Cahn-Ingold-Prelog Priority Rules

Robert Sidney Cahn, Christopher Kelk Ingold, and Vladimir Prelog came up with a system of nomenclature in 1965, that assigned the names to R-S, cis-trans, and E-Z molecules. The Cahn-Ingold-Prelog set priority rules stated that a group with more atomic number, isotopic priority, secondary position priority (by atomic number), and multiple numbers of bonds can be assigned priority over other functional groups.

CIP priority rules have the following deciding factors;

  1. Atomic numbers
  2. Secondary groups
  3. Post-secondary groups
  4. Isotopic priority
  5. Multiple bonds
  6. Molecular rotation (arrangement)

This set of nomenclature rules was named after these three scientists namely Cahn, Ingold, and Prelog (CIP) rules.

Why the CIP rules?

Cahn Ingold Prelog (CIP) rules assign the R and S nomenclature configuration to compounds with one stereocenter and E and Z nomenclature to double bonds. This way entire molecules can be uniquely specified by including R/S and E/Z descriptors to the IUPAC nomenclature.

The applications of Cahn, Ingold, and Prelog rules, i.e. the R/S nomenclature is used for absolute configuration of chiral molecules. The E/Z nomenclature systematics instead are mostly used for configuration across double bonds i.e. naming alkenes.

According to CIP rules, a compound is feasible to be named R/S or E/Z if the said molecule is chiral, or double bonded. Chiral molecules get R/S while (planar) double bonded molecules get E/Z configuration.

For example,

To give a name to the two enantiomers of stereoisomers like that of butan-2-ol, we must assist Cahn Ingold and Prelog’s rules.

Image of 2-butanol without RS configuration

Both the enantiomers of butan-2-ol have the same name as per the IUPAC system of nomenclatureThe R and S configuration of butan-2-ol gives the required distinction between the names of these enantiomers.

2-butanol with RS configuration

The first one has been named S-butan-2-ol because the priority order of its functional groups indicates an anticlockwise sequence, hence the configuration S.  For the next one, i.e. R-butan-2-ol, the priority order suggests a clockwise order hence the configuration R. This rule can be turned to a mnemonic such as;

Clockwise order = R configuration

Anticlockwise order = S configuration

It can be remembered as the C R (Class Representative).

Configuring cis-trans Isomers

The three-dimensional arrangement of groups about a stereocenter in a molecule is termed its configuration. It is the permanent geometry that results from the spatial arrangement, [three-dimensional (in this case)] of the bonds in a molecule.

Cis/Trans isomers are simply given names by writing prefixes cis or trans to the IUPAC nomenclature of compounds. The ‘cis’ means that two high-priority functional groups are on the same side of the double bond, while ‘trans’ means that those groups are on opposite sides. Now, as the priority order decides the whole ‘cis/trans’, first we need to set these rules.

Configuring E/Z Isomers

Sometimes, cis/trans terms are ambiguous. For example, the following compound’s IUPAC name is 1-chloro-1-fluoro-1-propene. One cannot designate whether it is cis or trans stereoisomer.

1-chloro-1-fluoro-1-propene - the ambiguous case of cis/trans

To designate the name to this type of compound, a set of rules E/Z configuration is introduced. The Z (from the German word zusammen, meaning together) and E (from the German word entgegen, meaning opposite). In this terminology, Z indicates that higher priority groups are on the same side of a double bond and E indicates these high priority groups are on opposite sides.

So, the priority order is the deciding factor here as well. These priorities are assigned by rules known as Cahn-Ingold-Prelog rules.

Cahn-Ingold-Prelog Rules

The unambiguous method of assigning handedness to stereoisomers was introduced by three scientists i.e. R. S. Cahn from London, C. K. Ingold also from London, and V. Prelog from Switzerland. This stereoisomerism can be analyzed by some experimental techniques like X-ray diffraction or chemical correlation with pre-analyzed x-ray diffracted compounds.

The priority orders according to CIP rules are assigned by the following rules:

Wedge and Dash

It is a three-dimensional representation of bonds necessary to understand CIP rules. A wedge (▲) shows the projection of a bond towards you (out of the page), while a dash (∆) or (≡) shows a bond away from you (into the page).

Rule 1 (Atomic numbers)

Atomic numbers are the primary basis of the priority of one group over another. All other rules are, in fact, secondary to this rule.

For stereogenic centers, the priority order is decided according to the atomic numbers of functional groups.

Rule no 1 for Cahn Ingold and Prelog Priority rules

In E/Z isomers, when different atoms are attached to the double-bonded carbons, the one with a higher atomic number has the higher priority. 

For example, the 1-chloro-1-fluoro-1-propene can be given the configuration ‘Z-compound’ because of the priority order Cl > F. It means that Cl, which has more priority has a CHbranch on the same side. Hence, the configuration ‘Z’ for ‘together’ or ‘same sides’.

Z-1-chloro-1-fluoro-1-propene - the ambiguous case of cis/trans

Rule 2 (Secondary substituents)

If in case, two bonds on a stereogenic center encounter the same element, like there is no difference between in primary stage, we then proceed to the secondary positions. In other words, if the first element doesn’t differ for priority order, the next atoms bonded to that atom do the differentiation. 

Rule no 2 for Cahn Ingold and Prelog Priority rules

The butan-2-ol drawn above is configurated as ‘S’, not an R because the priority order suggests an anticlockwise order. It is because of this rule, that the second carbon of CH2 gets a lead over the CH3 branch.

