WK1 : CHIRAL METHODOLOGY - Resolution of Enantiomers and Enzymatic Control

What is a configurational isomer (stereoisomer)?

Isomers with the same atom connectivity but different 3D arrangements in space.

What are the 3 important types of configurational isomers?

1. Enantiomers

2. Diastereomers

3. Geometric isomers (cis/trans)

What makes an organic molecule chiral?

A carbon atom (sp³ hybridized, tetrahedral) bonded to 4 different groups = chiral center.

How do you assign R/S configuration to a chiral center?

1. Assign priorities by atomic number

2. Orient so lowest priority points away

3. Trace 1→2→3: clockwise = R, anticlockwise = S

What does [α]²⁵_D = +3.12° (H₂O) mean?

• Sodium D-line light (λ=589.6 nm)

• Temperature = 25°C

• Solvent = water

• Positive rotation = +3.12°

What is enantiomeric excess (% ee) and how is it calculated from optical rotation?

% ee = (Observed [α] / [α] of pure enantiomer) × 100

If observed [α] = +1.151° and pure R has [α] = +5.756°, what is % ee and composition?

• % ee = (1.151/5.756)×100 ≈ 20%

  • 20/2 = 10 R= 50 +10 = 60 , S= 50-10 = 40

• R = 60%, S = 40% (R in excess)

Why can't enantiomers be separated by simple recrystallization or distillation?

They have identical physical properties (m.p., b.p., solubility) in achiral environments.

Compare these methods for obtaining enantiomerically enriched products:

1. Chiral auxiliary

2. Resolution

3. Chiral pool

1. Excellent ee but extra steps

2. Max 50% yield but both enantiomers accessible

3. Very high ee but limited substrates

What did Louis Pasteur do and why is it impractical?

Manually separated enantiomeric crystals with tweezers. Impractical because it requires perfect crystals and is time-consuming.

What is classical resolution?

Using a stoichiometric chiral resolving agent to form diastereomeric salts that can be separated by crystallization.

How does chiral column chromatography work?

Uses a chiral stationary phase that interacts differently with each enantiomer, causing different retention times.

What is inclusion complexing in chromatography?

Analytes fit into cavities of chiral hosts (like cyclodextrins), with selectivity depending on size/shape and hydrogen bonding.

What is kinetic resolution?

Using a chiral catalyst/reagent to react faster with one enantiomer, enriching the unreacted starting material in the other enantiomer.

What are advantages and limitations of using enzymes for kinetic resolution?

Advantages: Highly selective, green chemistry
Limitations: Limited substrate scope, enzymes can be expensive

Give two examples of enzymatic kinetic resolution.

1. Baker's yeast reduction of ethyl acetoacetate

2. Lipase-catalyzed ester hydrolysis

What are the 3 main methods for chiral resolution?

1. Diastereomeric salt formation

2. Chiral column chromatography

3. Kinetic resolution

What is the maximum yield of desired enantiomer from resolution of a racemate?

50% (unless coupled with racemization/recycling)

Why is chirality important in drug discovery?

One enantiomer may be therapeutic while the other is inactive or toxic (e.g., thalidomide).

If % ee = 80%, what is the composition if R is in excess?

R = 90%, S = 10%
(50 + 40, 50 - 40)

What is the difference between enantiomers and diastereomers?

Enantiomers: Mirror images, identical physical properties
Diastereomers: Not mirror images, different physical properties