SolutionsPyridine and six-membered heterocycles
Exercise 1
Rank by basicity: pyridine, piperidine, pyrrole and 4-dimethylaminopyridine (DMAP). Explain why DMAP is more basic than pyridine and why it is protonated on the ring nitrogen and not on the dimethylamino nitrogen.
Piperidine (pKaH 11.1) > DMAP (9.6) > pyridine (5.2) ≫ pyrrole (−3.8). In DMAP, the lone pair of the dimethylamino group is conjugated with the ring and pushes electron density to the ring nitrogen; when the latter is protonated, the positive charge is shared between both nitrogens (an amidinium-type resonance form). Protonating NMe2 would lose that conjugation and the cation would have no resonance stabilization.
Exercise 2
Propose a synthesis of 4-aminopyridine and another of 2-aminopyridine from pyridine. Why does 3-chloropyridine not react with sodium methoxide under the conditions in which 2-chloropyridine does?
4-Aminopyridine: oxidation to the N-oxide (H2O2, AcOH), nitration at C4 (HNO3, H2SO4) and reduction with Fe in acetic acid, which reduces both the nitro group and the N-oxide. 2-Aminopyridine: Chichibabin reaction (NaNH2, refluxing toluene, then water). In 3-chloropyridine, the anion formed when methoxide adds at C3 cannot place the negative charge on nitrogen (only on C2, C4 and C6), and the reaction is as slow as for chlorobenzene.