If -CH3 (order no 3) was to be given priority over -CH2CH3 (order no 2), it would be against this rule of Cahn Ingold Prelog priority rules, and the compound would have been ‘R’ configured.

Rule 3 (Post-secondary substituents)

Rule no 4 is a subsidiary of rule no 3. It says that if somehow, the secondary positions of two groups match too, this process must go on until a clear difference is obtained.

Rule no 3 for Cahn Ingold and Prelog Priority rules

Due to this rule no 3, the above molecule is ‘R’ configured, not ‘S’ configured.

Rule 4 (Isotopic priority)

Isotopic priority is also a subsidiary rule of rule no1, except, atomic weights are counted instead of atomic numbers.

Rule no 4 for Cahn Ingold and Prelog Priority rules

Isotopic priority is what makes the above compound ‘S’ configured according to Cahn-Ingold-Prelog priority rules.

Rule 5 (Double and Triple bonds)

Double and triple bonds that are part of the groups attached to double bonds are considered as they are constructed from two or three single bonds, respectively.

Rule no 5 for Cahn Ingold and Prelog Priority rules

The functional groups of molecules with multiple bonds are prioritized according to Cahn Ingold Prelog rules as;

triple bonds > double bonds > single bonds

Rule no 5 for Cahn Ingold and Prelog Priority rules

The above molecule is, therefore, ‘R’ configured.

Rule 6 (Molecular Rotation)

Hydrogen being the least priority holder group among functional groups, should always be on the backside of the molecule (with a dash) or (facing away). This gives the correct configuration of a stereoisomeric molecule.

Rule no 6 for Cahn Ingold and Prelog Priority rules

Flipping the above molecule corrects its configuration. Before it was wrongly configured as R, but it gets corrected once the least priority group goes backward.

Designating The Configuration Of Enantiomers

Cahn-Ingold-Prelog priority rules also apply to enantiomers of the chiral compounds. The following steps are involved for assigning R/S configuration. 

Priorities are assigned according to Cahn-Ingold-Prelog rules, starting from 1. The least priority groups are always pointed away from the viewer. There is either a chance of clockwise or counterclockwise priority order in that molecule. If the rotation is clockwise, the configuration is R (from Latin word rectus, which means right). If the rotation is counter-clockwise, the configuration is S (from the Latin word sinister, which means left).

Key Takeaway(s)

  • Cahn-Ingold-Prelog priority rules have been adopted by the International Union of Pure and Applied Chemistry (IUPAC).

Cahn Ingold Prelog Priority order - Image

Concepts berg

How do you rank substituents in order of Cahn-Ingold-Prelog priorities?

The ranking is made upon the reactivity and electronegativity basis. Grater the electronegativity greater would be the priority given and so on.

How do you use Cahn-Ingold-Prelog (CIP rules)?

Cahn Ingold Prelog rules are used in the configurational naming of organic compounds. By the IUPAC system, they are named in a systematic way, and CIP priority rules organize the prefix to that systematic name. For example R/S or E/Z or cis/trans.

Which has more priority according to CIP rules, Cl or NO2?

The Nitro group has more priority according to CIP rules because it has more electronegative atoms, oxygen attached to it. Moreover, THe mass no of Nitro (NO2) is also greater than the chloro (Cl) group.

What is the R/S configuration?

R/S configuration is the naming system for optical isomers i.e. with a chiral center and geometrical isomers as well. If the groups are in clockwise priority order, it’s called ‘R’ configured molecule, while the Anticlokwise priority shows ‘S’ configuration.

What is the difference between RS and DL configuration? Are they the same?

RS configuration is assigned on the basis of priority groups arrangements around the chiral center whereas, the Dextro or Levo configuration is due to the optical rotation of plane-polarized light when passed through a molecule. If the optical rotation of light by the substance is clockwise it will be named Dextro (+), while the left-sided rotation is known as Levo (-). 

How does a double bond influence chirality?

Some double bonded molecules are optically active. For example (biphenyl) has no chiral center but still rotates the plane polarised light. This is how they influence chirality.

Does cyclohexene show cis-trans isomerism?

Cis trans isomerism is the geometric isomerism due to different substituents present along with the double bonds. Cyclohexene has the same Hydrogens at all ends so cis-trans is not possible here.

Following the Cahn, Ingold Prelog priority rules CIP rules which has more priority isobutyl or butyl?

Isobutyl has more priority due to the high priority secondary methyl group attached instead of two hydrogens, as in n-butyl.

Which have the highest priority according to the Cahn-Ingold-Prelog sequence rules?

Atomic numbers, Isotopic priority, and secondary positions determine the CIP priority sequence.

Which among halogen and alkyl groups has less priority?

Halogens have a general priority above alkyl groups suggested by the IUPAC system of nomenclature, not the CIP.

References books

  • Organic chemistry by Joseph M. Hornback (Faculty of Chemistry, University of Denver, Denver, Colorado)
  • Organic chemistry by T. W. G. Solomons (Department of Chemistry, University of South Florida) & C. B. Fryhle (Chair and Professor of Chemistry at Pacific Lutheran University)
  • Chiral Analysis edited by Kenneth W. Busch (Baylor University, Waco, Texas, USA), Marianna A. Busch (Baylor University, Waco, Texas, USA)

Reference links

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