are those
containing carbonyl chromophores. There are three types of ORD curves, plane curves,
single cotton effect curves and multiple cotton effect curves.
Plane Curves: They are smooth curves; they do not contain maximum and minimum.
Plane curves do not cross the zero rotation line. They are either positive or negative.
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Single Cotton Effect Curves: Cotton effect (C.E.) is the manifestation of the refraction
in ORD or the absorption in CD in the vicinity of UV-visible absorption band. In ORD a
peak followed by a null followed by a trough or the reverse represents a cotton effect
curve. If peak occurs in the longer wave length region the curve is positive and if the
trough occurs in the longer wave length region the curve is negative. The vertical
distance between the peak and trough is called the amplitude and the horizontal distance
is called the breadth of the C.E. curve.
C.E. curves of enantiomers are mirror images of each other. In order t o show
cotton effect the chromophore should be chiral or it should be in a chiral environment.
Multiple Cotton effect Curves: These are complicated curves resulting from electronic
transitions of several chromophores.
Circular Dichroism
Chiral substance show differential absorption of circularly polarized lights. This is
called circular dichroism. Circular dichroism arises because the molar absorptivities of
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left and right circularly polarized light (εL and εR) are different for a chiral compound. If
εL > εR,,then CD is said to be positive and if εL < εR CD is negative. For a given
compound ORD and CD curves have the same sign. CD curve is also a cotton effect
curve.
CD spectra are simpler to interpret compared to ORD. In CD spectra bands are well
separated and the comparison with electronic absorption band is easier compared to
ORD. In many cases ORD curves are masked by back ground effects. This is not a
problem with CD. Therefore CD is preferred over ORD in many cases. However ORD
can be observed over entire wave length range whereas CD is observable only near an
electronic absorption.
Applications of ORD and CD
Plane ORD curves are useful for determining whether a sample is optically active
or racemic. Normal optical rotation is usually measured at longer wave length and hence
undetectable in many cases. If a sample shows zero rotation over a wave length range it
will be surely racemic.
Cotton effect curves (CD and ORD) can be used for locating the position of
absorption. It can also be used for determining the position of a functional group in a
molecule. Cotton effect curves can be used to determine the configurations of
compounds. ORD and CD curves of a sample can be compared with those of known
compounds to determine the configuration. Since cotton effect curves are affected by
conformational changes, it can be used for determining the conformer population of a
chiral compound. Cotton effect curves can give important information about the
secondary structures of polypeptides, proteins and nucleotides. It is to be noted that any
two of the three structural components, constitution, configuration and conformation
should be known in order to assign the third from ORD or CD. Also in order to predict
ORD or CD all the three structural components should be known.
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Axial Haloketone Rule
Axial haloketone rule is a generalization established as a result of the ORD
studies of cyclohexanone derivatives. ORD studies have shown that equatorial α-halogen
substituents have little effect on ORD curves. However axial α-halogen atoms cause
bathochromic shift increases the amplitude of ORD and may invert the sign of CE. The
axial haloketone rule can be stated as follows. When a halogen atom is introduced in the
α-equatorial position of a cyclohexanone then there will be no change in the sign of ORD
curve. But if halogen atom is introduced in the α-axial position, the sign may be affected.
The sign of the curve may be predicted by viewing the α-halogenocyclohexanone along
the O=C bond as shown below. If the halogen is on the left of the observer, there will be
a negative curve and if it is on the right, there will be positive curve.
O
O
X
+CE
X
O
X
O
-CE
X
An application of the rule is given below. Chlorination of (R)-(+)-3methylcyclohexanone gives 2-chloro-5-methyl derivative which shows a negative CE in
octane. The constitution of the product and the axial position of the halogen have been
established. The negative CE shows that the compound has a trans arrangement. But in
methanol a positive CE is observed. In polar methanol the diaxial conformer changes to
the diequatorial conformer which has higher dipole moment. The cis isomer should show
only +ve CE.
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O
CH3
Cl
CH3
O
Cl
-CE in octane
O
CH3
+CE in methanol
trans
O
CH3
O Cl
CH3
Cl
+CE
cis
+CE
Octant Rule
Octant rule relates the sign of the ORD curve with the configuration or
conformation of a keto steroid. The rule is applied as follows. The region of the keto
group is divided into eight octants by three mutually perpendicular planes. The C=O
double bond is made the x-axis with the origin at the mid-point of the bond. The y-and zaxes are also drawn along the origin. The observer views the molecule along the x-axis
from the positive side. The planes xy, xz and yz divide the region of the keto group into
eight octants. So there are four back octants and four front octants.
