Many natural products contain chiral centers. Furthermore, most of them exist in one sterochemical configuration. For example, all the naturally occuring amino acids have the configuration shown in Figure 1. None of them have the configuration in which the positions of the NH2 group and the R group are interchanged.
No Different Drummers here
Exercise 1 For each of the amino acids shown below, indicate whether the configuration is R or S.
Chemists have known for over 150 years that many natural products are optically active, which is to say that they rotate the plane of plane polarized light.
Plane Polarized Light
Light is electromagnetic radiation. This means that each photon has an electric field and a magnetic field associated with it. These fields are perpendicular to each other and to the direction of motion of the photon. Since the electric and magnetic fields are perpendicular, they may be treated independently. In the discussion that follows we will focus our attention on the electric field. The left hand panel of Figure 2 illustrates the sinusoidal nature of this field for a single photon traveling from left to right. The right hand panel shows an end-on view of the electric fields associated with a collection of photons (Imagine looking at the beam of a flashlight.). The plane of oscillation of each photon is randomly oriented.
The Electric Field of a Single Photon
Figure 3 shows what happens when a beam of unpolarized light is passed through a polarizing material such as a Nicol prism or the lens of polarized sunglasses.
Line 'em Up
The electric fields of the photons that emerge from the polarizer are aligned in parallel planes. The resultant beam of light is said to be plane polarized.
When a beam of plane polarized light is passed through a solution of a chiral compound such as (S)-alanine, the plane of polarization of the light that emerges is rotated relative to the original plane. This phenomenon is known as optical activity, and compounds that rotate the plane of polarized light are said to be optically active. Figure 4 demonstrates how two pieces of polarizing material may be used to measure the specific rotation of an optically active compound with a device known as a polarimeter. The light source is a sodium lamp One of the lines in the atomic emission spectrum of sodium is yellow. It is called the sodium D line.
A Simple Polarimeter
The light from the source passes through the polarizer. The resulting plane polarized light is directed into a sample tube which contains a solution of the optically active compound. The interaction of the light with the sample results in a net rotation of the plane of polarization. The value of the net rotation may be determined by viewing the emerging light through the analyser and rotating it until the light intensity reaches a maximum. In the example shown in the figure, the sample has rotated the plane of polarization by approximately 15 degrees in a clockwise direction. The specific rotation of a sample depends upon the number of encounters between the light and the molecules of optically active compound in solution. This, in turn, depends on the concentration of the solution and the length of the sample tube. The specific rotation of (S)-alanine, [a]D20 , is +14.5o. In this notation, [a] represents the specific rotation, the subscript D stands for the sodium D line, and the superscript 20 indicates the temperature in degrees Celsius. The direction of rotation of plane polarized light by a compound is indicated with a "+" or "-" sign. Thus, the complete designation of (S)-alanine is (S)-(+)-alanine. The enantiomer of (S)-(+)-alanine is (R)-(-)alanine. The specific rotation of (R)-(-)alanine is -14.5o.
If you think of a molecule as an atomic framework embedded in a cloud of electrons, then you will recognize that the movement of those electrons over that framework generates an electrical field. In other words, every molecule has an electrical field associated with it. When you shine light on that molecule, the light's electric field interacts with the electric field of the molecule in much the same way that the magnetic fields of two magnets interact when they are brought close together. If the light is plane polarized, the interaction results in a rotation of the plane of polarization. Individually, all molecules rotate plane polarized light. The magnitude of the rotation depends upon the relative orientation of the light as it encounters the molecule. If the orientation of one molecule is the mirror image of the orientation of another, the rotation by the first molecule will be the mirror image of the rotation by the second. The net rotation produced by a sample is the sum of the rotations produced by the individual molecules.
Let's consider three samples. Sample 1 = 2 molecules of bromochloromethane. Sample 2 = 2 molecules of (S)-bromochlorofluoromethane. Sample 3 = 1 molecule of (S)-bromochlorofluoromethane and 1 molecule of (R)- bromochlorofluoromethane. Interactive models of these samples are shown in separate windows in Figures 5, 6, and 7. Arrange your desktop so you can see one of the Figures and this window at the same time. Then answer the following questions for each sample.
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1. Can you orient the right hand model so that it is the mirror image of the left hand model?
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2. Is the molecule on the left superimposable on the molecule on the right?
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3. Could the net rotation of the sample be zero?
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Sample 3, above, is referred to as a racemic mixture, which is to say that it contains equal numbers of R and S enantiomers. While the individual molecules of a racemic mixture are optically active, the net rotation of the sample is zero.
The synthesis of new molecules has always intrigued organic chemists. Until recently most syntheses of chiral molecules have produced racemic mixtures. For pharmaceutical companies this can be a problem for two reasons. First, it is often the case that only one of the two enantiomers is physiologically active. Therefore, in a synthesis which produces a drug in racemic form, the 50% of the product that is inactive represents waste. A more serious situation arises when the enantiomer of the desired drug is also physiologically active. This was the case with the notorious drug thalidomide. This drug, which was manufactured as a racemic mixture, caused birth defects in the children of women who took it to relieve morning sickness. It now appears that (S)-thalidomide is responsible for the birth defects, while the (R)-thalidomide helps control morning sickness.
Along the same line, vitamin E, a free radical inhibitor, is currently popular as a dietary supplement. Free radicals are known to break specific bonds in DNA. The breakdown of DNA is thought to contribute to aging. The vitamin E in many supplements is synthetic and consists of a racemic mixture. Natural vitamin E exists as a single enantiomer. Figure 5 shows the structures of thalidomide and vitamin E.
Chiral Molecules: For Better or Worse
Exercise 2 How many chiral atoms are there in thalidomide? How many chiral atoms are there in Vitamin E?
A major goal of modern organic chemistry is the development of synthetic strategies that produce enantiomerically pure materials. While a growing array of methodologies is available, most approaches still produce products that contain both enantiomers, although not in equal amounts. Chemists use the term enantiomeric excess to describe product mixtures which contain more of one enantiomer than the other. The value of the enantiomeric excess can range from 0% to 100%. For a compound containing a single chiral center, a racemic mixture consists of 50% of the R enantiomer and 50% of the S enantiomer. The enantiomeric excess is 0. A sample that contains 100% of one enantiomer has an enantiomeric excess of 100%. Imagine a synthesis that produces 90% of the R enantiomer and 10% of the S enantiomer. In this case, the enantiomeric excess is 80%.
Exercise 3 A recent article in Chemical & Engineering News reported the reaction shown in Equation 1.
How much of the minor enantiomer is there in the mixture? %