High Performance, Low Cost…

Optical Rotation and Polarimetry

The light produced by a light emitting diode is randomly polarized. If this light passes through a piece of polaroid film (for example, from a pair of polaroid sunglasses) it becomes linearly polarized.

If a second piece of polaroid film is now rotated behind the first the intensity goes through maxima and minima; in the latter condition the two "polarizers" are said to be crossed.

If a cell containing just water is placed between the two polarizers, no change is observed.

However if the cell is filled with a sugar (sucrose) solution something interesting happens - the angular position of the second polarizer at which maxima and minima occur becomes rotated by a well defined angle, whose magnitude depends on two things - the length of the container and the concentration of the sugar solution. This angle describes the optical rotation of the sample.

Optical Enantiomers and Chirality

Sucrose displays the property known as optical rotation and is said to be "optically active", while water is optically "inactive".

Whether or not a molecule is optically active depends on whether it can exist in one of two mirror image forms that are non-superimposable, like a left hand and a right hand.

Amino acids (as seen at right) are optically active; the molecule and its mirror image form are non-superimposable. Molecules having this property are said to be “chiral”, the two forms being described as optical enantiomers.

A “chiral centre” arises in a molecule when a carbon atom in that molecule has 4 different functional groups attached to it, as in the case of the amino acid shown opposite (here R denotes a generic alkyl group). Complex molecules can contain many chiral centres.

A polarimeter is an instrument that measures optical rotation, and can therefore distinguish between two optical enantiomers of the one compound.
Stacks Image 2540

Enantiomers and Racemic Mixtures

Enantiomers have identical chemical and physical properties with two important exceptions – (i) they rotate plane polarized light by equal amounts but in opposite directions and (ii) they react at different rates with other enantiomers.

An enantiomer that rotates the plane of polarized light to the left i.e. counterclockwise (as viewed towards the light source) is called levo and is designated (-) whereas if the rotation is to the right (clockwise) it is dextro and is designated (+).

Any compound that is observed to produce such a rotation is described as being optically active, thus enantiomers are optically active. If a racemic mixture is tested (one having precisely equal amounts of a pair of enantiomers) it will be optically inactive because the individual rotations cancel each other. Mixtures containing predominantly one enantiomer are said to be enantiomerically-enriched and these are optically active because the individual rotations no longer cancel.

Because enantiomers have identical physical and chemical properties (but with the two exceptions noted above) racemic mixtures cannot be separated by normal methods such as crystallization or distillation. Separation of individual enantiomers from a racemic mixture is called resolution. Conventional chemical syntheses using non-chiral materials results in racemic mixtures. Usually, the resolution of racemic mixtures is time consuming and expensive. Enantiomerically-enriched mixtures can be prepared by asymmetric synthesis, using a chiral substrate, reagent, catalyst or solvent or by conducting the reaction in the presence of circularly polarized light.

Most pharmaceutical products utilize single enantiomer drugs. The principal benefit is that the enantiomer is a pure substance. For example, the S-(+) enantiomer of ibuprofen is a widely used over-the-counter anti-inflammatory drug. In general, regulatory authorities view the presence of the other enantiomer as an impurity and since the single enantiomer drug acts at a chiral receptor in the host the interaction is predictable and consistent.

The now infamous use of the thalidomide racemate to treat morning sickness in pregnant women between 1957 and 1962 vividly illustrates this point – while the R-(+) enantiomer is antiemetic, the teratogenic S-(-) enantiomer resulted in severe birth defects in a large number of children. However even if the R-(+) enantiomer had been available and prescribed at the time, the tragedy would (probably) still have occurred because at physiological pH the R-(+) enantiomer racemizes.

Continuing development of racemates raises numerous issues - of acceptable manufacturing control of synthesis and impurities, adequate pharmacologic and toxicologic assessment and appropriate clinical evaluation.

Note: The notations R (rectus, right) and S (sinister, left) are used to describe the absolute configuration in an enantiomeric stereocenter. These labels are deduced according to a set of priority rules - more information about this can be found in any organic chemistry text dealing with the subject of chirality.