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I came across a naming convention which I haven't seen before. I let ChemDraw name the following compound for me and got a name containing lowercase "r" and "s" configurations.

Can someone tell me what this means and something about the actual convention behind it? I think it must have something to do with rings and maybe with some kind of "pseudo-chirality" due to a certain conformation of the ethyl group which is attached to the ring, but I'm only guessing.

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This notation is used to designate so-called "pseudoasymmetric carbons." This occurs in instances in which precisely two of the groups bonded to a tetrahedral carbon are structurally indistinguishable in terms of connectivity (i.e., the same atoms, bonded with the same multiplicity, and in the same order moving outward from the carbon whose absolute configuration is being assigned), but contain chiral centers which have opposite configurations. See the IUPAC Gold Book entry on pseudo-asymmetric carbons.

As for the molecule in your example, it is named incorrectly. There is an inherent symmetry present in 1,4-disubstituted cyclohexanes that prevents them from being chiral (except in cases where the substituents on the ring themselves contain chiral centers, which methyl and ethyl groups do not), and without any chiral centers in the molecule, there obviously can be no pseudoasymmetric carbons either. I would add, however, that cis/trans isomerism is, of course, possible for 1,4-disubstituted cyclohexanes, but that's entirely different from the property of chirality. The only stereochemical designator that could reasonably be added to the molecule from your example is "cis-".

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  • $\begingroup$ Thanks for the answer. Then ChemDraw seems to contain a bug when it comes to naming such compounds. But I'm using only version 12, so maybe version 13 has solved this issue. $\endgroup$ – Philipp Jul 16 '13 at 18:00
  • $\begingroup$ @Philipp, no problem. I suspect you're right that it is a bug. If you feel so inclined, you could file a bug report with the developers. $\endgroup$ – Greg E. Jul 17 '13 at 18:18
  • $\begingroup$ @Greg E. I too had a doubt with the above question.Isn't this the ABSOLUTE NOMENCLATURE propoqed by Cahn,Ingold and Prelog?? $\endgroup$ – user1811 Jul 29 '13 at 1:41
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    $\begingroup$ @AanalDesai, I'm not quite sure what you're getting at. The r/s- designators are certainly part of the Cahn-Ingold-Prelog ruleset, but they're not applicable to this molecule since it has no chiral centers. $\endgroup$ – Greg E. Jul 29 '13 at 2:03
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    $\begingroup$ The name (1​s,4​s)-1-ethyl-4-methylcyclohexane is correct. This is not a bug in ChemDraw. Note that the presence of stereogenic units such as pseudoasymmetric centers does not require the molecule to be chiral. The absolute configuration of achiral cyclic molecules is specified by CIP stereodescriptors, too. $\endgroup$ – Loong Aug 28 '16 at 16:49
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The name (1​s,4​s)-1-ethyl-4-methylcyclohexane is correct; it is even the preferred IUPAC name (PIN). It refers to the cis isomer of 1-ethyl-4-methylcyclohexane.

(1s,4s)-1-ethyl-4-methylcyclohexane

The preferred IUPAC name for the corresponding trans isomer is (1​r,4​r)-1-ethyl-4-methylcyclohexane.

(1r,4r)-1-ethyl-4-methylcyclohexane


In general nomenclature, according to Subsection P-93.5.1.2 of the current version of Nomenclature of Organic Chemistry – IUPAC Recommendations and Preferred Names 2013 (Blue Book), the stereodescriptors 'cis' and 'trans' may be used to denote the relative configuration of substituted monocyclic compounds.

P-93.5.1.2 Relative configuration: the stereodescriptors 'cis' and 'trans'

The stereodescriptors 'cis' and 'trans' are used to show the relationship between two ligands (atoms or groups) attached to separate atoms that are contained in a ring or a ring system. The two ligands are said to be located 'cis' to each other if they lie on the same side of a plane. If they are on opposite sides, their relative position is described as 'trans'. The appropriate reference plane of a ring or ring system (the ring being in a conformation, real or assumed, without reentrant angles at the two substituted atoms) is the mean plane of the ring(s). The stereodescriptors denote relative configuration; the absolute configuration must be described by CIP stereodescriptors such as 'R' and 'S'.

