Welcome to another blog post about another type of stereoisomer, Atropisomers! 

“Atropisomers” is a word that is derived from Greek. “A” means “not” while tropos means “turn”.  

Now that we know what the different parts of the term means, this leads in nicely to the definition of atropisomers. Atropisomers are a result of hindered rotation about  single bonds  where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers [1]. To better understand the definition, let us recap some of the terms we have learnt.  

Firstly, steric strain refers to the repulsive interaction between two atoms or groups of atoms that are brought into close proximity and forced to occupy the same physical space in a way that is more than what the atomic radii allows. Secondly, conformers refer to different spatial arrangements of the same compound that are easily converted through rotation about a single bond.  

Usually, the free rotation of atoms in organic molecules with single bonds is possible, leading to different conformers [2]. However, in the case of atropisomers, there is so much steric strain that the molecules are unable to rotate. They interconvert with a half-life greater than 1000 seconds at a particular temperature so we are able to observe them separately. They are able to over come the steric energy barrier but it will take time, ranging from months to even decades. 

Atropisomers display axial chirality, in which there is a non-planar arrangement about an axis. They are enantiomers although they do not have chiral carbons. Hence, the atropisomers have rotate plane polarised light in different directions. While other chiral isomer compounds are able to achieve equilibrium by means of chemical methods, atropisomers are able to achieve an equilibrium thermally. Atropisomers can be separated via methods such as selective crystallisation. 

Examples  

An example of atropisomers is 6,6’-dinitro-2,2’-diphenic acid (Fig. 1). In fact, atropisomers was first detected in this particular molecule by Cristie back in 1922. In the case of this compound, when the aromatic compounds linked by a single bond tries to rotate, there is high steric strain due to the projection of the carboxylic acid groups and nitro groups projecting from the rings. As such, the aromatic rings are unable to rotate freely, and the compounds do not interconvert at room temperature and hence can be isolated separately. 6,6’-dinitro-2,2’-diphenic acid is a biaryl, which is an important class of atropisomers. 

 

Other examples of atropisomers are dimers of naphthalene derivatives such as 1, 1’-bi-2-naphthol (Fig 2.). Just like how aromatic ring systems with bulky substituents can create compounds that display atropisomerism, aliphatic ring systems such as cyclohexane can also show atropisomerism when bulky substituents are present. Other structures that can form atropisomers include bicyclic structures and hindered amides.  

  

Stereochemical Assignment 

In the case of atropisomers, the stereochemistry can be determined by using Newman projection. This projection will be done along the chirality axis. The substituents are assigned priority via the Cahn-Ingold-Prelog (CIP) rules [3]. In this case, the 4 substituents may not vary so if there are substituents that are the same, the substituents that are in front will be given a higher priority than the substituents further away by the proximity rule [4]. When moving from the substituent of the highest priority to the substituent of the lowest priority, the direction of movement will tell us whether the isomer is in a P or M configuration. If the direction is clockwise, it would be a P configuration. On the other hand, if the direction is counter-clockwise, the isomer would be in the M configuration. In order to be similar to the usual assignment of stereochemistry in compounds with a chiral centre, the P configuration is also known as the Ra configuration while the M configuration is also known as the Sa configuration.  

For example, when we are looking at the case of 6,6’-dinitro-2,2’-diphenic acid in Figure 3 below, we get the Sa configuration of the atropisomer. In this case, a has the highest priority, followed by b, c and d which has the lowest priority.  

 

References

1. Singh, K., P. Shakya, A. Kumar, S. Alok, M. Kamal, and S. Praksh. Stereochemistry and its role in drug design. 2014. International.
2. Ngyuen,T. Giving atropisomers another chance. 2018; Available from: https://cen.acs.org/pharmaceuticals/drug-development/Giving-atropisomers-another-chance/96/i33 

3. Applying R,S descriptors to biaryls. 2013; Available from: https://personalpages.manchester.ac.uk/staff/T.Wallace/20412tw2/3.2.4_RS_in_biaryls.html 

4. Werbung. Naming of the Absolute Configuration of Molecules with a Chirality Axis. Available from:
   http://www.chemgapedia.de/vsengine/vlu/vsc/en/ch/12/oc/vlu_organik/stereochemie/ weitere_chiralitaetselem.vlu/Page/vsc/en/ch/12/oc/stereochemie/benennung_axial/ benennung_axial.vscml.html