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Organic Chemistry Text Book (CHEM 3401 and 3402)

12.6.1 Substitution of the Hydroxyl Hydrogen

Because of its enhanced acidity, the hydrogen atom on the hydroxyl group is rather easily replaced by other substituents. A simple example is the facile reaction of simple alcohols with sodium (and sodium hydride), as described in the first equation below. Another such substitution reaction is the isotopic exchange that occurs on mixing an alcohol with deuterium oxide (heavy water). This exchange, which is catalyzed by acid or base, is very fast under normal conditions, since it is difficult to avoid traces of such catalysts in most experimental systems.


2 R–O–H   +   2 Na      2 R–O(–)Na(+)   +   H2
R–O–H   +   D2O      R–O–D   +   D–O–H


The mechanism by which many substitution reactions of this kind take place is straightforward. The oxygen atom of an alcohol is nucleophilic and is therefore prone to attack by electrophiles. The resulting "onium" intermediate then loses a proton to a base, giving the substitution product. If a strong electrophile is not present, the nucleophilicity of the oxygen may be enhanced by conversion to its conjugate base (an alkoxide). This powerful nucleophile then attacks the weak electrophile. These two variations of the substitution mechanism are illustrated in the following diagram.

The preparation of tert-butyl hypochlorite from tert-butyl alcohol is an example of electrophilic halogenation of oxygen, but this reaction is restricted to 3º-alcohols because 1º and 2º-hypochlorites lose HCl to give aldehydes and ketones. In the following equation the electrophile may be regarded as Cl(+).

(CH3)3C–O–H   +   Cl2   +   NaOH      (CH3)3C–O–Cl   +   NaCl  +   H2O

Alkyl substitution of the hydroxyl group leads to ethers. This reaction provides examples of both strong electrophilic substitution (first equation below), and weak electrophilic substitution (second equation). The latter SN2 reaction is known as the Williamson Ether Synthesis, and is generally used only with 1º-alkyl halide reactants because the strong alkoxide base leads to E2 elimination of 2º and 3º-alkyl halides.

One of the most important substitution reactions at oxygen is ester formation resulting from the reaction of alcohols with electrophilic derivatives of carboxylic and sulfonic acids. The following illustration displays the general formulas of these reagents and their ester products, in which the R'–O– group represents the alcohol moiety. The electrophilic atom in the acid chlorides and anhydrides is colored red. Examples of specific esterification reactions may be selected from the menu below the diagram, and will be displayed in the same space.