6.5: Leaving Groups

In a nucleophilic substitution reaction, a nucleophile displaces a functional group — called a leaving group — at the carbon atom in the substrate to give a substituted product.

A substrate with a good leaving group eases the displacement process and speeds up the reaction.

A leaving group departs the substrate through heterolytic cleavage, taking along the electrons to form a relatively stable weak base in the form of an anion or a neutral molecule.

In the reaction between the hydroxide ion and iodomethane, the leaving group — a halogen — exits the substrate as an iodide anion.

Iodide, being the conjugate base of a strong acid, is weak and stable. Due to its large size, the ion stabilizes the charge well, and thus is an excellent leaving group with good staying power.

By and large, the relative stabilities of halides can be estimated from the pK_a values of their corresponding hydrohalic acids. The stronger the acid, the weaker and more stable the conjugate base, and hence, the better the leaving group.

Therefore, among the halides, iodide is the best leaving group, followed by bromide and chloride.

Fluoride, being the conjugate base of a weak acid, is the least stable halide with a poorly stabilized negative charge. This makes fluoride a bad leaving group.

Some leaving groups, such as water and alcohol, are neutral. For example, in this reaction, water departs as a neutral molecule after the heterolytic cleavage of the protonated substrate.

Water is considered to be a good leaving group since it is the conjugate base of the hydronium ion.

As a general rule, conjugate bases of acids with negative pK_a values function as good leaving groups.

In essence, while the conjugate base of the strongest acid makes the best leaving group, the conjugate base of the weakest acid makes the worst leaving group, and others are intermediates.