(…)

In preferred IUPAC names, all stereogenic units shall be specified (unless an omission is explicitly allowed). The presence of stereogenic units does not require the molecule to be chiral.

According to Subsection P-93.5.1.1.1, the absolute configuration in substituted monocyclic compounds shall be described by Cahn-Ingold-Prelog (CIP) stereodescriptors.

P-93.5.1.1.1 Absolute configuration

In substituted monocyclic compounds the absolute configuration is specified in preferred IUPAC names by the CIP stereodescriptors such as 'R', 'S', 'r', and 's'.

This rule explicitly applies to achiral cyclic compounds, too.

P-93.5.1.1.2 Achiral cyclic compounds

The configuration of achiral cyclic molecules is also specified by CIP stereodescriptors in preferred IUPAC names.

(…)

Therefore, this rule also applies to (1​s,4​s)-1-ethyl-4-methylcyclohexane, which is given in the question, and its isomer (1​r,4​r)-1-ethyl-4-methylcyclohexane. (The examples mentioned in the Blue Book include the similar compounds (1​s,4​s)-cyclohexane-1,4-diol, (1​r,4​r)-cyclohexane-1,4-diol, and (1​r,4​r)-4-chloro-4-methylcyclohexan-1-ol.)


The lower-case stereodescriptors 'r' and 's' are CIP stereodescriptors like 'R' and 'S'. The stereodescriptor 'r' or 's' is chosen by applying the CIP sequence rules as for the stereodescriptors 'R' and 'S'. However, the stereodescriptors 'r' and 's' are used to indicate the absolute configuration of pseudoasymmetric centers, whereas 'R' and 'S' are used to indicate the absolute configuration of real chirality centers.

P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors

Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called 'CIP stereodescriptors', are recommended to specify the configuration of organic compounds, (…), and in the nomenclature of natural products (…). The following stereodescriptors are used as preferred stereodescriptors (…):

(a) 'R' and 'S', to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;

(b) 'r' and 's', to designate the absolute configuration of pseudoasymmetric centers;

(…)

The 'pseudoasymmetric' is defined in Subsection P-92.1.1 (d) as follows.

Stereogenic units are called pseudoasymmetric (center, axis or plane) when they have distinguishable ligands 'a', 'b', 'c', 'd', two and only two of which are nonsuperposable mirror images of each other (enantiomorphic). (…). The 'r/s' (…) stereodescriptors describing a pseudoasymmetric stereogenic unit are invariant on reflection in a mirror (for example 'r' remains 'r', and 's' remains 's'), but are reversed by the exchange of any two ligands ('r' becomes 's', and 's' becomes 'r'). Lower case stereodescriptors are used to describe pseudoasymmetric stereogenic units.

For example, (2​R,3​r,4​S)-2,3,4-trichloropentane contains two chirality centers (labeled 'R' and 'S', respectively) and one pseudoasymmetric center (labeled 'r').

(2R,3r,4S)-2,3,4-trichloropentane

The two 1-chloroethyl ligands of the pseudoasymmetric center are nonsuperposable mirror images of each other. On reflection of the entire molecule in a mirror, the configurations of the chirality centers are reversed ('R' becomes 'S', and 'S' becomes 'R'), but the configuration of the pseudoasymmetric center is invariant ('r' remains 'r').

The same principle applies to (1​s,4​s)-1-ethyl-4-methylcyclohexane, which is given in the question.

(2R,3r,4S)-2,3,4-trichloropentane

The two halves of the 1,4-disubstituted cyclohexane are nonsuperposable mirror images of each other. Therefore, the compound contains two pseudoasymmetric centers, which are invariant on reflection in a mirror ('1​s,4​s' remains '1​s,4​s').


Although this case is explicitly mentioned in the Blue Book, it may not be obvious how to choose the stereodescriptors 'r' or 's' for 1,4-disubstituted cyclohexanes. The ranking is a complex process and requires the use of auxiliary descriptors.

