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Most medicinal chemists know that fluorine is the “wild-child” of the halogens, shifting adjacent pKa’s and blocking metabolism.  This paper however is a deeply analytical study of how fluorine alters conformational preferences and undergoes very specific interactions with amino acid residues such as C-F:HN, C-F:C=O and interactions with arginines and electropositive cavities.  With systematic analyses of data from the PDB and CSD this paper should be essential reading particularly if you’re working in structure based compound design and have thoughts of ‘adding a fluorine as a bioisostere’. It may behave quite unlike you were expecting.  With over 3800 citations on google scholar, it’s the grandparent of systematic fluorine chemistry reviews.

“Fluorine in Pharmaceuticals: Looking Beyond Intuition.”

Muller, K., Faeh, C., & Diederich, F. Science, (2007), 317,  1881–1886.

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