CH437 CLASS 22

CHIROPTICAL METHODS FOR THE DETERMINATION OF ORGANIC

STRUCTURES: CIRCULAR DICHROISM (CD) AND OPTICAL ROTATORY
DISPERSION (ORD)

Synopsis. Classification of chromophores in chiral molecules. Application of CD to structure

determination. Semiempirical sector and helicity rules. The Octant rule.

Classification of Chromophores

The chromophores that can be analyzed by CD measurement fall into two broad
categories, on the basis of symmetry considerations.

1. Chromophores that are Inherently Achiral

These include carbonyl groups, simple alkene C=C bonds and S=O (sulfoxide)
groups.
Cotton effects are observed here because of chiral perturbations in the
chromophore during excitation.
These perturbations come from chirality centers located close to the chromophore or
from the molecular skeleton. Rotational strengths R of inherently achiral
chromophores tend to be low.

2. Chromophores that are Inherently Chiral

These include molecules like helicenes, where the whole molecule acts as a
chiral chromophore.
Other examples are biaryls, cyclic 1,3-dienes, twisted alkenes, enones and cyclic
disulfides. In each case, chirality is built into the chromophore. Rotational strengths
of inherently chiral chromophores tend to be very high.
The fact CD spectra can be observed at all for n* transitions and *
transitions, that lack electric transition moments () and magnetic transition
moments (m) (respectively) can be explained in several ways, but essentially
perturbation or mixing of transitions causes and m to have finite (but small) values.
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Application of CD to Structure Determination

The most important aspect of a CD curve is the sign of the Cotton Effect. Apart from
numerous assessments of the sign and magnitude of the Cotton Effect for particular
chromophores, using mostly MO-based theory, many applications use one of many
semiempirical rules: sector rules for achiral chromophores and helicity rules for
chiral chromophores. These are summarized below.

Rule type Applications

Sector Saturated ketones (the axial

haloketone and octant rules),
Non-distorted alkenes, allenes,
carboxylic acids, benzoates.
Helicity Twisted cycloalkenes, skewed
cyclanones, enones, helicenes,
biaryls.

Sector Rules for Achiral Chromophores

Whenever chiroptic atoms or groups are present in a molecule containing an achiral

chromophore, perturbation of the electronic transitions of the chromophore will be
sufficient to generate chiroptical properties (i.e. a Cotton Effect). The name sector
rule stems from the division of 3D space surrounding symmetric chromophores into
sectors by nodal or symmetry planes as well as by nodal surfaces. Such rules are
designed to assess the contributions of perturbing groups to the sign of the Cotton
Effect according to their positions in one or another sector that surrounds the
chromophore. Thus, the sign of the Cotton Effect depends on several factors,
including the nature of substituents, configuration and conformation. In general, any
two of three structural descriptors constitution, configuration and conformation
must be known if the third is to be deduced from chiroptical spectra (CD or ORD).
Therefore, in general, for chiral molecules having torsional degrees of freedom (free

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rotation), it is not possible to acquire information on both configuration and
conformation simultaneously from chiroptical spectra. This is why much work in this
area has been concentrated on cyclic systems, often fused systems, as torsional
isomerism is limited in these molecules.
Sector rules are widely used in the assignment of configuration by inspection of CD
spectra of homologous and analogous compounds that have an identical
chromophore. It is essential to know the nature of the transition in each case, since
only comparable transitions can be treated in such a way. It is also necessary to
know the transition symmetry properties of the chromophore and what effect
structural features have upon the strength of the CD band.

The Axial Haloketone Rule and the Octant Rule for Saturated Ketones

The octant rule is the most widely applied sector rule. It was developed from an
earlier rule, known as the axial haloketone rule, based on ORD measurements
carried out on steroidal ketones that had been (axially) substituted with a halogen
atom at the -carbon. Axial substitution (conformation) is often preferred because of
the dipole-dipole repulsions in the equatorial isomer:

O O

Cl
ax eq
Cl

The position of the halogen was observed to influence the sign of the Cotton Effect
and similar effects were found for other substituents, such as NR 2, SR, SO2R, etc.
It was suggested that prediction of the sign of the Cotton Effect is possible if
the ketone group is viewed along the O=C bond in the direction of the ring
with the carbonyl carbon at the head of the chair (the major conformer in
cyclohexane ring systems). If the axial halogen is found on the right (as in

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the (S)-enantiomer), then there exists a positive Cotton Effect; if it appears on
the left, a negative Cotton effect is observed, as shown below.

The following examples illustrate applications of the axial haloketone rule in structure
determination.

1. Determination of Position of Halogen Substitution (Constitution)

In the example below, a negative Cotton Effect is seen upon bromination of the
cyclic fused ring ketone. Therefore, substitution must have occurred predominantly
at the 5 position. The axial nature of bromine atom in the product was deduced from
IR spectroscopy.

