Nucleophilic addition - oxygen and sulfur nucleophiles

NUCLEOPHILIC ADDITION – OXYGEN AND SULFUR NUCLEOPHILES

Key Notes

Acetal and ketal formation

The reaction of aldehydes and ketones with two equivalents of an alcohol in the presence of anhydrous acid as a catalyst results in the formation of acetals and ketals respectively. The reaction involves nucleophilic addition of one molecule of alcohol, elimination of water, then addition of a second molecule of alcohol. The reaction is reversible and as a result acetals and ketals are good protecting groups for aldehydes and ketones. The synthesis of the acetal or ketal is carried out under anhydrous acid conditions while the reverse reaction is carried out using aqueous acid. Cyclic acetals and ketals are better protecting groups than acyclic ones.

Hemiacetals and hemiketals

Dissolving aldehydes or ketones in alcohol results in an equilibrium between the carbonyl compound and the hemiacetal/hemiketal. The reaction is slow and the equilibrium favors the carbonyl compound. Most hemiacetals and hemiketals cannot be isolated since they break back down to the original carbonyl compounds when the solvent is removed. However, cyclic hemiacetals are important in sugar chemistry.

Thioacetal and thioketal formation

Thioacetals and thioketals can be synthesized by treating aldehydes and ketones with a thiol or dithiol in the presence of an acid catalyst. These functional groups can also be used to protect aldehydes and ketones but are more difficult to hydrolyze. They can be useful in the reduction of aldehydes and ketones.

Acetal and ketal formation

When an aldehyde or ketone is treated with an excess of alcohol in the presence of an acid catalyst, two molecules of alcohol are added to the carbonyl compound to give an acetal or a ketal respectively (Fig. 1). The final product is tetrahedral.

The reaction mechanism involves the nucleophilic addition of one molecule of alcohol to form a hemiacetal or hemiketal. Elimination of water takes place to form an oxonium ion and a second molecule of alcohol is then added (Fig. 2).

The mechanism is quite complex and we shall look at it in detail by considering the reaction of methanol with acetaldehyde (ethanal; Fig. 3). The aldehyde is the electrophile and the electrophilic center is the carbonyl carbon. Methanol is the nucleophile and the nucleophilic center is oxygen. However, methanol is a relatively weak nucleophile. As a result, the carbonyl group has to be activated by adding an acid catalyst if a reaction is to take place. The first step of the mechanism involves the oxygen of the carbonyl group using a lone pair of electrons to form a bond to a proton. This results in a charged intermediate where the positive charge is shared between the carbon and oxygen of the carbonyl group.

Protonation increases the electrophilicity of the carbonyl group, making the car-bonyl carbon even more electrophilic. As a result, it reacts better with the weakly nucleophilic alcohol. The alcoholic oxygen now uses one of its lone pairs of elec-trons to form a bond to the carbonyl carbon and the carbonyl Ï€ bond breaks at the same time with the Ï€ electrons moving onto the carbonyl oxygen and neutralizing the positive charge (Fig. 4). However, the alcoholic oxygen now has an unfavor-able positive charge (which explains why methanol is a weak nucleophile in the first place). This charge is easily lost if the attached proton is lost. Both electrons in the O–H σ bond are captured by the oxygen to restore its second lone pair of electrons and neutralize the positive charge.

The intermediate formed from this first nucleophilic addition is called a hemi-acetal. If a ketone had been the starting material, the structure obtained wouldhave been a hemiketal. Once the hemiacetal is formed, it is protonated and water is eliminated by the same mechanism described in the formation of imines  – the only difference being that oxygen donates a lone pair of electrons to force the removal of water rather than nitrogen (Fig. 5). The resulting oxonium ion is extremely electrophilic and a second nucleophilic addition of alcohol takes place to give the acetal.

All the stages in this mechanism are reversible and so it is possible to convert the acetal or ketal back to the original carbonyl compound using water and an aqueous acid as catalyst. Since water is added to the molecule in the reverse mechanism, this is a process called hydrolysis.

Acid acts as a catalyst both for the formation and the hydrolysis of acetals and ketals, so how can one synthesize ketals and acetals in good yield? The answer lies in the reaction conditions. When forming acetals or ketals, the reaction is carried out in the absence of water using a small amount of concentrated sulfuric acid or an organic acid such as para-toluenesulfonic acid. The yields are further boosted if the water formed during the reaction is removed from the reaction mixture.

In order to convert the acetal or ketal back to the original carbonyl compound, an aqueous acid is used such that there is a large excess of water present and the equilibrium is shifted towards the carbonyl compounds.

Both the synthesis and the hydrolysis of acetals and ketals can be carried out in high yield and so these functional groups are extremely good as protecting groups for aldehydes and ketones. Acetals and ketals are stable to nucleophiles and basic conditions and so the carbonyl group is ‘disguised’ and will not react with these reagents. Cyclic acetals and ketals are best used for the protection of aldehydes and ketones. These can be synthesized by using diols rather than alcohols (Fig. 6).

Hemiacetals and hemiketals

When aldehydes and ketones are dissolved in alcohol without an acid catalyst being present, only the first part of the above mechanism takes place with one alcohol molecule adding to the carbonyl group.An equilibrium is set up between the carbonyl group and the hemiacetal or hemiketal, with the equilibrium favoring the carbonyl compound (Fig. 7).

The reaction is not synthetically useful, since it is not usually possible to isolate the products. If the solvent is removed, the equilibrium is driven back to starting materials. However, cyclic hemiacetals are important in the chemistry of sugars.

Thioacetal and thioketal formation

Thioacetals and thioketals are the sulfur equivalents of acetals and ketals and are also prepared under acid conditions (Fig. 8). These can also be used to protect aldehydes and ketones, but the hydrolysis of these groups is more difficult. More importantly, the thioacetals and thioketals can be removed by reduction and this provides a method of reducing aldehydes and ketones.