Cahn Ingold Prelog priority rules
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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 to name the stereoisomers of a molecule. A molecule may contain any number of stereocenters and any number of double bonds, and each gives rise to two possible configurations. The purpose of the CIP system is to assign an R or S descriptor to each stereocenter and an E or Z descriptor to each double bond so that the configuration of the entire molecule can be specified uniquely by including the descriptors in its systematic name.

The Cahn-Ingold-Prelog rules are distinctly different from those of other naming conventions, such as general IUPAC nomenclature, since they are designed for the specific task of naming stereoisomers rather than the general classification and description of compounds.

The steps for naming molecules using the CIP system are often presented as:

1. Identification of stereocenters and double bonds
2. Assignment of priorities to the groups attached to each stereocenter or double-bonded atom
3. Assignment of R/S and E/Z descriptors

Assignment of priorities

R/S and E/Z descriptors are assigned by reference to a priority ranking of the groups attached to each stereocenter (or double-bonded atom, henceforth). The procedure for assigning these priorities (also known as the sequence rule) is the heart of the CIP system.

Two groups are compared first by atomic number of the atoms directly attached to the stereocenter; the group having the atom of higher atomic number receives higher priority. If there is a tie, a list is made for each group of the atoms bonded to the one directly attached to the stereocenter, i.e., the atoms at distance 2 from the stereocenter. Each list is arranged in order of decreasing atomic number. Then the lists are compared atom by atom; at the earliest difference, the group containing the atom of higher atomic number receives higher priority. If there is still a tie, each atom in each of the two lists is replaced with a sub-list of the other atoms bonded to it (at distance 3 from the stereocenter), the sub-lists are arranged in decreasing order of atomic number, and the entire structure is again compared atom by atom. This process is repeated, each time with atoms one bond farther from the stereocenter, until the tie is broken.

Some examples will help to illustrate the subtleties of this procedure:

• -OH > -CH₃. The -OH groups directly attached to oxygen have a higher atomic number (8) than the -CH₃ groups directly attached to carbon (6).
• -CH(OH)CH₃ > -CH₂OH. The directly attached atoms are both carbon, but the distance-2 lists differ: they are (O, C, H) and (O, H, H), respectively. The earliest difference is in the second slot, where the carbon atom of -CH(OH)CH₃ takes priority over the hydrogen atom of -CH₂OH.
• -CH(OCH₃)CH₃ > -CH(OH)CH₂OH. The distance-2 lists are both (O, C, H), a tie. Replacing each atom with a list of its neighbors, we obtain the distance-3 lists: ((C), (H, H, H), ( )) and ((H), (O, H, H), ( )). The earliest difference is in the atom bonded to the distance-2 oxygen: -CH(OCH₃)CH₃'s carbon outranks -CH(OH)CH₂OH's hydrogen. It is irrelevant that the oxygen in the second list outranks the corresponding hydrogen in the first list.
• -CH(CH₂F)OCH₃ > -CH(CH₃)OCH₂F. The distance-3 fluorine in -CH(CH₂F)OCH₃ outranks the hydrogens in -CH(CH₃)OCH₂F. One might reason that the distance-4 fluorine in -CH(CH₃)OCH₂F outranks the hydrogens in -CH(CH₂F)OCH₃ at an earlier point in the list once atoms are arranged by decreasing atomic number, but this is irrelevant because the tie is already broken at distance 3.

Isotopes

If two groups differ only in isotopes, mass numbers are used at each step to break ties in atomic number.

Examples:

• -CDH₂ > -CH₃. The distance-2 lists are (D, H, H) and (H, H, H); the deuterium in -CDH₂ outranks the hydrogen in -CH₃.
• -CH(OD)CH₃ > -CH(OH)CTH₂. The distance-2 lists are both (O, C, H), and the distance-3 lists are ((D), (H, H, H), ( )) and ((H), (T, H, H), ( )); the deuterium outranks the hydrogen.
• -CH₂CH₂CH₃ > -CDHCH₃. There is a difference in elements (not just isotopes), so the groups are compared solely by atomic number, and -CH₂CH₂CH₃ takes priority at distance 3. It is irrelevant that -CDHCH₃ has a deuterium at distance 2 where -CH₂CH₂CH₃ has a hydrogen.