CH3
CH3 C8H17
HO2C
5 7
HO2C
O
H H

Br Br
Substitution by Br gives
-CE at 5 and +CE at 7

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2. Determination of Absolute Configuration

The configuration of the 11-bromo-12-ketosteroid product from the bromination of

the parent 12-ketosteroid was deduced to be (R) from the observation of a negative
Cotton Effect.

O
CH3
Br CO2CH3

CH3 11

AcO

11--Br (equatorial) gives +CE (as in the parent ketone)

11--Br (axial) gives -CE

3. Demonstration of conformational mobility

On chlorination of (R)-(+)-3-methylcyclohexanone, a crystalline 2-chloro-5-methyl

product is isolated that shows a negative Cotton Effect in octane, but a positive one
in methanol. The negative CE is consistent only with trans stereochemistry, with
independent evidence for axial Cl (in octane).

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The change in sign of the CE on changing the solvent to (more polar) methanol is
presumably a reflection of the greater stability of the equatorial conformer in that
solvent.

4. Demonstration of the existence of a boat conformer

Of the 2- and 2-bromo isomers of 2-bromo-2-methylcholestane-3-one, (with

axial Br established by IR spectroscopy) the latter displays a positive CE as

expected. The 2-bromo isomer unexpectedly shows a negative CE. This is best
explained by supposing the boat conformer is significant in ring A of this isomer,
because of steric hindrance between the (axial) methyl groups in the chair
conformer.

The Octant Rule

The axial haloketone rule is a special case of the octant rule for saturated ketones.
A set of left-handed Cartesian coordinates is drawn through the carbonyl group
with its origin at the center of the bond and with the z axis collinear with the bond,
as shown below. The coordinate system divides the space around the carbonyl
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group into 8 sectors or octants (diagram (a)). The effect on the CE associated with
the n-* transition of the carbonyl group is given by the position of a substituent (as
a product of its coordinates) in these segments (in practice, the rear segments are
more important). Thus, a substituent in the bottom right rear sector (diagram (b))
would have coordinates x, +y, -z and so would give a positive CE.

Substituents located on or near nodal planes make no contribution to the Cotton

Effect.
The octant rule was first applied to fused cyclohexanone ring systems, such as
those in steroids, because of their conformational rigidity. The cyclohexanone
skeleton is placed in the coordinate system as shown below, with the 2 and 6
carbon atoms in the yz plane and the carbonyl at the head of the chair (diagram

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(a)).

Diagram (b) shows the projection of the view along O=C with the signs of the rear
octants. Contributions from hydrogens in the simple cyclohexanone skeleton are
usually ignored, being assumed to more or less cancel. Substituents at position 4
will have no effect on the CE, since either equatorial or axial groups here in the
nodal xz plane. Likewise, equatorial groups at positions 2 and 6 will make only
small contributions to the CE, because of their proximity to the yz plane.
The working of the octant rule is illustrated by the following examples.

1. Determination of preferred conformation of a cyclohexanone of known

configuration

The compound (R)-(+)-3-methylcyclohexanone exhibits a positive Cotton Effect.

Application of the octant rule to the projections of the equatorial and axial
conformations (below) indicate clearly that the preferred conformer is the
equatorial one.

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 CH3 (eq)
3 (ax)
3
CH3
CH3 3
(ax)
O O

_ CH
+ _ 3
+
CH3
3 3

_ + _ +

2. Estimation of the Magnitude of CE in Ketosteroids

When applying the octant rule to ketosteroids, the sector with most carbons in it
will make the biggest contribution to the sign of the Cotton Effect. Hence, the
octant rule can be used to estimate the relative magnitudes of the CE for isomeric
1-, 2- and 3-cholestanones. The three isomers and their octant rule projections are
shown below, where it can be seen that for the 1-keto isomer, the balance of
carbons in negative sectors is greater, indicating a moderate negative CE. The 2-
keto isomer projection shows a majority of carbons in the + sector indicating a
large positive CE, whereas that of the 3-keto isomer has a small majority of
carbons in the + sector (and many on the xz plane, contributing zero), suggesting a
very small positive Cotton Effect.

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 CH3 _
+
CH3 C8H17
O
2 1 C D A B
A B 15 16
3 4 6 C D
5 7 _ +
1-Cholestanone (front octant)
CE small -ve

CH3
CH3 C8H17
O + _
C D CH3D
A B B
C CH3

2-Cholestanone A

_
+

CH3 CE large +ve

CH3 C8H17
C D
A B 15, 16
_
+ D
O
C
3-Cholestanone 7
B
6
A
CE medium +ve
_ +
The CD spectra of 1- and 3-cholestanone are in agreement with this prediction, as
can be seen below. The (positive) CD spectrum of 2-cholestanone would be off-
scale.

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