A leaving group is a molecular fragment that departs from a larger molecule during a chemical reaction, such as a substitution or elimination reaction, taking with it the pair of electrons from the broken bond. For a reaction to proceed efficiently, this departing fragment must be able to exist as a stable, independent species once it leaves the parent molecule. The hydroxyl group (OH) presents a significant challenge because the fragment it would naturally form upon departure, the hydroxide ion (\(\text{OH}^-\)), is highly unstable. Therefore, the simple hydroxyl ion is generally considered a very poor leaving group in standard reaction conditions. Chemists have developed effective strategies to chemically modify the hydroxyl group, transforming it into a much more stable and competent leaving group to facilitate desired reactions.
The Chemistry of Leaving Groups
The ability of a fragment to serve as an effective leaving group is fundamentally dictated by the stability of the resulting species after it has separated from the molecule. A good leaving group must be a weak base, meaning it is stable and non-reactive once it departs. This relationship is inverse: the stronger the base, the poorer the leaving group it will be.
The stability of the weak base is often explained by the strength of its conjugate acid. A stronger conjugate acid indicates a more stable, weaker conjugate base, which makes for a better leaving group. For example, halide ions like bromide (\(\text{Br}^-\)) and iodide (\(\text{I}^-\)) are excellent leaving groups because they are the conjugate bases of very strong acids. The large size of the iodide ion also helps to delocalize the negative charge, contributing significantly to its stability.
Why Hydroxide is a Poor Leaving Group
Applying the principles of leaving group ability to the hydroxyl group reveals why it is a poor leaving group. When the C-O bond breaks and the hydroxyl group leaves, it forms the hydroxide ion (\(\text{OH}^-\)). This ion is a strong base because the negative charge is concentrated on a single, relatively small oxygen atom. This localized charge makes the hydroxide ion highly reactive and unstable as an independent species.
Because chemical reactions favor the formation of more stable products, forming the unstable hydroxide ion is energetically unfavorable. This strong basicity places \(\text{OH}^-\) among the poorest leaving groups in neutral conditions. If the \(\text{OH}^-\) ion were forced to leave, the reaction would likely reverse immediately, as the strong base would quickly attack the parent molecule. The instability of the hydroxide ion is why alcohols do not readily participate in substitution or elimination reactions without activation.
Converting Hydroxide into Water
One common and effective strategy to activate the hydroxyl group is protonation. By treating an alcohol with a strong acid, the oxygen atom accepts a proton (\(\text{H}^+\)). This process converts the hydroxyl group (OH) into a protonated form, an oxonium ion (\(\text{OH}_2^+\)).
This transformation converts the poor leaving group into an excellent one: a neutral water molecule (\(\text{H}_2\text{O}\)). Water is a stable and non-reactive species, making it an ideal candidate for departure from the carbon chain. The basicity of water is approximately \(10^{14}\) times less than that of the hydroxide ion, creating a driving force for the reaction. This protonation step is a common tactic in acid-catalyzed substitution (\(\text{S}_{\text{N}}1\)) and elimination (\(\text{E}1\)) reactions, allowing the OH group to leave as a neutral molecule.
Transforming Alcohols into Sulfonate Esters
While protonation is effective, it requires a strongly acidic environment, which can cause unwanted side reactions, such as carbon skeleton rearrangement. An alternative method for activating the hydroxyl group, useful when neutral or basic conditions are required, is to convert the alcohol into a sulfonate ester. This is typically achieved by reacting the alcohol with a sulfonyl chloride, such as \(p\)-toluenesulfonyl chloride (TsCl) or methanesulfonyl chloride (MsCl).
This reaction produces an alkyl sulfonate ester (a tosylate or a mesylate). When this ester breaks away, it forms a sulfonate anion, a stable species due to resonance stabilization. The negative charge is highly delocalized across the three oxygen atoms bonded to the sulfur atom. This distribution of charge makes the sulfonate anion a very weak base, often a better leaving group than halide ions. The formation of these sulfonate esters allows chemists to perform substitution reactions, like the \(\text{S}_{\text{N}}2\) reaction, under non-acidic conditions.