Classical bioisosteres

Question

Classical bioisosteres are functional groups that satisfy with the Grimm's hydride displacement law and Langmuir's definition of isosteres.

My question is why chlorine can be replaced by trifluoromethyl or cyano group and the replacement is categorized in univalent atoms replacement?

Because as seen from the criteria of classical bioisosteres aforementioned, the replacement atoms do not have any hydrogen atom therefore I think Grimm's law is devoid. However both trifluoromethyl and cyano group do not have the same number of atom nor electron as well as electron arrangement as in chlorine.

So what explains that these functional groups are classical bioisosteres?

Answer 1

I think you are right. Grimm's law in its original version (1925) should not apply to the $\ce{-CF3}$ , $\ce{-CN}$ pair. This "law" is very restrictive and has only historical significance. To be honest I could not recall its statement and I have never come across it in the last 10 years or so that I work in the field. The modern definition of classical bioisosteres (as opposed to non-classical bioisosteres like the $\ce{-CO2H}$, tetrazole pair) has been extended exactly for this reason, to include functional group pairs with similar physiochemical properties that do not follow Grimm's law or any other classification of less general scope.