Pyridine 19 2.2 Electrophilic Substitution 2.2.1 Attack at Nitrogen and at Carbon From the resonance description you might conclude that although the primary site for electrophilic attack is at N-1,reactions at carbon C-3(5) might be possible,even if not as likely.However,an important point to remember is that the N atom of pyridine carries a lone pair of electrons; these electrons are NOT part of the n-system.As a result,pyridine is a base(pK.5.2).reacting with acids,Lewis acids and other electrophiles me2.2 Direct attack at a ring carbon,even C-3,is normally slow (a)because the concentration of free pyridine in equilibrium with the pyridinium salt is extremely low,and(b)attack upon the salt would also require the pos- Pyndinesulfonic acids are strongly itive pyridinium cation to bond to a positively charged reactant Indeed,where reactions at a ring carbon take place under relatively mild conditions,special circumstances are at work.For example,2,6-tert- butylpyndine N-protonaton is butylpyridine combines with sulfur trioxide in liquid sulfur dioxide at -10C to give the corresponding 3-sulfonic acid(Scheme 2.3).An expla nation is that the bulky tert-butyl groups prevent access of the 'large' electrophile to N-1.Steric hindrance is much less at C-3 and sulfonation ectrophlc attacks strongly is diverted to this site using the 'free'pyridine as the substrate. SO3H S03 Me Me M Me Me Scheme 2.3Pyridine I9 2.2 Electrophilic Substitution 2.2.1 Attack at Nitrogen and at Carbon From the resonance description you might conclude that although the primary site for electrophilic attack is at N-1, reactions at carbon C-3(5) might be possible, even if not as likely. However, an important point to remember is that the N atom of pyridine carries a lone pair of electrons; these electrons are NOT part of the n;-system. As a result, pyridine is a base (pKa 5.2), reacting with acids, Lewis acids and other electrophiles (E') to form stable pyridinium salts (Scheme 2.2), in which the hetero￾cycle retains aromatic character. 0 0 -,o N - 0 N - o+ N Y+ I I I N E E E E Direct attack at a ring carbon, even C-3, is normally slow (a) because the concentration of free pyridine in equilibrium with the pyridinium salt is extremely low, and (b) attack upon the salt would also require the pos￾itive pyridinium cation to bond to a positively charged reactant. Indeed, where reactions at a ring carbon take place under relatively mild conditions, special circumstances are at work. For example, 2,6-tert￾butylpyridine combines with sulfur trioxide in liquid sulfur dioxide at -10 "C to give the corresponding 3-sulfonic acid (Scheme 2.3). An expla￾nation is that the bulky tert-butyl groups prevent access of the 'large' electrophile to N- 1. Steric hindrance is much less at C-3 and sulfonation is diverted to this site using the 'free' pyridine as the substrate. Scheme 2.2 Pyridinesulfonic acids are strongly acidic, so that the 3-sulfonic acid that forms then protonates a second molecule of 2,6-tert￾butylpyridine (N-protonation is permitted because of the small size of the proton). Once protonated, however, further electrophilic attack is strongly disfavoured, and so the overall conversion is limited to 50%. Scheme 2.3