When synthesising a molecule containing one or more rings, the chemist may decide on a synthetic route that includes ring-forming reactions or may instead be able to rely on starting materials that already incorporate the desired rings. The choice depends on many factors, including cost of starting materials, likely yields, and ease of access to additional analogs.
Some ring systems are very common – a phenyl ring springs to mind, of course – but yet they are not often formed as part of a typical synthetic route. Let’s automate the process of finding whether a particular ring system is likely to be formed in a reaction.
As a dataset we will use reactions extracted from the text of US and European patents by LeadMine and where Indigo produces an atom-mapping. Only one reaction per patent is used, and exact duplicates are discarded. Given these 212K reactions, here are the most common ring systems (*) in the products along with their frequency:
Next, we use the mapping to identify those instances where a ring was formed. For each of these reactions, we take each of the common ring systems in turn and see whether it appears on the right-hand side (RHS) but not on the left-hand side. Here are the most commonly formed rings:
Finally, we divide the corresponding figures from the diagram above to calculate the likelihood that, given a particular ring system on the RHS, it was formed by the reaction. For example, for phenyl ring, the likelihood is 807/151983 or 0.5%. Here are the rings with the highest likelihoods:
…and those with the lowest:
So what is it about these rings that places them at the top and bottom of the likelihood lists? Comments welcome…
* Depending on how you slice-and-dice molecules to find ring systems, the exact results will vary. Here I included exocyclic double bonds as part of the ring system. In addition, I hashed tautomers to the same representation and removed any stereochemistry.