The rates of nucleophilic addition to carbonyl groups that you met in Chapter 6 depend on the basicity of nucleophiles. As nitrogen bases are much stronger than oxygen bases (or, if you prefer, ammonium ions are much weaker acids than H₃O⁺), amines are also much better nucleophiles than water or alcohols. This is dramatically illustrated in an amide synthesis from aniline and acetic anhydride in aqueous solution.

Aniline is not very soluble in water but addition of HCl converts it into the soluble cation by protonation at nitrogen. The solution is now warmed and equal amounts of acetic anhydride and aqueous sodium acetate are added. The pKa of acetic acid is about 5, as is the pKa of PhNH₃⁺, so an equilibrium is set up and the solution now contains these species:

The only electrophile is acetic anhydride, with its two electrophilic carbonyl groups. The nucleophiles available are water, aniline, and acetate. Water is there in great abundance and does react with acetic anhydride but can’t compete with the other two as they are more basic (by about 105). If acetate attacks the anhydride, it simply regenerates acetate. But if aniline attacks, the amide is formed as acetate is released.

The isolation of the product is easy as the amide is insoluble in water and can be filtered off. Environmental considerations suggest that we should not use organic solvents so much and should use water when possible. If we have some idea about pKas we can estimate whether water will interfere in a reaction we are planning and decide whether it is a suitable solvent or not. It is even possible to acylate amines with the more reactive acid chlorides in aqueous solution, and we will return in detail to acylation reactions such as these in Chapter 10.

مواضيع ذات صلة

Organometallics as bases

How to make organolithium reagents

Making organometallics, How to make Grignard reagents

Organometallic compounds contain a carbon–metal bond

Lewis acids and bases

pKa in action—the development of the drug cimetidine

Carbon acids

Substituents affect the pKa

The ‘pKas’ of bases

Nitrogen compounds as acids and bases

Delocalization of the negative charge stabilizes the conjugate base

Constructing a pKa scale