Académique Documents
Professionnel Documents
Culture Documents
e2
The position of the halogen was obser(ed to influence the sign of the Cotton *ffect
and similar effects were found for other substituents, such as 3#
4
, S#, SO
4
#, etc.
I! 2as s,--(s!(+ !$a! '%(+i!i"# "f !$( si-# "f !$( C"!!"# Eff(! is '"ssi)l( if
!$( 0(!"#( -%",' is *i(2(+ al"#- !$( O6C )"#+ i# !$( +i%(!i"# "f !$( %i#-
2i!$ !$( a%)"#3l a%)"# a! !$( $(a+ "f !$( $ai% (!$( &a7"% "#f"%&(% i#
3l"$(.a#( %i#- s3s!(&s)/ If !$( a.ial 8$al"-(# is f",#+ "# !$( %i-$! (as i#
3
!$( (S)4(#a#!i"&(%)1 !$(# !$(%( (.is!s a '"si!i*( C"!!"# Eff(!9 if i! a''(a%s "#
!$( l(f!1 a #(-a!i*( C"!!"# (ff(! is ")s(%*(+1 as s$"2# )(l"2/
The following e!amples illustrate applications of the a!ial haloketone rule in structure
determination.
1. !etermination of "osition of Halo#en Su$stitution %Constitution&
'n the e!ample below, a negati(e Cotton *ffect is seen upon bromination of the
cyclic fused ring ketone. Therefore, substitution must ha(e occurred predominantly
at the 5 position. The a!ial nature of bromine atom in the product was deduced from
'# spectroscopy.
C6
%
O
6O
4
C
6O
4
C
6 6
C6
%
C
7
6
$8
9r 9r
Substitution by 9r gi(es
&C* at 5 and :C* at 8
5
8
4
2. !etermination of A$solute Confi#uration
The configuration of the $$&bromo&$4&ketosteroid product from the bromination of
the parent $4&ketosteroid was deduced to be R" from the obser(ation of a negati(e
Cotton *ffect.
CO
4
C6
%
C6
%
C6
%
9r
O
+cO
$$
$$&&9r e2uatorial" gi(es :C* as in the parent ketone"
$$&&9r a!ial" gi(es &C*
'. !emonstration of conformational mo$ility
On chlorination of R"&:"&%&methylcyclohe!anone, a crystalline 4&chloro&5&methyl
product is isolated that shows a negati(e Cotton *ffect in octane, but a positi(e one
in methanol. The negati(e C* is consistent only with trans stereochemistry, with
independent e(idence for a!ial Cl in octane".
5
The change in sign of the C* on changing the sol(ent to more polar" methanol is
presumably a reflection of the greater stability of the e2uatorial conformer in that
sol(ent.
(. !emonstration of the existence of a $oat conformer
Of the 4& and 4&bromo isomers of 4&bromo&4&methylcholestane&%&one, with
a!ial 9r established by '# spectroscopy" the latter displays a positi(e C* as
e!pected. The 4&bromo isomer une!pectedly shows a negati(e C*. This is best
e!plained by supposing the boat conformer is significant in ring + of this isomer,
because of steric hindrance between the a!ial" methyl groups in the chair
conformer.
The Octant Rule
The a!ial haloketone rule is a special case of the octant rule for saturated ketones.
+ 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 a!is collinear with the bond,
as shown below. The coordinate system di(ides the space around the carbonyl
6
group into 7 sectors or octants diagram a"". The effect on the C* associated with
the n&) transition of the carbonyl group is gi(en 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 ha(e coordinates 1!, :y, &z and so would gi(e a positi(e C*.
Substituents located on or near nodal planes make no contribution to the Cotton
*ffect.
The octant rule was first applied to fused cyclohe!anone ring systems, such as
those in steroids, because of their conformational rigidity. The cyclohe!anone
skeleton is placed in the coordinate system as shown below, with the 4 and ;
carbon atoms in the yz plane and the carbonyl at the head of the chair diagram
7
a"".
Diagram b" shows the pro<ection of the (iew along O=C with the signs of the rear
octants. Contributions from hydrogens in the simple cyclohe!anone skeleton are
usually ignored, being assumed to more or less cancel. Substituents at position =
will ha(e no effect on the C*, since either e2uatorial or a!ial groups here in the
nodal !z plane. >ikewise, e2uatorial groups at positions 4 and ; will make only
small contributions to the C*, because of their pro!imity to the yz plane.
The working of the octant rule is illustrated by the following e!amples.
1. !etermination of preferred conformation of a cyclohexanone of kno)n
confi#uration
The compound R"&:"&%&methylcyclohe!anone e!hibits a positi(e Cotton *ffect.
+pplication of the octant rule to the pro<ections of the e2uatorial and a!ial
conformations below" indicate clearly that the preferred conformer is the
e2uatorial one.
8
% %
%
3
3
C6
%
:
?
?
:
:
?
?
:
C6
%
a!"
(a.)
((:)
CH
3
O
C6
%
O
CH
3
O
2. *stimation of the +a#nitude of C* in etosteroids
.hen applying the octant rule to ketosteroids, the sector with most carbons in it
will make the biggest contribution to the sign of the Cotton *ffect. 6ence, the
octant rule can be used to estimate the relati(e magnitudes of the C* for isomeric
$&, 4& and %&cholestanones. The three isomers and their octant rule pro<ections are
shown below, where it can be seen that for the $&keto isomer, the balance of
carbons in negati(e sectors is greater, indicating a moderate negati(e C*. The 4&
keto isomer pro<ection shows a ma<ority of carbons in the : sector indicating a
large positi(e C*, whereas that of the %&keto isomer has a small ma<ority of
carbons in the : sector and many on the !z plane, contributing zero", suggesting a
(ery small positi(e Cotton *ffect.
9
O
C6
%
C6
%
C
7
6
$8
+ 9
C D
D C
9 +
C6
%
C
7
6
$8
C6
%
O
D C
9 +
C6
%
C
7
6
$8
C6
%
O
:
?
?
:
+ 9
C D
C* small &(e
$&Cholestanone
4&Cholestanone
%&Cholestanone
+
C6
%
9
D
C
C6
%
C* large :(e
:
:
?
?
D
C
9
+
:
?
?
:
;
8
$5, $;
C* medium :(e
front octant"
$ 4
%
=
5
;
8
$5 $;
The CD spectra of $& and %&cholestanone are in agreement with this prediction, as
can be seen below. The positi(e" CD spectrum of 4&cholestanone would be off&
scale.
10
11