Revised Cahn-Ingold-Prelog Rules - IUPAC 2013

How to Manipulate JSmol Structures

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The lower numbered rule precedes the higher one.

Rule Description
1a
Higher atomic number precedes lower. Br > Cl > O > N > C > H
1b
Inner sphere identical atoms precede outer sphere identical atoms.
2
Higher atomic mass precedes lower. D > H; 13C > 12C; 81Br > 79Br
3
Seqcis precedes Seqtrans; Z precedes E and this precedes non-stereogenic double bonds.
4a
Chiral stereogenic units precede pseudoasymmetric stereogenic units which precede non-stereogenic units.
4b
Like pair R,R=lk or S,S=lk precedes unlike pair R,S=ul or S,R=ul; and M,M=lk or P,P=lk precedes M,P=ul or P,M=ul; and R,M=lk or S,P=lk precedes R,P=ul or S,M=ul; and M,R=lk and P,S=lk precedes M,S=ul or P,R=ul.
4c
'r' precedes 's'; 'm' precedes 'p'.
5
Atom or group descriptor 'R', 'M' or 'Seqcis' precede 'S', 'P' and 'Seqtrans', respectively.





(R)-1-Bromo-1-chloroethane

Fig. 1



(R)-Butan-2-ol

Fig. 3





(S)-1-Bromo-2-chloro-2-methylbutane

Fig. 5

CIP Rule 1a

The CIP rules are a heirarchical system for assigning configurations at stereogenic centers. Lower level rules are applied exhaustively before proceeding to the next level. Figures 1 and 2 are the two enantiomers of 1-bromo-1-chloroethane. Align the two structures as mirror images following the instructions located here. Four different atoms are attached to C1 creating chiral stereoisomers in what is referred to as the first sphere. The higher the atomic number, the higher the priority of the atom: Br > Cl > C > H. To assign the CIP configuration apply the "hand rule", which is described here. Confirm your R/S assignment by clicking the "show R/S" button in Fig. 1 and 2.

 

 

 

 

 

Fig. 3 represents (R)-butan-2-ol and Fig. 4 is the digraph of butan-2-ol. All atoms in the digraph are treated as if they were quadrivalent even though some are not. Note that the oxygen in sphere 1 is not only connected to a hydrogen but also it is attached to two ""0's" in sphere 2. These two atoms are known as phantom atoms and have an atomic number of zero. This level of rigor is only required in special cases. To assign the configuration of C2, only the atoms in spheres 1 and 2 are required. In sphere 1, O > C1 = C3 > H. To distinguish between C1 and C3, their attachments in sphere 2 must be evaluated. Each one is, respectively, connected to H,H,H and C4,H,H. Because C4 > H, the priorities are O > C3 > C1 > H. Butan-2-ol in Fig. 3 is of the (R)-configuration.

 

 

 

In most cases hydrogen is the lowest priority atom. But that need not be the case. In Fig. 5 C2 has four different groups attached to it none of which is hydrogen. The digraph Fig. 6 determines the priorities. Sphere 1 has Cl > C1 = C3 = C5. Sphere 2 resolves the secondary priorities in the following order: C1[Br,H,H], C3[C,H,H] and C5[H,H,H]. Note that the triads in brackets in sphere 2 are listed in descending order. A decision is made in the first position: Br > C > H. Accordingly, 1-bromo-2-chloro-2-methylbutane in Fig. 5 has the (S)-configuration. In this digraph the phantom atoms were ignored. There presence was not required for the determination of the C2-configuration.

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(S)-1-Bromo-1-chloroethane

Fig. 2

 


Butan-2-ol

Fig. 4




1-Bromo-2-chloro-2-methylbutane

Fig. 6




(S)-1-(2H)-Ethanol

Fig. 7

CIP Rule 2

Isotopes are ranked by descending mass. The more common isotopes that are encountered are deuterium (2H) and carbon-13 (13C).

Place your cursor over the dark blue atom in ethanol in Fig. 7. It reads "D7 #7". The presence of deuterium at C1 produces stereochemistry at this carbon. The priorities are O > C > 2H > 1H in sphere 1. C1 has the (S)-configuration.

Place your cursor over the black carbon in 2-methylbutane in Fig. 8. It reads "13C5 #5". C2 has the priorities C3[C,H,H] > 13C[H,H,H] > 12C[H,H,H] > H. C2 has the (R)-configuration.

