Six-Membered Rings

      Properties
The chemical reactivity of the saturated members of this class of heterocycles: tetrahydropyran, thiane and piperidine, resemble that of acyclic ethers, sulfides, and 2º-amines, and will not be described here. 1,3-Dioxanes and dithianes are cyclic acetals and thioacetals. These units are commonly used as protective groups for aldehydes and ketones, as well as synthetic intermediates, and may be hydrolyzed by the action of aqueous acid. The reactivity of partially unsaturated compounds depends on the relationship of the double bond and the heteroatom (e.g. 3,4-dihydro-2H-pyran is an enol ether).
Fully unsaturated six-membered nitrogen heterocycles, such as pyridine, pyrazine, pyrimidine and pyridazine, have stable aromatic rings. Oxygen and sulfur analogs are necessarily positively charged, as in the case of 2,4,6-triphenylpyrylium tetrafluoroborate.

From heat of combustion measurements, the aromatic stabilization energy of pyridine is 21 kcal/mole. The resonance description drawn at the top of the following diagram includes charge separated structures not normally considered for benzene. The greater electronegativity of nitrogen (relative to carbon) suggests that such canonical forms may contribute to a significant degree. Indeed, the larger dipole moment of pyridine compared with piperidine supports this view. Pyridine and its derivatives are weak bases, reflecting the sp² hybridization of the nitrogen. From the polar canonical forms shown here, it should be apparent that electron donating substituents will increase the basicity of a pyridine, and that substituents on the 2 and 4-positions will influence this basicity more than an equivalent 3-substituent. The pK_a values given in the table illustrate a few of these substituent effects. Methyl substituted derivatives have the common names picoline (methyl pyridines), lutidine (dimethyl pyridines) and collidine (trimethyl pyridines). The influence of 2-substituents is complex, consisting of steric hindrance and electrostatic components. 4-Dimethylaminopyridine is a useful catalyst for acylation reactions carried out in pyridine as a solvent. At first glance, the sp³ hybridized nitrogen might appear to be the stronger base, but it should be remembered that N,N-dimethylaniline has a pK_a slightly lower than that of pyridine itself. Consequently, the sp² ring nitrogen is the site at which protonation occurs.

The diazines pyrazine, pyrimidine and pyridazine are all weaker bases than pyridine due to the inductive effect of the second nitrogen. However, the order of base strength is unexpected. A consideration of the polar contributors helps to explain the difference between pyrazine and pyrimidine, but the basicity of pyridazine seems anomalous. It has been suggested that electron pair repulsion involving the vicinal nitrogens destabilizes the neutral base relative to its conjugate acid.