Science of Synthesis

Percy, J. M., Science of Synthesis, (2005) 34, 379.

General Introduction

Monofluorination β to an amino function has the extremely useful effect of lowering the pKa (protonation) by between 1 and 2 units;[‌1‌] the effect has been exploited to improve the performance of pharmaceutical agents. For example, ‌1‌ (R1 = H) and ‌1‌ (R1 = F) (‌Scheme 1‌) are both effective ligands for the 5HT1D (5-hydroxytryptamine or serotonin) receptor; whereas both have similar potencies, the fluorinated ligand ‌1‌ (R1 = F) is more bioavailable because of the lower pKa of the piperidine nitrogen [8.7 for ‌1‌ (R1 = F), compared to 9.7 for ‌1‌ (R1 = H)].[‌2‌] Monofluorination thus assists the medicinal chemist in achieving the correct balance between overall polarity and lipophilicity.

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References