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(R)-2-(13C)-Methylbutane

Fig. 8





(R,2Z,5E)-3,5-dichlorohepta-2,5-dien-4-ol

Fig. 9

CIP Rule 3

The dichlorodienol in Fig. 9 is chiral by virtue of the stereochemistry of the double bonds. Using the CIP rules for the E/Z stereochemistry of double bonds, the 2,3-double bond is Seqcis (Z) and the 5,6-double bond is Seqtrans (E). Because Seqcis > Seqtrans (Z > E), C4 has the (R)-configuration with the priorities: O > Z > E > H. Note: If the two chlorine atoms were hydrogens, then C4 would have the (S)-configuration.

Click "show carbon #" in Fig. 10. Double bond C4-C5 is stereogenic while double bond C7-C8 is non-stereogenic. In the former case C4 has a (Z)- and (E)-double bond attached and in the latter case C8 has two (Z)-double bonds attached to it. Click "show R/S-E/Z". The stereogenic double bond has the (Z)-configuration because the C2-C3 double bond (Z) has priority over the C12-C13 (E) double bond and C6 > H. The non-stereogenic double bond (C7-C8) has no designation. Because stereogenic units precede non-stereogenic units, the priorities for C6 are O > C4-C5 > C7-C8 > H. C6 has the (R)-configuration.

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(R,2Z,4Z,9Z)-4-((E)-Prop-1-en-1-yl)-8-((Z)-prop-1-en-1-yl)undeca-2,4,7,9-tetraen-6-ol


Fig. 10





(2R,4R,5s,6S)-3,5-bis((R)-1-hydroxyethyl)heptane-2,4,6-triol

Fig. 11a





(2S,3R,4S,5S,6S)-heptane-2,3,4,5,6-pentaol

Fig. 12a



(2S,3r,4S,5s,6S)-3,5-bis((R)-1-hydroxyethyl)heptane-2,4,6-triol

Fig. 13a








(2S,3r,4R,5S,6S,7s,8S)-3,7-bis((R)-1-hydroxyethyl)
nonane-2,4,5,6,8-pentaol

Fig. 14a










(2S,3s,4R,5S,6S,7r,8S)-3,7-bis((R)-1-hydroxyethyl)nonane-2,4,5,6,8-pentaol

Fig. 15a

CIP Rule 4a

Pentaol 11 has a non-stereogenic center (C3), among four others, and a pseudoasymmetric center (C5). The former situation arises because C2 and C8 both have the same stereochemistry---namely (R). That is, two of the groups attached to C3 are identical and no configuration can be assigned. On the other hand C5 has the same groups attached to it but C5 is (R) and C10 is (S). They are enantiomeric thereby rendering C5 pseudoasymmetric.The priorities for C5 are, therefore, C4 > C5 > C3> H. C5 has the (s)-configuration. Accordingly, C4 has the (R)-configuration because C5 > C3.

 

 

 

CIP Rule 4b

The linear pentaol 12a has the configurations at four carbon centers determined by Rule 1a except for C4. Digraph 12b shows how the stereochemical assignmnet is made. The horizontal line is the carbon chain and the dotted line is C4, the root or target atom. Bold hydroxyl groups are above the horizontal line and dashed hydroxyl groups are below the line. One might conclude that the priorities for C4 are O > C3 > C5 > H because R > S. and C4 would have the (R)-configuration. This analysis applies only when C4 is pseudoasymmetric, which it is not. Like (lk) pairs of atoms precede unlike (ul) pairs. Thus, SS > RS. C4 has the (S)-configuration because O > SS > RS > H. This is a basic analysis. For more complex cases, visit the inositols.

 

 

CIP Rule 4c

 

 

The pentaol of Fig. 13 is similar to the example in Rule 4a except that C3 and C5 are both pseudoasymmetric bearing enantiomeric, identical groups. The priorities for both centers are O > R > S > H thereby assigning the (r)-configuration to C3 and the (s)-configuration to C5. Accordingly, C4 has the priorities O > r > s > H. C4 has the (S)-configuration.

 

 

 

 

 

 

 

 

The assignment of the S-configuration to C5 of heptaol 14 seemingly is determined by the sequence O>R>S>H. But this is not the case. The configuration is the result of the priorities O>r>s>H because the CIP heirarchy dictates that r/s (Rule 4c) precedes R/S (Rule 5). This issue is more pronounced in Fig. 15 below.

