Sequence rule in stereochemistry

In stereochemistry, sequence rules are used to assign priorities to substituents around a stereocenter, allowing chemists to distinguish between stereoisomers such as enantiomers and diastereomers. These rules are known as the Cahn-Ingold-Prelog (CIP) priority rules. They help assign configurations like R or S to stereocenters and E or Z to double bonds.

Here’s a breakdown of the CIP priority rules: 

1. Atomic Number Rule

The higher the atomic number of the atom directly attached to the stereocenter, the higher the priority.

• Example: For a carbon attached to a hydrogen (atomic number 1), a chlorine (atomic number 17), a bromine (atomic number 35), and an oxygen (atomic number 8), the priorities would be:
  • Br > Cl > O > H.

2. First Point of Difference

If two substituents have the same atom directly attached to the stereocenter, you move outward to the next set of atoms until a difference is found.

• Example: Comparing an ethyl group (-CH₂CH₃) and a methyl group (-CH₃):
  • The first atom in both groups is carbon, so you compare the next set of atoms. In ethyl (-CH₂CH₃), you find another carbon, while in methyl (-CH₃), there are only hydrogens (atomic number 1). Carbon (12) has a higher atomic number than hydrogen, so ethyl has a higher priority.

3. Multiplicity (Double and Triple Bonds)

For double or triple bonds, treat the atoms as if they are bonded to an equivalent number of phantom atoms.

• Example: In the case of a carbonyl group (C=O), treat it as if the carbon is singly bonded to two oxygens (C-O-O). Similarly, for a nitrile group (C≡N), treat it as if the carbon is bonded to three nitrogens (C-N-N-N).

4. Isotopes

If isotopes are present, the atom with the higher mass number receives the higher priority.

• Example: Deuterium (²H) has a higher priority than hydrogen (¹H) because it has a higher atomic mass.

5. Configuration Assignment (R and S)

Once priorities are assigned, the stereocenter is viewed so that the lowest priority group (usually hydrogen) is pointing away from the observer. The direction in which the remaining three substituents decrease in priority determines the configuration:

• If the sequence is clockwise, the configuration is R (rectus, meaning right).

• If the sequence is counterclockwise, the configuration is S (sinister, meaning left).

• Example: Consider a molecule with a stereocenter carbon bonded to Br, Cl, O, and H. Priorities are:

  • 1: Br, 2: Cl, 3: O, 4: H (lowest).
    Looking from a perspective where H is facing away:
  • If the sequence from Br → Cl → O is clockwise, the configuration is R.
  • If it is counterclockwise, the configuration is S.

6. E/Z Notation for Double Bonds

For double bonds, the substituents on each carbon of the double bond are ranked using the same CIP rules:

• If the two highest-priority groups on each carbon are on the same side of the double bond, the configuration is Z (zusammen, meaning together).

• If they are on opposite sides, the configuration is E (entgegen, meaning opposite).

• Example: In 2-butene (CH₃CH=CHCH₃), compare the groups attached to the carbons of the double bond:

  • On the left carbon, you have a methyl group (CH₃) and a hydrogen. On the right carbon, you also have a methyl group (CH₃) and a hydrogen.
  • If the methyl groups are on the same side, it is Z-2-butene.
  • If the methyl groups are on opposite sides, it is E-2-butene.

Summary of Rules:

1. Atomic number: Higher atomic number → higher priority.
2. First point of difference: Compare the next set of atoms if necessary.
3. Multiplicity: Treat double/triple bonds as equivalent multiple bonds.
4. Isotopes: Heavier isotopes have higher priority.
5. R/S configuration: Assign clockwise (R) or counterclockwise (S).
6. E/Z configuration: Assign based on the relative positions of the highest-priority groups.

These rules are foundational for understanding and describing stereochemistry in organic molecules.