Stereochemistry and Enantiomers Notes

Stereochemistry & Enantiomers

Chirality and Stereoisomers

Stereochemistry is the study of the three-dimensional structure of molecules. Isomers that differ in spatial arrangement are called stereoisomers. Chirality, derived from the Greek word for "hand," is a key concept. Just as our left and right hands are mirror images but not superimposable, chiral molecules also exist as non-superimposable mirror images.

Chiral Center: An atom, typically carbon, bonded to four different groups. This tetrahedral arrangement gives rise to two possible spatial arrangements, leading to enantiomers.
Achiral: Molecules that are superimposable on their mirror images are achiral. They lack a chiral center or possess a plane of symmetry.

Naming Enantiomers: The R,S -System

Using IUPAC naming alone, enantiomers like 2-Butanol would have the same name, which is undesirable since each compound needs a distinct name. To resolve this, the R,S system was developed.

Enantiomers are distinguished by adding the prefix R or S to the IUPAC name.
- R = Rectus (Latin) – Right (clockwise)
- S = Sinister (Latin) – Left (anticlockwise)
This naming system is called the Cahn-Ingold-Prelog (CIP) system.

Rules and Regulations of Cahn-Ingold-Prelog (CIP) System

The Cahn-Ingold-Prelog (CIP) system provides a systematic way to assign R and S configurations to chiral centers. It involves assigning priorities to the groups bonded to the stereogenic center and then determining the spatial arrangement.

Rule 1: Element

Priorities are assigned to each group bonded to the stereogenic center, based on decreasing atomic number. The atom with the highest atomic number receives the highest priority (1).

Br > Cl > F > O > N > C > H

If isotopes are bonded to the stereogenic center, priority is assigned based on decreasing mass number. For example, tritium ( $^3H$ ) has higher priority than deuterium ( $^2H$ ), which has higher priority than protium ( $H$ ).

Rule 2

If Rule 1 cannot determine priority (due to same atoms bonded to the stereogenic center), priority is assigned based on the atomic number of the atoms bonded to these atoms. One atom of higher atomic number determines the higher priority. This process is continued until a difference is found.

Rule 3

Double/triple bonds are treated as an equivalent number of singly bonded atoms. For example, the C of a C=C is considered to be bonded to two C atoms.

Rule 4

After assigning priorities, the molecule is rotated so the lowest priority group (4th priority) faces away from the observer. Then, trace a path from highest to lowest priority.

Clockwise arrow: (R) configuration
Counterclockwise arrow: (S) configuration

Examples

2-Butanol example:

Step 1: Assign priorities: O > C > C > H
Step 2: Rotate the molecule to have the lowest priority (H) facing away. Determine the direction (clockwise or counterclockwise) for R/S.

Other examples demonstrating the assignment of R/S configurations based on CIP rules and the manipulation of the molecule to orient the lowest priority group away from the viewer. These include:

Bromine (Br)
Chlorine (Cl)
Methyl Group (Me)
Ethyl Group (Et)
Other functional groups.

Special Cases and Considerations

When comparing groups with double/triple bonds, consider the equivalent number of singly bonded atoms. For example, $CH=CH_2$ is considered as $(C, C, H)$ . If the lowest priority group is not facing behind, rotate the molecule or count as is and then invert the counting.

Further Examples

Examples of molecules like 3-methylhexane, 2-amino-3-buten-2-ol, 2-methyloxirane, and 3-isobutyl-1-cyclohexene. These showcase the application of CIP rules to more complex structures.

The Story of Thalidomide

The activity of drugs containing chirality centers can vary significantly between enantiomers, leading to serious consequences. Thalidomide serves as a stark reminder of this.

Thalidomide, used to alleviate morning sickness in pregnant women before 1963, was found to cause horrible birth defects. The drug was sold as a mixture of both enantiomers.

One enantiomer of thalidomide was effective against morning sickness, while the other caused birth defects.
This case highlighted the importance of producing enantiomerically pure drugs.

Stereochemistry: Identifying Stereogenic Centers

The ability to identify stereogenic centers is crucial in stereochemistry. Examples include compounds like Limonene, Dichlorocyclopentane, Menthol, and Glucose.

cis-Dichlorocyclopentane is meso. Meso compounds contain stereocenters but are achiral due to an internal plane of symmetry.
trans-Dichlorocyclopentane is enantiomeric.

Properties of Enantiomers

Enantiomers have identical physical properties such as melting point, boiling point, refractive index, and solubility in achiral environments.

Example: 2-bromobutane.

Boiling point: $91.2^\circ C$
Melting Point: $-112^\circ C$
Density: $1.253 g/ml$
Refractive Index: $1.463$

However, they differ in their interaction with chiral substances and polarized light.

Examples of boiling points and melting points for (R)-2-Butanol, (S)-2-Butanol, (+)-(R,R)-Tartaric Acid, (–)-(S,S)-Tartaric Acid and (+/–)-Tartaric Acid.

