Stereochemical descriptors 2: Assignment of configuration for helical and axial chirality

Introduction

Every undergraduate chemistry course covers the determinination of stereochemical descriptors (R/S) for tetrahedral stereocentres, and there has been an earlier blog about this HERE. But what about the other forms of chirality? How do you determine the descriptor for a chiral helix or an axially chiral molecule (a molecule with a stereogenic axis)? What about compounds with a plane of chirality (a stereogenic plane)? It turns out, that after I published the one page summary of stereochemical descriptors for stereocentres HERE, a surprisingly large number of people suggested I should do one for the other descriptors. Bizarrely, considering my love of [2.2]paracyclophane, this hadn’t even crossed by mind.

Today’s summary deals with helices and axial chirality, next week will handle my beloved cyclophanes (and the more contentious examples of metallocenes). Before we go any further:

The CIP Priority Rules: A Recap

In a desire to make this page standalone, it is necessary to quickly recap how to determine the priority of groups attached to a stereochemical element. This will be very brief, and for those that have already mastered the basics, I’ve added a couple of the more esoteric priority rules:

Rule 1: Higher atomic number has higher priority (#1) than lower atomic number (#2, #3 & #4).

Rule 2: If the atoms directly attached to the stereogenic element are the same, then compare the next atom in the chain until a difference is found (compare same position, so compare all 2nd atoms then all the third atoms).

Rule 3: Multiple bonds have the same number of single bonds

And if you want to get into complicated examples …

Rule 4: Higher atomic mass precedes lower atomic mass (isotopes)

Rule 5: Cis (Z) has higher priority than trans (E)

Rule 6: R is higher priority than S (and M higher than P (see below for the meaning of the helical descriptors))

But the compound above is achiral you cry! Yes, it has a plane of symmetry, but it is still necessary to define each stereocentre so that you can differentiate the diastereomers. In other words, the stereochemical descriptors are still important. The use of the lower case ‘s’ for atom 3 is a result of symmetry and reflects (no pun intended) that it is reflection invariant (or some such, I was never good with my symmetry operations and point groups).

There are more guidelines but this covers the vast majority of examples that most chemists ever meet. 

The CIP Priority Rules: Rule 0

There is one more rule that permits the descriptor of stereogenic axis and planes (as well as certain stereocentres, such as spirocyclic compounds like olean) to be determined.

Rule 0: The end of the axis, or side of the plane, closest to the viewer has the higher priority

It doesn’t matter which end or face you view the molecule the molecule from you will get the same descriptor if you apply this rule rigorously.

Stereochemical descriptor for helical chirality (in organic molecules)

Organic chemists rarely use helicity to define the chirality of molecules, preferring to stick to the more familiar R & S nomenclature of central/point chirality. So why am I covering it first? It has been argued (possibly even ‘recommended’) that it would be better to use helicity to describe the configuration of planes and axes of chirality. This argument has mostly fallen on deaf ears, but, by describing it first, I can include the helicity definitions in the following discussion of axes and planes.

Helicenes are a class of molecule that is said to be inherently chiral. All the molecules we have discussed so far have been chiral due to groups or substituents breaking the symmetry of an achiral scaffold. Inherently chiral molecules cannot be achiral, their very structure is chiral regardless of any groups attached to them (obviously, they can be racemic mixtures). To determine the stereochemical descriptor of a molecule such as a helicene:

Step 1 - identify the axis of the helix.

Step 2 - look along the axis. If the molecule rotates clockwise as you move from the front to the rear (away from viewer), the descriptor is P or plus. If the molecule rotates anticlockwise direction, it is M or minus.

This is shown for [6]helicene below:

Determining the configuration of [6]helicene - looking along the axis of the helix, if rotation is anticlockwise as you move away (front to rear) then the configuration is S. If it is clockwise then it is P.

The helical descriptors P and M have also been used to describe chiral conformers (which, if you think, about it is the majority of conformers). It is rare to see this used, presumably due to the ease of rotation around most bonds (and possibly, people just not caring that much ;) ), but the method described below will be used for axial and planar chiral molecules so is worth introducing:

Step 1 - Identify the axis of the helix (the bond being rotated).

Step 2 - Identify the highest ranked groups at the front of the axis (closest atom) and at the rear of the axis (distant atom).

Step 3 -  Draw the shortest possible arrow (smallest angle) from the front group to the back group.

Step 4 - If the arrow is clockwise the descriptor is P (plus). If it is anticlockwise, it is M (minus).

