Oxygen Nucleophiles

Water, hydroxides, and alcohols are typical oxygen nucleophiles, electron-rich species. When water reacts with an aldehyde or a ketone under acidic conditions, it forms a hydrate. A hydrate is a compound formed by the union of water with some other substance. The acidic conditions are necessary because water is a weak nucleophile and requires an activated carbonyl group for the nucleophilic addition to take place. By contrast, hydroxides are strong nucleophiles and do not require activation of the carbonyl group (protonation of the oxygen of the carbonyl). Instead, the formation of the hydrate proceeds through an alkoxide intermediate, a negatively charged oxygen connected to a carbon atom. The hydrate of an aldehyde is a gem-diol, a carbon with two alcohol (${-}{\rm{OH}}$) groups on the same carbon. Hydrates are generally too unstable to be isolated, and they exist in equilibrium with the starting material. When an alcohol is used as a nucleophile, it will react with the carbonyl group to form either a hemiacetal or an acetal. A hemiacetal is an organic compound characterized by the grouping C(OH)(OR), where R is an alkyl group and is usually formed as an intermediate in the preparation of an acetal from an aldehyde or ketone. An acetal is an organic compound characterized by the grouping C(OR)₂, where R is an alkyl and is obtained by heating an aldehyde or a ketone with an alcohol. An acetal that forms from a ketone is called a ketal.

The product of a reaction of an alcohol and a carbonyl group depends on the amount of the alcohol used in the reaction. A stoichiometric amount of the alcohol should form a hemiacetal, while the addition of an excess of the alcohol with an acid catalyst will lead to the formation of an acetal.

Hemiacetals and acetals are formed through the same mechanism. The carbonyl oxygen donates its electron pair to a proton (H⁺), the acid catalyst, activating the carbonyl. The alcohol's oxygen atom, the nucleophile, then donates its electron pair to the carbon, the electrophile, of the carbonyl. This donation causes the $\pi$ bond between the carbon and the oxygen to break, and the shared electrons move to the oxygen of the carbonyl. The previously nucleophilic oxygen atom becomes positively charged and needs to lose a proton to yield the hemiacetal, which is the intermediate in the formation of an acetal.

To form the acetal, the alcohol group (${-}{\rm {OH}}$) of the hemiacetal donates its electron pair to a proton and becomes water, which is a good leaving group. The water leaving group leaves, and the oxygen from the ether group (${-}{\rm{OR}}$) donates its electron pair to form a $\pi$ bond between itself and the carbon. This new carbonyl group is already activated by the positive charge on the oxygen. Another oxygen atom (the nucleophile) from an alcohol donates its electron pair to the carbon (the electrophile) of the carbonyl. This donation causes the $\pi$ bond between the carbon and the oxygen to break, causing the shared electrons to move back to the oxygen of the carbonyl. The nucleophilic oxygen atom is positively charged and needs to lose a proton to yield the final acetal. Because all these reaction steps are reversible, the only way to drive the reaction forward and obtain an acetal is to use an excess of alcohol or to remove water from the reaction system. Hemiacetals are difficult to isolate because they are intermediates in the formation of acetals. Cyclic hemiacetals are an exception because of the increased stability of the ring form of hemiacetals. In cyclic hemiacetals, the equilibrium of the reaction favors the hemiacetal rather than the starting material.

When ethylene glycol (HOCH₂CH₂OH) is mixed with an acid catalyst, the product is a cyclic acetal. Both cyclic and acyclic acetal formation are catalyzed by acids, and the reaction is formed under equilibrium conditions, which means the reaction is reversible. Therefore, depending on the conditions, an acetal can both be formed in the presence of acid and can be converted back to a carbonyl in the presence of acid. Acetals are removed with the addition of dilute acids and formed with the addition of an acid catalyst. While acetals are removed with acids, acetals are generally nonreactive to bases, nucleophiles, and oxidation and reducing reagents. Therefore, acetals are the protected (nonreactive) form of a carbonyl similar to protecting groups used to protect alcohols. A protecting group is a modified functional group that is unaffected by some reagents but easily removed by other reagents.