Cahn-Ingold-Prelog priority rule

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File:Cahn-Ingold-Prelog-priority-diagram.png
An example of the prioritisation of structure within the CIP system. Priority is assigned according to the substitution of elements with higher atomic numbers, or other attached groups

The Cahn-Ingold-Prelog priority rules, CIP system or CIP conventions are a set of rules used in organic chemistry. Based upon the atomic number and the first point of reference, the rules determine the orientation and definition of geometric and configurational enantiomers and diastereomers, as well as bonded properties such as double bonds present in alkenes. Any atom attached to a stereocenter or double bonded system such as that of alkenes, is given a Cahn-Ingold-Prelog priority based on the atomic number or, in the case of isotopes, the mass number.

The Cahn-Ingold-Prelog rules are distinctly different to those of other naming conventions, such as IUPAC nomenclature due to the fact it is largely concerned with determining the orientation of isomers, rather than the simple classification of compounds.

Convention

The convention itself defines the priority of isomers relative to their composition and bonded properties. The general rules of CIP priorities are determined through examination of the isomer's bonded units or subunits, and their relative position to the stereocenter of the isomer.

Common steps for identifying via the CIP are often presented as:

  1. Determination of the chiral center (often referred to as the stereogenic center)
  2. Priority assignation of units
  3. Positioning of the lowest priority unit away from the observer.
  4. Determination of other units (rectus or sinister)

Assigning the R/S configuration descriptors to a stereocenter

If two atoms attached to the stereocenter have the same atomic number, then the atomic number of the atoms bonded to these atoms is compared. The atom of highest atomic number on the first bonded atom is compared to the atom of highest atomic number on the second bonded atom, then the atoms of second highest atomic number are compared, and so on. If the atoms directly bonded to the stereocenter are bonded to exactly the same set of atoms, then the two atoms of highest priority are compared in the same fashion.

If these are equivalent, the process would continue on the atoms of highest atomic number that are attached to the last evaluated piece. If these prove to be the same through the end of the molecule, the bonds to the atoms of second highest value would be compared next (starting these comparisons at the last point of difference, not the first.) Any double or triple bonds are counted as if the atom was attached to two or three, respectively, of the atom it is bonded to. If the atom contains specific isotopes of atoms then these are compared only if everything else is the same.

It should also be noted that a common misnomer is to label tetrahedral atoms with four distinct substituents as chiral centers. This is incorrect, since the fact that the center has such a structure does not mean that it is part of a chiral molecule. It may be part of a molecule which is an optically inactive diastereoisomer. They should correctly be labeled as stereocenters. Furthermore, chirality is a topological property which pervades the entire molecule, and is not localized to a single atom or group of atoms.

Examples:
-CH2OH outranks -C(CH3)3 (As O (Z = 8) is a higher priority than C (Z = 6) on the second atom along)
-CH2Br outranks CH2OH
-CH=O outranks -CH(CH3)OH
-CH2CH2CH3 outranks -CH(CH3)D, although -CH2D outranks -CH3

Positioning of lowest-priority unit

After the substituents of a stereocenter have been assigned their priorities, the molecule is so oriented in space that the group with the lowest priority is pointed away from the observer. If the lowest priority substituent is assigned the number 1, and the highest 4, then the sense of rotation of a route passing through 4, 3 and 2 distinguishes the stereoisomers. A center with a clockwise sense of rotation is an R or rectus center and a center with a counterclockwise sense of rotation is an S or sinister center. The names are derived from the Latin for right and left, respectively.

Determination of other bonded units

For alkenes and similar double bonded molecules, the same prioritizing process is followed for the substituents. In this case, it is the placing of the two highest priority substituents with respect to the double bond which matters. If both high priority substituents are on the same side of the double bond, ie. in the cis configuration, then the stereoisomer is assigned a Z or Zusammen configuration. If, by contrast they are in a trans configuration, then the stereoisomer is assigned an E or Entgegen configuration. In this case the identifying letters are derived from German for 'together' and 'in opposition to', respectively.

It is important to note that there can be more than one of each type of system requiring assignment in a particular molecule. For example, ephedrine exists in both 1-(R), 2-(S) and 1-(S), 2-(R) forms. A compound with the same formula also exists in 1-(R), 2-(R) and 1-(S), 2-(S). Said stereoisomers are not ephedrine, but pseudoephedrine. They are chemically distinct from ephedrine, with only the three dimensional configuration in space, as notated by the Cahn-Ingold-Prelog rules to distinguish them in systematic nomenclature (both are 2-methylamino-1-phenyl-1-propanol in systematic nomenclature). The ephedrine enantiomers are referred to as being diastereoisomers of the pseudoephedrine enantiomers. In general where there are n stereocenters, there will be 2n stereoisomers possible. However, often there are situations where some of these stereoisomers are superimposable, reducing the number of different molecules which actually exist.

Faces

Stereochemistry also plays a role assigning faces to trigonal molecules such as ketones. A nucleophile in a nucleophilic addition can approach the carbonyl group from two opposite sides or faces. When an achiral nucleophile attacks acetone, both faces are identical and there is only one reaction product. When the nucleophile attacks butanone, the faces are not identical (enantiotopic) and a racemic product results. When the nucleophile is a chiral molecule diastereoisomers are formed. When one face of a molecule is shielded by substituents or geometric constraints compared to the other face the faces are called diastereotopic. The same rules that determine the stereochemistry of a stereocenter (R or S) also apply when assigning the face of a molecular group. The faces are then called the re-faces and si-faces. In the example displayed on the right, the compound acetophenone is viewed from the re face. Hydride addition as in a reduction process from this side will form the S-enantiomer and attack from the opposite Si face will give the R-enantiomer.

References

  • J.March Advanced Organic Chemistry 3Ed. ISBN 0-471-85472-7

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