Freezing conformations by adding a ring...revisited

Aromatic (and heteroaromatic)-ethers have a strong tendency to be planar. A quick look in the CSD (repository of >1,000,000 small molecule Xray structures (using Conquest and Mercury) finds more than 13,000 examples of structures containing an anisole and confirms this preference. The preference is mainly to conjugation with the delocalization of one of the lone pairs of the oxygen atom on the π- system of the aromatic. This effect overrides the steric repulsion between the methyl and the ortho-hydrogens. As a consequence, any ortho substituent or reduction in conjugation (for instance with O-CF3 groups) will minimise this preference.

Keeping this in mind, Inventiva scientists published a really fascinating finding a few years ago (Chemistry Europe 2018).

Indeed, by mining the COD (open source database of small molecule XRay structures), the authors found that when switching from phenyl to napthyl, a clear preferred orientation of the alkoxy group appeared. A quick looksie in the CSD confirmed this finding with over 500 examples. To the authors credit, they then undertook an exhaustive study to confirm, quantify and elucidate the driving force behind this observation.

They confirmed their finding by studying NOE effects in solution NMR and by extensive computational work (they also show that force fields do not recapitulate this at all, and advocate for a change in the parameters). In the end, they were able to estimate a difference between the 2 conformations of 1.2 -1.8kcal/mol. To put things in context, this will not make your compound go from active to inactive but you will it will impact your potency (I always keep the rule of thumb of 1.4kcal/mol = 10x potency- but that is probably a best case scenario) and if your bioactive conformation requires the extended conformation and not the preferred bent one, then you will have a great rationale for your next design iteration!

As mentioned, they explain the driving forces for this observation, which I tried to summarise below, but would strongly encourage you to read in their paper.

It turns out that not all bonds are equal in an extended aromatic system and the C1-C2 has more of a double bond character than the C2-C3. This is confirmed by X-Ray and high-level calculations. The consequence is that in order to maximise orbital overlap with the double bond, the C=C-O angle will increase slightly. The authors really do a great job at navigating very high level notions (NBO...) and dumbing things down for ...me. They mention that the same preference is well-known in vinyl ethers, which you can argue is the case here.

The authors do not stop there and also extend this to other bicyclic aromatics - because naphtyl groups are no one's favourite. Looking in the CSD at every hetero-bicylic-aromatic I could think of, confirms the trend on over 700 examples.

To sum up, by adding a ring (on the other side!) your can favour one conformation (not completely "freeze" as the clickbait title mentioned :-)).

Below are 4 examples of PDB-derived bioactive conformation of 5-alkoxy indazoles from unrelated proteins. I am not claiming that this was a major driver in the design but it is interesting that the same preference can be found in the PDB realm.

This got me thinking. First, were there other groups off of a (hetero)napthyl where a similar preference could be found? Second, could there be ways to change the double bond character in monocyclic systems.

It turns out that vinyl groups also have a preference... and it is for the other orientation! The search in the CSD was done on napthyl/hetero-bicyclic-aromatics combined (only 70 in total). The Styrene search (over 3800 examples) is there for comparison.

Not claiming to fully understand why there is this preference, it does match the preferred conformation of isoprene - to use the authors vinyl ether analogy.

I looked for preferences around amides but there was none as far as I could tell.

Broadening the search, there might be a slight preference with alkyl groups and also surprisingly with ortho sp2 N heteroaryls... on a very, very, very small number of examples.

As for the second point, forcing a double bond character in a monocyclic system... I drew a bit of a blank and could only come up with pyridones. Unfortunately, there are only a half a dozen examples in both the CSD and PDB. But I guess, as a first result, it's certainly heading in the right direction :-).