Structure-drawing conventions to define configurations
We live in a 3D world, but our tools for exchanging information remain mostly 2D. (This is true whether we’re working digitally or on paper.) To work around that limitation, humans have developed some clever methods. Artists have perspective, and chemists have stereo bonds.
Chemical structure drawings include many conventions for indicating configurations, from Fischer projections to a carbohydrate chemist’s chair conformations. But the simplest and most widely used is probably the dashed and solid wedges convention. (Dashed wedges indicate bonds pointing “below the page,” away from the viewer. Solid wedges indicate bonds pointing “above the page,” towards the viewer.)
Figure 1. Wedged bonds indicate the configurations of two chiral centers.
This system will seem elementary and unambiguous to most chemists. It’s simple enough that we teach it to secondary and first-year undergraduate students. It allows us to define 3D arrangement of atoms in 2D media.
But there are some limitations it doesn’t fully resolve.
Enhanced stereochemistry labels provide a shortcut for communicating state of knowledge
The classic wedge system is perfect for definition of a single known isomer. For example, the chemist knows and means exactly the (S) configuration, and no other.
But when our knowledge is incomplete or we are dealing with mixtures, a traditional structure drawing is cumbersome. For example:
- We have a pure sample of one stereoisomer, but we’re not sure which one. We draw all the possibilities and indicate that we mean only one of the above.
- We have a mixture of stereoisomers. We don’t want to draw the structure without stereochemistry, which might indicate we don’t know or don’t care about configurations. (The wavy bond convention has a similar ambiguity: it could mean either a mix or that we don’t know.) So we draw all the components and indicate that we mean all of the above.
- We want to search for several diastereomers in our compound database. We’re interested in some combinations of orientation but not in others. We draw every possibility we’re interested in and add it to the query.
- For a database, this approach (attaching several structures to one record) affects the calculated formula and formula weight.
All the solutions are suitable, but far from optimal and clearly inconvenient. There’s an easier and more rigorous way—enhanced stereochemistry labels. These labels were introduced by MDL in Molfile V3000 (about 25 years ago), but they’re still slowly making their way to printed and electronic media.
To use these labels, add ‘&’ or ‘or’ to a stereocenter. ‘&’ indicates a mixture of the two possible configurations and ‘or’ indicates either orientation, but not both. It’s most useful when assigned to multiple atoms in a structure, where it indicates whether their configurations are synced. For example, say two ‘or’-marked chiral centers are both drawn with solid wedges. Then either both bonds point below the page or both bonds above the page. (It’s also possible to use multiple ‘or’ groups, differentiated by a numeric index. Each ‘or’-labelled bond syncs with others that have the same index.)
Figure 2. The OH bond is labelled with ‘or’. That means it could point either above or below the plane (even though it’s drawn with a solid wedge). But the sample will only contain one enantiomer, not a mixture of both.
Figure 3. The C-O bond is labelled with ‘&’. That means a mixture of both configurations. The C-Cl bond is labelled with ‘or’ and indicates only one of the two possible configurations, but doesn’t specify which one. Taken together, this definition means the sample contains a mixture of two enantiomers, but no other diastereomers. (Can you draw the possibilities?)
Chemical structure searches can use enhanced stereo labels to filter search results
Enhanced stereo labels provide stereoconfiguration filtering when searching a chemical structure database.
For example, when performing structural searches in ACD/Labs’ software, the following results get returned.
Figure 4. Search results for the indicated query when doing an exact search or a substructure search. Structures marked with a check are returned in the results. Structures marked with an ‘X’ are not returned.
Let’s walk through the examples one by one:
Stereoconfiguration can have significant effects, especially in biological and pharmaceutical contexts. (Well-known cases like the thalidomide tragedy illustrate this only too well.) To communicate these important properties, traditional drawing conventions allows chemists to indicate 3D stereochemistry in a 2D medium. Enhanced stereo labels enhance that ability by indicating state of knowledge and providing shortcuts for communication, storage, and structural searches.
Need to draw chemical structures with enhanced stereochemistry labels? Try ACD/ChemSketch, free for academic and personal use and available with a commercial license for industry use.