For example, you could discriminate the two gauche (synclinal) conformers of butane by using the helical stereochemical descriptor. Here the two methyl groups are the highest priority substituents and the diagram below shows how you could name the two conformations.

Differentiating the two gauche conformers of butane by defining the stereochemical descriptor of the helix.

To determine the descriptor, look along the axis of the helix, in this case the central C–C bond. Draw the arrow going from the highest priority group at the front of the axis to the highest priority group at the rear of the axis. If that arrow is rotating anticlockwise, as in the example on the left, the helix is M or minus.

The use of M and P is recommended for molecules with chiral axis and chiral planes, but is rarely used by organic chemists.

Stereochemical Descriptor for a Stereogenic Axis

Most organic chemists are comfortable with the R/S descriptors for stereogenic centres and use them for axial and planar chiral molecules as well. In the case of a stereogenic axis, this means treating the molecule as an elongated tetrahedron. After that, all the rules used for stereocentres can be followed, and the resulting descriptors are appended with an ‘a’ to indicate that it is a stereogenic axis (either R_a or aR and S_a/aS):

Examples of determining the stereochemical descriptor of an axis of chirality by considering it as an elongated tetrahedron.

This can be simplified by drawing the axis in the form of a Newman projection instead of manipulating a tetrahedron. Viewing the allene shown below from the lefthand side means the methyl group and the hydrogen atom are closer to the viewer and will have a higher priority than any groups on the back (furthest) atom. Thus the rankings are C = 1 and H = 2. The groups further from the viewer are ranked 3 and 4 according to the CIP rules. If a line connecting the highest priority groups 1→2→3 rotates clockwise, to the right, the descriptor is R_a or aR. If it is anti-clockwise, the descriptor is S_a or aS. It is unimportant which end of the axis you view the molecule from as long as you follow Rule 0 and give the closest groups priorities 1 and 2. This is highlighed by working through the determination of the configuration from the other side:

Simplified determination of the stereochemical descriptor for an axis. The direction the axis is viewed from is immaterial as long as the nearest groups take priority.

The assignment of the configuration of a biaryl compound, or any other atropisomer, is determined in the same manner. The stereogenic unit comprises of the six atoms around the bond with restricted rotation. It may be necessary to move out further along each group to differentiate the priorities. To assign the descriptor to the biaryl acid below, you would follow these steps:

Simplified determination of the stereochemical descriptor for a stereogenic axis in a chiral biaryl compound.

Step 1 - Identify and view the molecule along the axis (highlighted).

Step 2 - The groups on the nearest ring have a higher priority than those on the second ring.

Step 3 - Move outwards from the central bond until all four groups are ranked.

Step 4 - Draw a line starting at the highest priority and passing through the second priority to the third. 

Step 5 - If the line is clockwise, the descriptor is R_a and if it is anti-clockwise it is S_a.

There is an argument (and possibly IUPAC recommendations, although I confess I haven’t read the Gold Book recently) that an axially chiral molecule is better thought of as a helix and the descriptors P and M used (see below). This is probably true but is not common amongst organic chemists. Most literature uses R and S.

To use M or P slightly simplifies the above five steps. First, view the molecule along the axis by drawing a Newman projection. Instead of ranking all four groups coming off the axis just identify the highest ranking group at the near end of the axis and the highest ranking group at the far end (like you did with the conformer of butane). Draw an arrow from the group on the front to the group on the back so that it has the smallest angle. If the arrow is pointing clockwise the axis is P or plus. In the diagram below, I’ve performed these steps for the allene and biaryl that you determined the R/S configuration for earlier.

A stereogenic axis can be treated as a helix and the configuration assigned the descriptor P or M.

Generally speaking, S_a corresponds to P, and R_a to M, but note that this is specific for axially chiral molecules. The opposite relationship is true of planar chiral molecules.

Conclusion

This has been a brief introduction to determining the stereochemical descriptor for axial chirality using either R_a/S_a or P/M nomenclature. The former is more common within the chemical literature but it is not necessarily the recommended descriptor. Originally, I was going to include planar chirality into this summary, but that is a slightly more complicated area (cyclophanes and metallocenes get treated differently even though they are both classified as planar chiral) so this will have to wait until next week ... you lucky things.

There are bound to be mistakes in the above description. It was written at a rather busy time and hasn’t had its normal proof-reading (not that that always helps). If you spot mistakes, please point them out politely either in the comments or through Twitter.

At last, there are some practice questions HERE.