Optical Isomers and Polarimetry

Optical isomers are considered different compounds because they are non-superimposable mirror images. The pivotal difference lies in how they interact with and rotate plane-polarized light.

Properties of Enantiomers: Optical Activity

Enantiomers are mirror images that are not superimposable. This property leads to optical activity.

Optical activity is the property of chiral substances to rotate the plane of polarization of plane-polarized light.

Polarization of Light

Ordinary light oscillates in all possible planes. Passing it through a polarizer results in plane-polarized light, oscillating in only one plane.

Measuring Optical Activity

Rotation of plane-polarized light occurs in the presence of a single enantiomer. The degree of rotation is quantified using a polarimeter.

Polarimeter: A device for measuring the extent of rotation of plane-polarized light.

A light source passes through a polarizing filter, then through the sample tube, and finally through an analyzing filter. The analyzing filter is turned until the field is dark.

Dextrorotatory (+): Rotates plane-polarized light clockwise.
Levorotatory (-): Rotates plane-polarized light counterclockwise.
Observed rotation: The number of degrees, $\alpha$ , through which a compound rotates the plane of polarized light.
Specific rotation: observed rotation when a pure sample is placed in a tube 1.0 dm in length and concentration in g/mL (density); for a solution, concentration is expressed in g/ 100 mL.

Modern Polarimeter Components

Light source, filter, polarizer, Faraday cells, sample, analyzer, and PMT detector. Modern polarimeters often use sophisticated electronic components to improve accuracy and ease of use.

Specific Rotation Formula

$[\alpha]_D^{25} = \frac{\alpha}{c \cdot l}$

$\alpha$ : observed rotation
c: concentration of sample solution in g/mL
l: length of cell in dm (1 dm = 10 cm)
Temperature & wavelength annotation

The value of $\alpha$ depends on the experiment, but specific rotation $[\alpha]$ should be the same regardless of concentration.

Example Calculation of Specific Rotation

Observed rotation $\alpha = -0.142^\circ$ . Sample: 13 mg dissolved in 10 ml of $CHCl_3$ . Cell path length: 10 cm.

Convert concentration to g/100 ml: 0.013 g/10 ml = 0.13 g/100 ml.
Convert path length to dm: 10 cm = 1 dm.
Calculate the specific rotation $[\alpha]$ :

$[\alpha] = \frac{100 \times \alpha}{c \times l} = \frac{100 \times (-0.142)}{0.13 \times 1} = -109.2^\circ$

Polarimeter Output

Example polarimeter output showing sodium D line, temperature, solvent, and concentration during measurement.

Sodium Lamp

Spectrum of Sodium Lamp with the most intense emission at 589nm. This is a common light source for polarimetry.

If the wavelength of light used is 589 nm (sodium D line), the symbol “D” is used. Fraunhofer lines are dark lines appearing against the bright background of the continuous solar spectrum.

Specific Rotation of Enantiomers

Two enantiomers should have the same value of specific rotation, but with opposite signs. This is a fundamental property of enantiomers.

Racemic Forms

An equimolar mixture of two enantiomers is called a racemic mixture (or racemate or racemic form).

A racemic mixture causes no net rotation of plane-polarized light because the rotation by one enantiomer is canceled out by the equal and opposite rotation of the other.

Enantiomeric Excess and Optical Purity

A sample of an optically active substance consisting of a single enantiomer is enantiomerically pure or has an enantiomeric excess (ee) of 100%.

Enantiomeric excess (ee) reflects the degree to which a sample contains one enantiomer in greater amounts than the other.

A racemic mixture has an ee of 0%. A single completely pure enantiomer has an ee of 100%. A sample with 70% of one enantiomer and 30% of the other has an ee of 40%.

Example

An enantiomerically pure sample of (S)-(+)-2 butanol shows a specific rotation of $+13.52$ . An enantiomerically pure sample of (S)-(+)-2 butanol has ee of 100%.

Optical Purity (op)

$optical \ purity = \frac{observed \ specific \ rotation}{specific \ rotation \ of \ the \ pure \ enantiomer} \times 100\%$ . Optical Purity (op) is a measurement of how much one enantiomer is present in excess of the racemic mixture.

Example

(-)-2-butanol has a specific rotation of -13.5° while the specific rotation of (+)-2-butanol is +13.5°. Calculate the optical purity of a mixture containing (+) and (-)-2-butanol if the mixture has an observed rotation of – 8.55°.

$op = \frac{-8.55^\circ}{-13.5^\circ} \times 100\% = 63.3\%$ .

The mixture consists of 63.3% (-)-2-butanol and 36.7% (+)-2-butanol. Hence, the enantiomeric excess, $ee = 63.3\% - 36.7\% = 26.6 \%$ .