S_N2 reactions- The Leaving Group

Still another variable that can affect the S_N2 reaction is the nature of the group displaced by the incoming nucleophile. Because the leaving group is expelled with a negative charge in most S_N2 reactions, the best leaving groups are those that best stabilize the negative charge in the transition state. The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction. But the groups that best stabilize a negative charge are also the weakest bases. Thus, weak bases such as Cl^-, Br^-, and tosylate ion make good leaving groups, while strong bases such as OH2 and NH₂^- make poor leaving groups.

It’s just as important to know which are poor leaving groups as to know which are good, and the preceding data clearly indicate that F^-, HO^-, RO^-, and H₂N^- are not displaced by nucleophiles. In other words, alkyl fluorides, alcohols, ethers, and amines do not typically undergo S_N2 reactions. To carry out an S_N2 reaction with an alcohol, it’s necessary to convert the ^-OH into a better leaving group. This, in fact, is just what happens when a primary or secondary alcohol is converted into either an alkyl chloride by reaction with SOCl₂ or an alkyl bromide by reaction with PBr₃.

Alternatively, an alcohol can be made more reactive toward nucleophilic substitution by treating it with para-toluenesulfonyl chloride to form a tosylate.

As noted previously, tosylates are even more reactive than halides in nucleophilic substitutions. Note that tosylate formation does not change the configuration of the oxygen-bearing carbon because the C - O bond is not broken.

The one general exception to the rule that ethers don’t typically undergo S_N2 reactions pertains to epoxides, the three-membered cyclic ethers. Because of the angle strain in their three-membered ring, epoxides are much more reactive than other ethers. They react with aqueous acid to give 1,2-diols, and they react readily with many other nucleophiles as well. Propene oxide, for instance, reacts with HCl to give 1-chloro-2-propanol by a S_N2 backside attack on the less hindered primary carbon atom.