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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.

Classifi a!i"# "f C$%"&"'$"%(s 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 sulfo!ide" groups. C"!!"# (ff( !s a%( ")s(%*(+ $(%( )( a,s( "f $%"&"'$"%( +,%i#- (. i!a!i"#/ These perturbations come from chirality centers located close to the chromophore or from the molecular skeleton. #otational strengths # of inherently achiral chromophores tend to be low. 2. Chromophores that are Inherently Chiral T$(s( i# l,+( &"l( ,l(s li0( $(li (#(s1 2$(%( !$( 2$"l( &"l( ,l( a !s as a $i%al $%"&"'$"%(/ Other e!amples are biaryls, cyclic $,%&dienes, twisted alkenes, enones and cyclic disulfides. 'n each case, chirality is built into the chromophore. #otational strengths of inherently chiral chromophores tend to be (ery high. The fact CD spectra can be obser(ed at all for n ) transitions and ) transitions, that lack electric transition moments " and magnetic transition $i%al '(%!,%)a!i"#s i# !$(

moments m" respecti(ely" can be e!plained in se(eral ways, but essentially perturbation or mi!ing of transitions causes and m to ha(e finite but small" (alues. 1

A''li a!i"# "f CD !" S!%, !,%( D(!(%&i#a!i"# The most important aspect of a CD cur(e is the sign of the Cotton *ffect. +part from numerous assessments of the sign and magnitude of the Cotton *ffect for particular chromophores, using mostly ,O&based theory, many applications use one of many s(&i(&'i%i al %,l(s- s( !"% %,l(s for achiral chromophores and $(li i!3 %,l(s for chiral chromophores. These are summarized below. R,l( !3'( S( !"% A''li a!i"#s Sa!,%a!(+ 0(!"#(s (!$( a.ial all(#(s1

$al"0(!"#( a#+ " !a#! %,l(s)1 N"#4+is!"%!(+ H(li i!3 al0(#(s1 a%)".3li a i+s1 )(#5"a!(s/ T2is!(+ 3 l"al0(#(s1 s0(2(+ 3 la#"#(s1 )ia%3ls/ S( !"% R,l(s f"% A $i%al C$%"&"'$"%(s .hene(er 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 *ffect". The name /sector rule0 stems from the di(ision of %D 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 *ffect according to their positions in one or another sector that surrounds the chromophore. Thus, the sign of the Cotton *ffect depends on se(eral factors, including the nature of substituents, configuration and conformation. 'n general, any two of three structural descriptors 1 constitution, configuration and conformation 1 must be known if the third is to be deduced from chiroptical spectra CD or O#D". Therefore, in general, for chiral molecules ha(ing torsional degrees of freedom /free 2 (#"#(s1 $(li (#(s1

rotation0", it is not possible to ac2uire 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 ha(e an identical chromophore. 't is essential to know the nature of the transition in each case, since only comparable transitions can be treated in such a way. 't is also necessary to know the transition symmetry properties of the chromophore and what effect structural features ha(e upon the strength of the CD band. The Axial Haloketone Rule and the Octant Rule for Saturated etones The octant rule is the most widely applied sector rule. 't was de(eloped from an earlier rule, known as the /a!ial haloketone rule0, based on O#D measurements carried out on steroidal ketones that had been a!ially" substituted with a halogen atom at the &carbon. +!ial substitution conformation" is often preferred because of the dipole&dipole repulsions in the e2uatorial isomer-

O a! Cl Cl 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#, SO4#, 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# 3 l"$(.a#( %i#- s3s!(&s)/ If !$( 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% C6% 6O4C 5 6O4C 6 O 8 6 C76$8

9r

9r

Substitution by 9r gi(es &C* at 5 and :C* at 8

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.

O 9r C6% $$

C6%

CO4C6%

+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".

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

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 e2uatorial one. below" indicate clearly that the preferred conformer is the

CH3 ((:) 3 CH3

a!" C6% % O
(a.)

O O : % ? : ?

C6%

C6 ? % %

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.

C6% 4 % = $ + O C6% C 9 ; 8 D $5 $; C76$8

: + ?

? 9 C : D

$&Cholestanone

front octant" C* small &(e

C6% O + C6% C 9 D C76$8 C6%D C : 9 C6% + ? C6% C6% C + O %&Cholestanone 8 ; C* medium :(e ? 9 + : C 9 D C76$8 $5, $; : ? C* large :(e : ?

4&Cholestanone

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.

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