The sign of octant is the sign of the product of the coordinates x, y and z. Signs of the
back octants are shown below.
17
upper right
upper left
_
+
lower right
lower left
_
+
Signs of back octants
According to octant rule atoms lying in the back upper left and back lower right
octants make positive contributions to ORD while atoms in back lower left and back
upper right make negative contributions. Atoms lying in any of the three planes make no
contributions. Hydrogen atoms are generally ignored. Equatorial substituents on α-carbon
atoms (carbon atoms 2 and 6) make no contributions because they lie in the xy-plane.
Carbon-4 lies in the xz-plane and carbon-2 and carbon-6 lie in the xy plane. So
contributions from these atoms are zero. Generally contributions of C3 and C5 cancel one
another. Substituents on C4 also lie in xz-plane and do not make any contribution.
Therefore only axial substituents on C2 and C6 and substituents on C3 and C5 make
contributions to the sign of ORD. The contribution of an atom to the sign of the ORD
curve is the sign of the products of its co-ordinates. The projection of cyclohexanone with
equatorial and axial substituents is given below.
a
a
e
5
e
3
e
2
a
e
4
6
e
1
a
a
Fluorine shows opposite behaviour, because fluorine has the lowest atomic
refraction.
(+)-3-methylcyclohaxanone shows a positive CE. In this molecule contribution to
the sign of ORD is only from the methyl group. Since the configuration is R, octant rule
predicts equatorial conformation and this is actually the case.
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3
4
3
5
4
6
2
5
6
1
2
1
Axial
ORD should be negative
Equatorial
ORD should be positive
Conformations of R(+)-3-methylcyclohexanone. The actual
conformation should be equatorial since the observed ORD
is positive.
Thus if we know the sign of the ORD curve, the conformation can be elucidated.
Since the equatorial conformation is the preferred one in most of the cases, octant rule
can be used for predicting the sign of ORD. Octant rule is qualitative. It is based on the
assumption that contributions of atom are same irrespective of their positions with respect
to the keto group. In some cases these assumptions do not apply. In general the farther is
the atom from the keto group; the smaller is its contribution to the sign of the ORD curve.
Conformational Analysis
If two different 3D arrangements in space of the atoms in a molecule are
interconvertible by free rotation about bonds, they are called conformations. If they are
not interconvertible, they are called configurations. Configurations represent isomers that
can be separated. Conformations represent conformers, which are rapidly interconvertible
and thus cannot be separated.
Conformations of Ethane
For ethane there are two extreme conformations, i.e. conformations having
highest and lowest energy. Those are shown below.
For ethane the staggered conformation has the lowest potential energy and the
eclipsed conformation has the highest potential energy. The difference in energy between
the two forms is 12 kJmol-1. At ordinary temperatures, enough rotational energy is
present for the ethane molecule rapidly to rotate, although it still spends most of its time
at or near the energy minimum.
19
Conformational energy diagram for ethane.
Conformations of Butane
For 1,2-disubstituted ethanes, for example, n-butane, there are four extreme
conformations. These are (i) a fully staggered conformation called anti, trans or
antiperiplanar, (ii) another staggred conformation called gauche, (iii) a fully eclipsed
conformation called synperiplanar and a partially eclipsed conformation.
Anti conformation is the most stable conformation for n-butane and the energy
difference between anti and gauche conformations is 3.8 kJmol-1. Eclipsed conformations
are less stable compared to staggered conformations. The fully eclipsed conformation is
the least stable. The energy difference between fully eclipsed and anti conformations is
17-25 kJmol-1.
20
In 1,2-disubstituted compounds the molecules generally adopts anti and gauche
conformations. For example in 1,2-dichloroethane in CCl4, approximately 70% of the
molecules are in anti conformation and around 30% of the molecules are in gauche
conformation. For 1,2-dibromoethane the approximate percentages of anti and gauche
conformations are 89% and 11% respectively. The eclipsed conformations are
unpopulated and are pathways for the change from one staggered conformation to
another.
