Lecture 4- Isomers 2 (stereoisomers)

What is a chiral center, and what type of isomerism does its presence lead to in molecules

A chiral center is a tetrahedral atom (often carbon, but not always, e.g., sulfur in omeprazole) with four different ligands attached to it.

The presence of a chiral center makes the molecule chiral and leads to the existence of two enantiomeric configurations. This type of isomerism is called chirality.

What are enantiomers?

Enantiomers are a type of isomer that are non-superimposable mirror images of each other.

What happens to the configuration of a molecule with a chiral center if any two ligands around it are interchanged?

Interchanging any two ligands around a chiral center inverts the configuration, changing the compound into its enantiomer.

Give examples from the source illustrating that different enantiomers can have profoundly different properties in the body.

The source provides several examples:

• One enantiomer of thalidomide is a sedative/anti-emetic, while the other causes congenital malformations/foetal death.

• One enantiomer of penicillamine removes heavy metal poisons, while the other can cause serious eye defects and blindness.

• One enantiomer of the methyl ester of phenylalanine is sweet (a sugar substitute), while the other is bitter.

Are the effects of enantiomers always different or harmful? Provide an example from the source.

No, it is not always the case. Sometimes an enantiomer can be harmless and inactive. The source mentions citalopram, where the original drug was a mixture of enantiomers, but now pure (S)-escitalopram is available. Omeprazole and esomeprazole also represent this concept.

Why is chirality a critical consideration in the study of drug metabolism? Provide an example from the source.

Chirality is critical because different enantiomers of a drug can be metabolized by different routes. The source gives the example of Warfarin, an anti-clotting drug where each of the two enantiomers is metabolized differently.

What is the R/S system used for?

The R/S system provides a way to distinguish between enantiomers by assigning them the designations R-enantiomer or S-enantiomer. This is critical in medicines and drug structure.

What is the first rule of the sequence rules used in the R/S system?

If the ligands are atoms, they are arranged in order of decreasing atomic number. The atom with the higher atomic number takes precedence (e.g., I > Br > Cl > F).

How are priorities assigned if the first-bonded atom in two groups is the same?

If the first-bonded atom is the same, the atomic number rule is applied to succeeding atoms until a difference is found.

How are multiple bonds treated when assigning priorities using the sequence rules?

Multiple bonds are treated as separate single bonds with attached "phantom" atoms.

What is the priority order for isotopic atoms and a lone pair?

Isotopic atoms are arranged in order of decreasing mass number (e.g., T > D > H). A lone pair has the lowest priority of all.

Describe the process of designating a chiral center as R or S using the sequence rules.

1. Assign priority to the four substituents around the chiral center using the sequence rules (1 being the highest, 4 being the lowest).

2. Orient the molecule so that the lowest priority group (4) is directed away from the viewer.

3. View the molecule from the side opposite to the lowest priority group.

4. If the sequence of decreasing priority of the remaining three groups (1 -> 2 -> 3) is clockwise, the enantiomer has the R-configuration.

5. If the sequence is anticlockwise, the enantiomer has the S-configuration.

6. Remember: clockwise = right (R), anticlockwise = left (S).

What can be done if the lowest priority group is not oriented away from the viewer?

One approach is to perform two swaps of ligands. One swap inverts the configuration (R to S or S to R), so two swaps will return the configuration to the original.

For example, swap the lowest priority group with the group at the back, and simultaneously swap the other two groups. Then, the R/S designation can be determined.

Briefly describe the D/L system of designation for chiral molecules.

The D/L system is a historic system based on Fischer projections, which are drawn as crosses with horizontal lines coming out of the plane and vertical lines going into the plane. The designation (D or L) is often determined by the position of the OH group in carbohydrates or the NH2 group in amino acids in their respective Fischer projections.

What is a major limitation of the D/L system, and what system is now accepted as unambiguous?

A major problem with the D/L system is that it cannot cope easily with compounds which are not chemically related to carbohydrates and amino acids. The R/S system is therefore the accepted unambiguous system. However, knowledge of the D/L system is still important as it is used in some drug names like L-DOPA.

How do enantiomers differ in their physical and chemical properties in an achiral environment?

Enantiomers have identical physical and chemical properties in an achiral environment, such as melting point, boiling point, density, refractive index, spectra, chromatographic retention time, and thermodynamic stability. However, they differ in the way they rotate the plane of polarised light.

• How is optical activity measured, and what is the instrument used?

Optical activity is measured using a polarimeter. A polarimeter passes plane-polarized light through a solution of a chiral sample and detects the amount of rotation of the light.

• Define specific rotation ([α]) and give the formula, including the units of the variables.

Specific rotation ([α]) takes concentration and cell length into account. The formula is: [α]tD = α / (l ⋅ c) where:

• α is the angle of rotated light (in degrees).

• l is the cell length in dm (decimeters).

• c is the concentration in g/mL (grams per milliliter).

• t is the temperature.

• D is the wavelength of light used (typically the sodium D line).

What is the relationship between the specific rotations of (R) and (S) enantiomers? What is the rotation of a racemic mixture?

(R) and (S) enantiomers will have equal and opposite specific rotations.

A 50/50 mixture of (R) and (S) enantiomers, called a racemic mixture or racemate, has a rotation of zero.

How can optical purity be related to rotation?

For known chiral compounds, optical purity (the excess of one enantiomer over another) can be related to the observed rotation.

Specifically optical purity is calculated as the ratio of the observed optical rotation of a mixture to the rotation of a pure enantiomer.

How are alkene isomers with double bonds described using priority rules?

Alkene isomers are described as (E) or (Z) using the priority rules.

Describe the steps involved in assigning (E) or (Z) configuration to an alkene.

1. Apply the sequence rules to the two ligands on each carbon atom of the double bond to assign priorities as high or low.

2. Draw an imaginary horizontal line through the double bond.

3. If the two higher priority groups are on the same side of this imaginary line, the isomer is designated (Z)(from Zusammen, meaning "together" in German).

4. If the two higher priority groups are on opposite sides of the imaginary line, the isomer is designated (E)(from Entgegen, meaning "opposite" in German).

Summarize the key concepts of chirality discussed in the source.

• Drug molecules can exhibit chirality, a form of isomerism.

• A carbon (or sulfur) atom is chiral if it has four different groups attached.

• The resulting isomers are called enantiomers.

• A set of priority rules is used to describe the four groups, allowing designation as R or S.

• [α]D is a physical constant related to chirality and the percentage of R versus S enantiomers.

• Alkene isomers with double bonds should be described as E or Z using priority rules.