One of the more enlightening facts about conformational analysis I learnt in the last couple of years was related to the simple question, "What is the proportion of the axial conformer in 3-fluoro piperidine?" Contrary to what most of our knowledge about six membered ring conformational analysis says, the answer is:
100%. The axial conformer is present to the extent of 100%. The equatorial- 0%
The situation arises because of a stabilizing C-F...N-H+ dipole effect that also raises the pKa of this molecule over what we would assume. This analysis was done in a series of papers by Lankin, Snyder et al.
This study is part of a recent ChemMedChem review that tackles the wide range of amine basicities in drug like molecules, and the factors that influence them. I have now learnt to mentally protonate requisite nitrogens when I see them in a drug almost as a reflex action, but I still get a little bamboozled sometimes. While the influence of inductive and polar effects on the lowering of amine pKas is well known, effects like the one noted above are more subtle and unexpected and such trends are discussed in the review.
For example, the above 1,3 syn kind of fluorine-amine interaction also extends to acyclic systems, and nicely explains the simple differences in basicities of the simplest of compounds; mono, di, and trifluoro ethyl amines (pKas drop down from around 10-11).
One of those set of principles well kept in mind
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