In order to understand the chemistry of the carboxylic acid derivatives, i.e. esters, amides, acid halides, and anhydrides, it is useful to think of the carbonyl group of aldehydes and ketones as a reference point. The two major types of reactions that are characteristic of aldehydes and ketones are nucleophilic addition and abstraction of an a-hydrogen. Figure 1 summarizes these alternatives in general terms.
Whether B acts as a nucleophile or a base depends upon several factors:
The same alternatives outlined in Figure 1 for the carbonyl group are possible for the acyl group. We'll begin by considering those reactions that involve nucleophilic addition to the acyl carbon.
Carboxylic acids react with alcohols in the presence of an acid catalyst to produce esters. The reaction is called Fischer esterification. Equation 1 illustrates the formation of methyl salicylate by the acid catalysed reaction of salicylic acid with methanol. The mechanism of the reaction is called nucleophilic acyl substitution.
Carboxylic acid chlorides also react with alcohols to form esters by nucleophilic acyl substitution. Equation 2 describes the preparation of t-butyl acetate from acetyl chloride and t-butyl alcohol. Pyridine, C5H5N, an organic base, is added as a catalyst and an "acid trap" to react with the HCl that is formed along with the ester.
Preparation of t-butyl acetate by Fischer esterification would not work well because the acid catalyst would also catalyse dehydration of the t-butyl alcohol. Figure 2 presents a step-by-step description of this transformation.
Acid chlorides react with primary and secondary amines to produce amides. The preparation of N,N-diethyl-meta-toluamide, DEET, by this method is summarized in Equation 3. DEET is the active ingredient in many insect repellants.
In this case 2 moles of diethylamine are used for each mole of acid chloride. One mole acts as a nucleophile while the second acts as an acid trap.
The synthesis of sulfanilamide involves the reaction of a sulfonic acid chloride with ammonia to produce a sulfonamide as shown in Equation 4.
All of the reactions discussed above are examples of nucleophilic acyl substitution reactions. It is the principal reaction pathway of the acyl group. It is interesting to consider why the carbonyl group undergoes nucleophilic addition while the acyl group prefers nucleophilic substitution. Figure 3 compares several alternative reaction pathways in terms of their approximate equilibrium constants.
The equilibrium constant for reaction A, the addition of hydroxide ion to the carbonyl carbon, is approximately 1. This means that the forward reaction, Af, and the reverse reaction, Ar, are about equally probable; they occur at about the same rates. Note that Ar involves regeneration of the carbon-oxygen double bond and expulsion of hydroxide ion. Alternatively, it is possible, in principle, to regenerate the carbonyl group by expelling methanide ion rather than hydroxide, as shown by the reaction labeled Bf. The equilibrium constant for this reaction should be approximately 10-34. Clearly this is not a viable option. The normal pattern of reactivity of a carbonyl group of aldehydes and ketones with nucleophilic reagents is addition.
Reaction C is an alternative path that is available to aldehydes and ketones under special circumstances. It is the path to aldol reactions.
Compare the situation involving equilibria A and B with that involving equilibria D and E. The equilibrium constant for reaction D should be approximately 1. In other words, nucleophilic addition of hydroxide ion to the carbon atom of an acyl group is about as likely as nucleophilic addition to the carbon atom of a carbonyl group. Similarly, regeneration of the carbon-oxygen double bond can be accompanied by the expulsion of either of two leaving groups, hydroxide ion (reaction Dr ), or chloride ion (reaction Ef ). Since the pKa of HCl is -7, the equilibrium constant for reaction E should be about 1023!! In other words, reformation of the carbonyl group will be accompanied by expulsion of chloride ion rather than hydroxide ion. Hence the normal pattern of reactivity of an acyl group with nucleophilic reagents is substitution.
Figure 4 compares equilibria A, B, and E in terms of the relative potential energies of the species involved in each reaction.