Double and triple bonds

If an atom A is double-bonded to an atom B, A is treated as being singly bonded to two atoms: B and a ghost atom that has the same atomic number as B but is not attached to anything except A. In turn, when B is replaced with a list of attached atoms, A itself is excluded in accordance with the general principle of not doubling back along a bond that has just been followed, but a ghost atom for A is included so that the double bond is properly represented from both ends.

Examples:

• -CH=O > -CH₂OH. The distance-2 lists are (O, ghost O, H) and (O, H, H); the ghost oxygen outranks the hydrogen.
• -CH(OCH₃)₂ > -CH=O. The distance-2 lists are (O, O, H) and (O, ghost O, H). This is a tie, but at distance 3, nothing else is attached to the ghost oxygen, so it loses to the second oxygen of -CH(OCH₃)₂; the lists are ((C), (C), ( )) and ((ghost C), ( ), ( )).
• -CH=CH₂ > -CH(CH₃)₂. The distance-2 lists are (C, ghost C, H) and (C, C, H), a tie. However, at distance 3, the lists are ((ghost C, H, H), ( ), ( )) and ((H, H, H), (H, H, H), ( )); the ghost carbon representing the reverse direction of -CH=CH₂'s double bond outranks -CH(CH₃)₂'s hydrogens.

A triple bond is handled the same way except that A and B each carry two ghost atoms instead of one.

It needs to be mentioned also that two substituents on an atom may, in rare cases, be geometrical isomers. Consider for example the compound (3Z,6E)-3,5,7-trimethylnona-3,6-diene. It soon becomes clear that the 5-carbon is chiral because it has four different substituents. Thus it is necessary to introduce the rule that the Z-isomer has higher priority than the E-isomer.

Cycles

To handle a molecule containing one or more cycles, one must first expand it into a tree (called a hierarchical digraph by the authors) by traversing bonds in all possible paths starting at the stereocenter. When the traversal encounters an atom through which the current path has already passed, a ghost atom is generated in order to keep the tree finite. A single atom of the original molecule may appear in many places (some as ghosts, some not) in the tree.

Assigning descriptors

Stereocenters: R/S

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 substituents are numbered from 1 (highest priority) to 4 (lowest priority), then the sense of rotation of a curve passing through 1, 2 and 3 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.

It is possible in rare cases that two substituents on an atom differ only in their absolute configuration (R or S). If the relative priorities of these substituents need to be established, R takes priority over S. When this happens, the descriptor of the stereocenter is a lowercase letter (r or s) instead of the uppercase letter normally used.

Double bonds: E/Z

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.

Multiple descriptors in one molecule

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 superposable, 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

The following two papers define the CIP system. The papers provide a number of additional rules beyond the main points covered above, such as describing less common forms of stereoisomerism (such as chiral axes and planes), and resolving more difficult priority assignments. For example, note that the above rules fail to generate stereo descriptors for compounds such as (1s,2s,3s)-1,2,3-trichlorocyclopropane (in which all three chlorine atoms are on the same side of the ring).

• Robert Sidney Cahn; Christopher Kelk Ingold; Vladimir Prelog (1966). "Specification of Molecular Chirality". Angewandte Chemie International Edition 5 (4): 385-415. doi:10.1002/anie.196603851. 
• Vladimir Prelog (1982). "Basic Principles of the CIP-System and Proposals for a Revision". Angewandte Chemie International Edition 21 (8): 567-583. doi:10.1002/anie.198205671. 

Other references:

• J. March. Advanced Organic Chemistry 3Ed. ISBN 0-471-85472-7
• IUPAC Rules for the Nomenclature of Organic Chemistry. Section E, Stereochemistry (Recommendations 1974). [1]