A leaving group is a fragment of a molecule that detaches during a chemical reaction, taking a pair of electrons from the broken bond. For substitution and elimination reactions to occur efficiently, this fragment must be stable once it has left the rest of the molecule. The hydroxyl group (\(\text{–OH}\)), present in all alcohols, is chemically ubiquitous but cannot easily depart on its own. This inertia is the central challenge in transforming alcohols into other functional groups, requiring chemists to first modify it to create a suitable leaving group.
Understanding Why Hydroxide Is a Poor Leaving Group
A good leaving group must be a stable, very weak base. The stability of the detached fragment determines how readily the reaction proceeds. When a hydroxyl group leaves a molecule, it departs as the hydroxide ion (\(\text{OH}^-\)).
The hydroxide ion is considered a strong base because its negative charge is highly concentrated and unstable. This instability makes it reluctant to leave and gives it a strong desire to reattach to the molecule. In contrast, excellent leaving groups are the conjugate bases of strong acids, such as the chloride or bromide ion, which are inherently stable and weak bases.
Activating the Hydroxyl Group with Acids
One of the simplest ways to transform the hydroxyl group is through protonation using a strong acid, such as hydrobromic acid (\(\text{HBr}\)) or sulfuric acid (\(\text{H}_2\text{SO}_4\)). The alcohol accepts a proton (\(\text{H}^+\)) from the acid. This initial acid-base step converts the alcohol (\(\text{R–OH}\)) into an alkyloxonium ion (\(\text{R–OH}_2^+\)).
This protonation converts the poor leaving group into a neutral water molecule (\(\text{H}_2\text{O}\)), which is an excellent leaving group and an exceptionally weak base. The water molecule can then spontaneously depart, often forming a carbocation intermediate via the \(\text{S}_{\text{N}}1\) or \(\text{E}1\) reaction pathway. A drawback of this method is that the highly acidic conditions can lead to unwanted side reactions, such as alkene formation or carbon skeleton rearrangement.
Transformation into Sulfonate Esters
A more versatile and gentler technique involves converting the hydroxyl group into a sulfonate ester, creating an internal weak base. This is achieved by reacting the alcohol with a sulfonyl chloride, such as \(p\)-toluenesulfonyl chloride (\(\text{TsCl}\)) or methanesulfonyl chloride (\(\text{MsCl}\)), typically in the presence of a non-nucleophilic base like pyridine. The reaction forms a tosylate (\(\text{–OTs}\)) or mesylate (\(\text{–OMs}\)) functional group.
The resulting sulfonate ion is exceptionally stable due to resonance stabilization. The negative charge is delocalized over the three oxygen atoms attached to the sulfur, which significantly disperses the charge density. This charge dispersal makes the sulfonate ion a very weak base, establishing it as one of the best leaving groups available in synthesis.
A significant advantage is that the reaction is conducted under neutral or basic conditions, avoiding the side reactions common in the acid-catalyzed method. This makes sulfonate esters the preferred choice for complex or sensitive molecules. Furthermore, the conversion retains the stereochemical configuration at the carbon center because the carbon-oxygen bond of the original alcohol is not broken.
Direct Substitution to Form Alkyl Halides
Chemists can also directly replace the hydroxyl group with a halogen using specialized phosphorus and sulfur-based reagents, bypassing the need for protonation or sulfonate ester formation. Thionyl chloride (\(\text{SOCl}_2\)) is commonly employed for alkyl chlorides, while phosphorus tribromide (\(\text{PBr}_3\)) is used for alkyl bromides. These reagents first react with the alcohol to form a highly reactive intermediate species.
When using thionyl chloride, an alkyl chlorosulfite intermediate is formed, which undergoes an internal substitution reaction. This often proceeds through an \(\text{S}_{\text{N}}2\) mechanism, resulting in a product with an inverted stereochemical configuration. A practical benefit is that the byproducts, sulfur dioxide (\(\text{SO}_2\)) and hydrogen chloride (\(\text{HCl}\)), are gases that easily escape the reaction mixture, simplifying purification.