6.3: \(\mathrm{O}\), \(\mathrm{S}\), and \(\mathrm{N}\) as Leaving Groups
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Recall that a good leaving group should be able to accept (in a stable form) the pair of electrons from the bond that breaks. Typically, good leaving groups are weak bases. For this reason, hydroxide (\({}^{-}\mathrm{OH}\)) and amide (\({}^{-}\mathrm{NH}_{2}\)) are unlikely to be produced during a nucleophilic substitution reaction. However, as noted earlier, alcohols can be converted into good leaving groups by protonation, which results in \(\mathrm{H}_{2}\mathrm{O}\) as the leaving group.
Alcohols can also be modified (or derivatized) to produce better leaving groups. This is particularly useful when we need to carry out a reaction that is sensitive to acidic conditions when the method we have used earlier (protonation of the \(\mathrm{OH}\)) cannot be used. The most common derivative used to make the \(\mathrm{OH}\) group into a good leaving group is the Tosyl group (para-toluenesulphonate). It can be formed by reacting an alcohol with p-toluenesulfonylchloride (\(\mathrm{TosCl}\)) in the presence of a base (such as pyridine) that acts to remove the \(\mathrm{HCl}\) that is produced).
We can consider the derivatization reaction as mechanistically similar to other nucleophilic substitutions we have considered, except that it takes place at an \(\mathrm{S}\) instead of a \(\mathrm{C}\).
The resulting \(\mathrm{OTos}\) group is a very good leaving group, making the molecule reactive to nucleophilic substitution reactions. In effect, we have changed the leaving group from \({}^{-}\mathrm{OH}\), which is a relatively strong base, to \({}^{-}\mathrm{OTos}\) which is a very weak base—it is the organic equivalent of sulfate, the conjugate base of sulfuric acid. The negative charge on \({}^{-}\mathrm{OTos}\) becomes delocalized to the other oxygens bound to the \(\mathrm{S}\), thereby stabilizing the base.
In a similar manner, sulfides can be transformed into leaving groups, most commonly through the methylation of the sulfide, which produces a powerful reagent that can be used to methylate other species.
In biological systems, a common methylating agent, S-adenosylmethionine (\(\mathrm{SAM} \rightarrow\)), uses this mechanism