CH437 CLASS 22CHIROPTICAL 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. 1 Application of CD to Structure Determination The most important aspect of a CD curve is the sign of the Cotton Effect. allenes. Therefore.e. configuration and conformation – must be known if the third is to be deduced from chiroptical spectra (CD or ORD). for chiral molecules having torsional degrees of freedom (“free 2 . carboxylic acids. a Cotton Effect). helicenes. Helicity Twisted cycloalkenes. using mostly MO-based theory. configuration and conformation. Sector Rules for Achiral Chromophores Whenever chiroptic atoms or groups are present in a molecule containing an achiral chromophore. Rule type Applications Sector Saturated ketones (the axial haloketone and octant rules). These are summarized below. Non-distorted alkenes. the sign of the Cotton Effect depends on several factors. 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. In general. biaryls. many applications use one of many semiempirical rules: sector rules for achiral chromophores and helicity rules for chiral chromophores. skewed cyclanones. 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. Thus. benzoates. any two of three structural descriptors – constitution. in general. perturbation of the electronic transitions of the chromophore will be sufficient to generate chiroptical properties (i. including the nature of substituents. enones. Apart from numerous assessments of the sign and magnitude of the Cotton Effect for particular chromophores. 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). known as the “axial haloketone rule”. such as NR 2. 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. This is why much work in this area has been concentrated on cyclic systems. often fused systems. it is not possible to acquire information on both configuration and conformation simultaneously from chiroptical spectra. SO2R. 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. The Axial Haloketone Rule and the Octant Rule for Saturated Ketones The octant rule is the most widely applied sector rule. If the axial –halogen is found on the right (as in 3 .rotation”). etc. SR. based on ORD measurements carried out on steroidal ketones that had been (axially) substituted with a halogen atom at the -carbon. since only comparable transitions can be treated in such a way. It was developed from an earlier rule. 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. as torsional isomerism is limited in these molecules. It is essential to know the nature of the transition in each case. substitution must have occurred predominantly at the 5 position. Determination of Position of Halogen Substitution (Constitution) In the example below. The following examples illustrate applications of the axial haloketone rule in structure determination. CH3 CH3 C8H17 HO2C 5 7 HO2C O H H Br Br Substitution by Br gives -CE at 5 and +CE at 7 4 . then there exists a positive Cotton Effect. a negative Cotton effect is observed. as shown below. The axial nature of bromine atom in the product was deduced from IR spectroscopy. 1. Therefore.the (S)-enantiomer). if it appears on the left. a negative Cotton Effect is seen upon bromination of the cyclic fused ring ketone. 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. 5 . The negative CE is consistent only with trans stereochemistry. with independent evidence for axial Cl (in octane).2. 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. O CH3 Br CO2CH3 CH3 11 AcO 11--Br (equatorial) gives +CE (as in the parent ketone) 11--Br (axial) gives -CE 3. but a positive one in methanol. This is best explained by supposing the boat conformer is significant in ring A of this isomer. 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. 4. as shown below. because of steric hindrance between the (axial) methyl groups in the chair conformer.and 2-bromo isomers of 2-bromo-2-methylcholestane-3-one. Demonstration of the existence of a boat conformer Of the 2. The 2-bromo isomer unexpectedly shows a negative CE.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. (with axial Br established by IR spectroscopy) the latter displays a positive CE as expected. The Octant Rule The axial haloketone rule is a special case of the octant rule for saturated ketones. The coordinate system divides the space around the carbonyl 6 . The octant rule was first applied to fused cyclohexanone ring systems.group into 8 sectors or octants (diagram (a)). such as those in steroids. because of their conformational rigidity. the rear segments are more important). a substituent in the bottom right rear sector (diagram (b)) would have coordinates –x. Thus. +y. -z and so would give a positive CE. 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. with the 2 and 6 carbon atoms in the yz plane and the carbonyl at the head of the chair (diagram 7 . Substituents located on or near nodal planes make no contribution to the Cotton Effect. The cyclohexanone skeleton is placed in the coordinate system as shown below. Contributions from hydrogens in the simple cyclohexanone skeleton are usually ignored. since either equatorial or axial groups here in the nodal xz plane. because of their proximity to the yz plane. Likewise. Determination of preferred conformation of a cyclohexanone of known configuration The compound (R)-(+)-3-methylcyclohexanone exhibits a positive Cotton Effect. being assumed to more or less cancel. 8 . 1. Substituents at position 4 will have no effect on the CE. equatorial groups at positions 2 and 6 will make only small contributions to the CE. The working of the octant rule is illustrated by the following examples.(a)). Diagram (b) shows the projection of the view along O=C with the signs of the rear octants. 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. 9 . Hence. contributing zero).and 3-cholestanones. CH3 (eq) 3 (ax) 3 CH3 CH3 3 (ax) O O O _ CH + _ 3 + CH3 3 3 _ + _ + 2. The 2- keto isomer projection shows a majority of carbons in the + sector indicating a large positive CE. the balance of carbons in negative sectors is greater. 2. the sector with most carbons in it will make the biggest contribution to the sign of the Cotton Effect. whereas that of the 3-keto isomer has a small majority of carbons in the + sector (and many on the xz plane. The three isomers and their octant rule projections are shown below. Estimation of the Magnitude of CE in Ketosteroids When applying the octant rule to ketosteroids. the octant rule can be used to estimate the relative magnitudes of the CE for isomeric 1-. indicating a moderate negative CE. suggesting a very small positive Cotton Effect. where it can be seen that for the 1-keto isomer. 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. The (positive) CD spectrum of 2-cholestanone would be off- scale. as can be seen below. 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. 10 . 11 .