 

 

 

 

 

 

 

 

 

 

 

In Fig. 15 the pseudoasymmetric centers of C3 and C7 are switched (se Fig. 15b) from what they were in Fig. 14 with the configurations at C4 (R) and C6 (S) remaining unchanged. Click the "show R/S" button in Fig. 15a. Notice that C5 has the R-configuration. This result is consistent with the configuration being determined by the r/s carbons (C3 and C7) and not the R/S (C4 and C6) ones.

 

 

(2R,4R,5s,6S)-3,5-bis((R)-1-hydroxyethyl)heptane-2,4,6-triol

Fig. 11b

 

 



(2S,3R,4S,5S,6S)-heptane-2,3,4,5,6-pentaol

Fig. 12b



 



(2S,3r,4S,5s,6S)-3,5-bis((R)-1-hydroxyethyl)heptane-2,4,6-triol

Fig. 13b








(2S,3r,4R,5S,6S,7s,8S)-3,7-bis((R)-1-hydroxyethyl)
nonane-2,4,5,6,8-pentaol

Fig. 14b








(2S,3s,4R,5S,6S,7r,8S)-3,7-bis((R)-1-hydroxyethyl)nonane-2,4,5,6,8-pentaol

Fig. 15b




(2R,3r,4S)-pentan-2,3,4-triol

Fig. 16a



(3M,5r,7P)-5-ethyl-5-methylnona-2,3,6,7-tetraene

Fig. 17a



(4S,2Z,5E)-hepta-2,5-dien-4-ol

Fig. 18a





Rule 5

 

After the preceding four rules have been exhausted, Rule 5 applies. The middle carbon (C3) in Fig. 16 is stereogenic and achirotopic. That is to say, it is pseudoasymmetric in that it is flanked by two mirror image groups at C2 and C4. The configuration of the latter two centers is determined by Rule 1a. The priorities at C3 are O > R > S > H. Therefore, C3 has the r-configuration.

 

 

 

 

 

C5 in the bis-allenic compound of Fig. 17 is also stereogenic and achirotopic (pseudoasymmetric) with an r-configuration. The two allenic residues C3 and C7 are enantiomeric and of the M and P configuration, respectively. The priorities for C5 are M > P > C2H5 > CH3. The allenic residues take priority over the ethyl and methyl groups through rule 1a.

 

 

 

 

 

 

 

C4 of the dienol of Fig. 18 has the S-configuration and not of the s-configuration. This is because the E and Z-double bonds are not mirror images but stereoisomeric unlike the examples of Figs. 14 and 15. The S-configuration arises from the priorities O > Z > E > H.

 

 

(2R,3r,4S)-pentan-2,3,4-triol

Fig. 16b

 

 

 

 

 

 

(3M,5r,7P)-5-ethyl-5-methylnona-2,3,6,7-tetraene

Fig. 17b

 

 

 

 

 

 

 

 

(4S,2Z,5E)-hepta-2,5-dien-4-ol

Fig. 18b






Fig. 17

 

 

 

Rule 1b

[Rule 1b has been placed out of order and last because to understand it requires a grasp of linear, stripped-down digraphs. You might benefit by looking at rules 2-5 first. If not, a fuller treatment of digraphs is located here. The example in Fig. 16 is from the IUPAC Blue Book 2013.]

The assignment of the (S)-configuration to C5 in the accompanying bicyclohexene presents a problem. A linear digraph is constructed that omits hydrogens and attaches duplicate atoms shown in parentheses for the double bond. There are six possible pathways from C5 around the rings and back to duplicate C5 [shown as (5)]. Consequently, there are six duplicate C5's. The lowest priority group in sphere 1 is hydrogen and the highest priority carbon group is C1[C,C,H] while C4[C,H,H] and C6[C,H,H] are tied for the middle two priorities. But this latter issue cannot be resolved by Rule 1a because these two pathways in the digraph have the same substitution pattern! Hence, Rule 1b was created which states that the duplicate atom, i.e., (5), closest to the root atom, i.e., C5, takes priority over the more remote ones. In the right hand pathway the closer (5) is in sphere 3 while in the left hand pathway the closer (5) is in sphere 5. Therefore, the overall priorities for C5 are C1 > C6> C4 > H. C5 has the (S)- configuration.

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