In most molecules of the type YCH2-CH2Y and YCH2-CH2X the anti
conformation is the preferred conformation, but there are several exceptions. For
example, molecules containing small electronegative atoms generally prefer gauche
conformation. This is known as gauche effect, i.e. the tendency to adopt the structure
which has the maximum gauche interactions between adjacent polar bonds. Thus
molecules like 2-fluoroethanol and 1,2-difluoroethane prefer gauche conformation. In
ethylene glycol gauche conformation is preferred. This is not only due to gauche effect
but also due to hydrogen bonding between oxygen atoms on adjacent carbon atoms.
Conformational Analysis of Cycloalkanes
Cyclohexane
The most stable conformation of cyclohexane is the chair conformation.
Two other important conformations of cyclohexane are the boat and the twist
conformations. These are less stable than chair conformation. The chair form is more
stable than the twist form by about 21 kJmol-1. The twist form is more stable than the
boat by about 6.3 kJmol-1 because the twist form has less eclipsing interactions. The twist
and boat conformations are more flexible than chair but are destabilized by torsional
strain. Boat form is destabilized also due to the interaction between flagpole hydrogens.
21
In the chair form six bonds are different from the other six. The up and down
bonds are called axial and the others are called equatorial. At room temperature one
cyclohexane chair conformation rapidly interconvert to another chair conformation. This
interconversion is known as ring flip or ring inversion. During this interconversion all the
axial bonds become equatorial and vice versa. Interconversion from one chair form to
another is possible only through boat form and twist form.
Ring inversion in cyclohexane
In substituted cyclohexanes most of the compounds exist in chair conformation. But in
certain bicyclic compounds the cyclohexane ring is forced to adopt a boat or a twist
conformation.
In mono-substituted cyclohexanes, the substituent normally prefers the equatorial
position because in the axial position there is interaction between the substituent and the
axial hydrogens in the 3 and 5 positions. This interaction is known as 1,3-diaxial
interaction. Alkyl groups have a greater preference for the equatorial position than polar
groups. For alkyl groups, the preference increases with size, although size seems to be
unimportant for polar groups.
In disubstituted compounds, the most stable conformation will have as many
groups as possible in the equatorial position. In a cis-1,2-disubstituted cyclohexane, one
substituent must be axial and the other equatorial. In a trans-1,2 compound both may be
equatorial or both axial. Generally trans isomer (ee) is more stable than the cis-isomer.
The relative stability is in the order, trans-ee > cis >trans-aa. Between the two cis
isomers, the more stable isomer will have the bulky substituent in the equatorial position.
22
This is also true for 1,4-disubstituted cyclohexanes, but the reverse holds for 1,3
compounds: the trans isomer must have the ae conformation and the cis isomer may be aa
or ee. For alkyl groups, the ee conformation predominates over the aa, but for other
groups this is not necessarily so. For example, both trans-1,4-dibromocyclohexane and
the corresponding dichloro compound have the ee and aa conformations about equally
populated and most trans-1,2-dihalocyclohexanes exist predominantly in the aa
conformation. In such cases the two halogen atoms are anti in the aa conformation, but
gauche in the ee conformation.
Ring inversion is slow in substituted cyclohexanes. Certain substituents slow
down ring flip considerably, for example tertiary-butyl group. In polysubstituted
cyclohexanes, if t-butyl group is present, it will always occupy an equatorial position. In
most of the polysubstituted compounds, the bulky group occupies equatorial position.
The relative sizes of various substituents are given below. Conformations of a few
substituted cyclohexanes are described below.
(a) 1,2-dimethyl cyclohexane:- The cis isomer will have ae arrangement and the trans
isomer can have ee or aa conformation. Among the three, trans-ee is the most stable. Ring
inversion of this conformation gives trans-aa which is the least stable. The cis isomer is
intermediate in stability.
trans-ee
trans-aa
cis (both conformations are equivalent)
(b) 3-methylcyclohexanol:- The cis-ee conformation is the most stable one and the cis-aa
is the least stable. Trans isomer is intermediate in stability. Among the trans isomers, the
isomer with bulky methyl group in the equatorial position is more stable than the other.
The stability order is shown below.
