Stereochemistry
R/S configuration, chirality, and 3D molecular structure
Cahn-Ingold-Prelog Priority Rules
Higher Atomic Number = Higher Priority
Look at atoms directly attached to chiral center
Priority: I (53) > Br (35) > Cl (17) > S (16) > F (9) > O (8) > N (7) > C (6) > H (1)
If Tied, Go to Next Atom
Move outward from chiral center atom by atom
Example: -CH₂CH₃ vs -CH₃ → Both start with C, but ethyl has another C while methyl has H
Multiple Bonds Count as Multiple Atoms
C=O treated as C bonded to two O's
• C=O → C bonded to (O, O, _)
• C≡N → C bonded to (N, N, N)
• C=C → each C bonded to (C, C, _)
Isotopes: Higher Mass Number = Higher Priority
Deuterium (²H) > Hydrogen (¹H)
Tritium (³H) > Deuterium (²H) > Hydrogen (¹H)
Assigning R/S Configuration
Step-by-Step Procedure
Identify the chiral center
Carbon with four different groups attached
Assign priorities (1-4)
Using Cahn-Ingold-Prelog rules, 1 = highest, 4 = lowest
Orient molecule
Put lowest priority (#4) in the back (away from you)
Trace 1 → 2 → 3
If clockwise = R (Rectus, right)
If counterclockwise = S (Sinister, left)
Memory Aid
R = Right turn (clockwise) 🔄
S = Sinister (left/counterclockwise) 🔃
Worked Example
Example: 2-Bromobutane
Structure:
CH₃-CHBr-CH₂-CH₃
Step 1: Identify chiral center
C2 (the carbon with Br attached) has 4 different groups:
- • Br
- • H
- • CH₃ (to the left)
- • CH₂CH₃ (to the right)
Step 2: Assign priorities
| 1 | Br | Highest atomic number (35) |
| 2 | -CH₂CH₃ | C attached to (C, H, H) vs methyl's (H, H, H) |
| 3 | -CH₃ | C attached to (H, H, H) |
| 4 | H | Lowest priority |
Step 3: Orient (H to the back)
Imagine looking at the molecule with H pointing away from you
Step 4: Trace 1 → 2 → 3
Br (1) → CH₂CH₃ (2) → CH₃ (3)
If clockwise: (R)-2-bromobutane
If counterclockwise: (S)-2-bromobutane
(Actual configuration depends on 3D orientation - both enantiomers exist!)
Types of Stereoisomers
Enantiomers
Definition: Non-superimposable mirror images
Properties:
- • Opposite R/S configurations at all chiral centers
- • Identical physical properties (mp, bp, density)
- • Rotate plane-polarized light in opposite directions
- • Different biological activity (one may be drug, other inactive/toxic)
Example: (R)-ibuprofen vs (S)-ibuprofen
Diastereomers
Definition: Stereoisomers that are NOT mirror images
Properties:
- • At least one (but not all) chiral center has opposite configuration
- • Different physical properties (mp, bp, solubility)
- • Different chemical reactivity
- • Can be separated by standard techniques (crystallization, chromatography)
Example: (2R,3R)-tartaric acid vs (2R,3S)-tartaric acid
Meso Compounds
Definition: Achiral molecule with chiral centers (internal plane of symmetry)
Properties:
- • Contains 2+ chiral centers but overall achiral
- • Internal mirror plane cancels optical activity
- • Does NOT rotate plane-polarized light
Example: (2R,3S)-tartaric acid = meso-tartaric acid
Number of Stereoisomers
Maximum stereoisomers = 2ⁿ
where n = number of chiral centers
Examples:
- • 1 chiral center → 2¹ = 2 stereoisomers (1 pair of enantiomers)
- • 2 chiral centers → 2² = 4 stereoisomers (2 pairs of enantiomers, unless meso)
- • 3 chiral centers → 2³ = 8 stereoisomers
Exception: Meso compounds reduce the count!
If molecule has internal symmetry, actual # < 2ⁿ
Optical Activity
Specific Rotation [α]
[α] = α / (l × c)
α = observed rotation (degrees)
l = path length (dm)
c = concentration (g/mL)
Terminology
(+) or d = dextrorotatory (rotates right)
(-) or l = levorotatory (rotates left)
Important: (+)/(-) ≠ R/S!
R can be (+) or (-), determined experimentally
Common Mistakes
Forgetting to Put #4 in Back
If #4 is in front, your R/S assignment will be backwards!
Confusing R/S with (+)/(-)
R/S is configuration (structure). (+)/(-) is optical rotation (experimental).
Missing Chiral Centers
A carbon with 2 identical groups is NOT chiral!
Pro Tip: Fischer Projections
Vertical lines go back, horizontal lines come forward. Makes R/S easier!