Sulfonation may lead to ortho selectivity without lithiation
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص565
2025-06-24
633
We introduced sulfonation but have left detailed discussion until now because sulfonation has some features that make it more interesting than fi rst meets the eye. One important difference between sulfonation and other examples of electrophilic substitution is that sulfonation is reversible. Heating an arene sulfonic acid causes it to decompose with loss of gaseous SO3. Here’s an example of how we can exploit this to gain control of regioselectivity without resorting to lithiation. In stage 1 the phenol is sulfonated twice—the fi rst sulfonic acid group (which adds para to the OH group) is electron-withdrawing and deactivates the ring, making the introduction of the second group (which goes ortho to the OH and meta to the first sulfonic acid) harder and that of the third group harder still, which is why we can isolate the disulfonated phenol.
In the second stage, the bromination, the OH directs to the ortho and para positions, but only one ortho position is vacant, so the bromine attacks there. Sodium hydroxide is needed to deprotonate the sulfonic acid groups to make them less deactivating. The sulfonation reaction is reversible, and in the third stage it is possible to drive the reaction over to the products by distilling out the relatively volatile 2-bromophenol at high temperature. The loss of SO3 involves attack of H+ on the aromatic ring.
Overall, we have succeeded in making 2-bromophenol where direct bromination of phenol itself would have given (at low temperatures) mainly p-bromophenol and at higher temperatures, 2,4,6-tribromophenol. The sulfonic acid groups are useful reversible blocking groups. The same method can be used with anilines because para-sulfonation of aromatic amines is possible. This seems surprising because in sulfuric acid essentially all the amine will be protonated. You might expect the resulting ammonium ion to react in the meta position (because NH3+ is no longer electron-rich) but instead the para-sulfonic acid (sulfanilic acid) is formed. At the high temperature of the reaction, it is probable that any meta-substituted product reverts to the starting material, while the para-sulfonic acid accumulates because it is stabilized by delocalization and is less hindered.
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