HO
HO
OH
OH
trans
cis-aa
trans
(c) Cyclohexane-1,3-diol:- In this case between the two cis-isomers, the diaxial isomer is
more stable than the diequatorial isomer because of intramolecular hydrogen bonding.
cis-ee
O
O
H
(d) 3-substituted cyclohexanones:- In 3-substituted cyclohexanones, the axial position is
more stable than that in cyclohexane because in cyclohexanones, axial hydrogen is absent
23
at 1-position. Therefore, there is only one 1,3-diaxial interaction for an axial substituent
in the 3-position. This effect is known as 3-alkylketone effect.
X
H O
(f) 2-bromocyclohexanone:- In this compound axial bromo conformation is favoured. In
this compound both C-Br and C=O bonds are strongly polar. When the bromine atom is
equatorial dipolar repulsion is maximum and when bromine is axial dipolar repulsion is
minimum. The dipolar repulsion is larger than 1,3-diaxial interactions and hence the
conformation with bromine in the equatorial position is favoured.
(g) Cyclohexane-1,4-diol:- This compound exists in twist boat conformation because
intramolecular hydrogen bonding is possible in this conformation and it is not possible
with chair form.
H
O
H
O
(h) Cyclohexane-1,4-dione:- This compound shows a dipole moment. Since for the chair
form, dipole moment is zero, the conformation should be something else. The actual
conformation is a twist (twist boat) conformation.
O
O
Decalin (bicyclo[4.4.0]decane)
Two isomers are possible for decalin, cis and trans. Trans isomer is more stable
by about 10.05 kJmol-1. Decalins can be regarded as 1,2-disubstituted cyclohexanes, then
the trans form is ee form and the cis isomer is ae form. The cis isomer has three gauchebutane interactions which are not present in the trans form.
Trans decalin is rigid and incapable of ring inversion. But cis form is
conformationally mobile and undergoes ring inversion readily. Trans decalin gives two
24
NMR peaks, one due to axial hydrogens and the other due to equatorial hydrogens. But
cis-decalin shows only one NMR peak because ring inversion interchanges axial and
equatorial positions.
Since cis-decalin has two possible conformations (because of ring inversion),
There are four possible conformations for cis-2-decalol.
H
H
H
H
HH
OH
OH
1a
H
1b
H
HHO
H
OH
H
H
2b
2a
Since an equatorial position is favoured, 1a and 2b are more stable than the other
two.
Trans decalin has only one stable conformation. Therefore trans-2-decalol has
only two possible conformations, i.e. the OH group can be either equatorial or axial. The
equatorial conformation is the more stable one. These two conformations are not
interconvertible.
H
H
OH
H
H
OH
H
H
Asymmetric Synthesis
The preparation of a chiral compound in the form of a single enantiomer or a
diastereomer is termed as asymmetric synthesis. In asymmetric synthesis during the
creation of the asymmetric centre, the two isomers are formed in unequal amounts. There
are several methods for achieving asymmetric synthesis.
(i) By using an active Substrate:- If a new chiral center is created in a molecule that is
already optically active, the two diastereomers are not formed in equal amounts. An
example is shown below.
In this reaction according to Cram’s rule 3 will be formed in larger amounts.
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(ii) By using an active reagent:- A pair of enantiomers can be separated by using an
optically active reagent which reacts faster with one enantiomer than the other. In certain
case compounds containing no chiral centres can also be converted to an optically active
compound. An example is shown below.
(iii) By using optically active catalyst or solvent:- Ketones and substituted alkenes can
be converted to optically active secondary alcohols and alkanes by treatment with
hydrogen and chiral homogeneous catalysts. Several other examples are also known.
Similarly asymmetric synthesis can be achieved by using chiral solvents also.
(iv) By reactions in the presence of circularly polarized light:- If in photochemical
reactions, circularly polarized light is used one enantiomer should be formed in more
quantities than the other. But this could not be achieved so far. In certain cases use of left
and right circularly polarized light has given enantiomers in unequal amounts. But the
optical purity has always been very less.
E-Z Nomenclature for Geometrical Isomers
According to the E-Z nomenclature the groups at both doubly bonded carbon
atom are arranged according to the sequence rule. If the higher priority groups are on the
same side that isomer is called Z-isomer and if the higher priority groups are on the
opposite side that isomer is called E-isomer. Some examples are given below.
26