Generally, the stereodescriptors 'r' and 's' are assigned by applying the Cahn-Ingold-Prelog (CIP) Priority System as for the stereodescriptors 'R' and 'S'. The order of precedence is reached by the construction of a hierarchical digraph and the application of the Sequence Rules.

The constitutional formula of a cyclic molecule is transformed into an acyclic digraph according to the methodology that is described in Subsection P-92.1.4.3 and which has been recommended by Prelog and Helmchen.

In order to obtain the acyclic digraph of a stereogenic unit, the didentate ligand (i.e. the ring) is transformed into two monodentate ligands by leaving intact in each case one bond with the core of the stereogenic unit and cleaving the other bond. At the end of each of the two branches thus obtained, a duplicate atom of the core is attached. (Note that this methodology is similar to the case of multiple bonds.) For example, for the pseudoasymmetric stereogenic unit at the atom numbered '1' of (1​s,4​s)-1-ethyl-4-methylcyclohexane:

Transformation of (1s,4s)-1-ethyl-4-methylcyclohexane into an acyclic digraph

where $\ce{(C)}$ is a duplicate representation of the core of the pseudoasymmetric stereogenic unit.

As the digraph is acyclic, it is now possible to specify the stereodescriptor 'R' or 'S' for the stereogenic unit at the atom numbered '4', which is carrying the methyl group, in each branch. These are auxiliary descriptors that are different in each branch.

auxiliary descriptors

Since the auxiliary descriptors are different, they allow the branches to be ranked using Sequence Rule 5, which states that 'R' has priority over 'S'.

P-92.1.3.5 Sequence Rule 5

An atom or group with descriptor 'R', 'M', and 'seqCis' has priority over its enantiomorph 'S', 'P' or 'seq Trans'.

Therefore, the configuration of the pseudoasymmetric stereogenic unit at the atom numbered '1' of (1​s,4​s)-1-ethyl-4-methylcyclohexane can be determined to be 's'.

Configuration of the pseudoasymmetric stereogenic unit

In the same way, the configuration of the pseudoasymmetric stereogenic unit at the atom numbered '4' of (1​s,4​s)-1-ethyl-4-methylcyclohexane can be determined as 's'.

Transformation of (1s,4s)-1-ethyl-4-methylcyclohexane into an acyclic digraph and determination of the configuration of the pseudoasymmetric stereogenic unit

Therefore, the complete configuration of (1​s,4​s)-1-ethyl-4-methylcyclohexane, which is given in the question, is indeed (1​s,4​s).

(1s,4s)-1-ethyl-4-methylcyclohexane

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  • $\begingroup$ ChemDraw16 confirms this, but Marvin 18.3 generates this: "(1s,4r)‐1‐ethyl‐4‐methylcyclohexane". I can't confirm that anywhere online, places like this pubchem.ncbi.nlm.nih.gov/compound/1-Ethyl-4-methylcyclohexane don't use r/s descriptors in any of the 63 synonyms they list and it seems like the IUPAC name should be "cis-1-Ethyl-4-methylcyclohexane". My confusion in what you wrote here is why it's valid to assign an R/S to an achiral site after sketching it as an acyclic digraph. I don't have easy access to the Blue book but the Gold book seems to require chirality in the ligands. $\endgroup$ – amos Feb 6 '18 at 14:49
  • $\begingroup$ I did some more reading about "auxiliary descriptors" here: onlinelibrary.wiley.com/doi/10.1002/anie.198205671/abstract (see their 1,3-cyclobutanediol example) and that really helped me understand how pseudo-asymmetric centers are identified. $\endgroup$ – amos Feb 12 '18 at 14:44
  • $\begingroup$ "The two halves of the 1,4-disubstituted cyclohexane are nonsuperposable mirror images of each other." I have some trouble understanding this. I have two doubts: (1) Would 1,4-dimethylcyclohexane need the s / r stereodescriptors? I think NO because it's superimposable on its two halves (2) Is the non-superimposability of the two halves of 1-ethyl-4-methylcyclohexane because of the ethyl group at one end? The ethyl has one extra sp3 carbon, which the methyl does not. Is this the reason? $\endgroup$ – Gaurang Tandon Mar 1 '18 at 11:19

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