Chapter 2 gave the structural features of carboxylic acids and acyl derivatives.
These compounds can be seen as functional classes with one heteroatom bond which is modified by a carbonyl group. In Chapter 6, we saw how this explains the acidity of carboxylic acids in which the alcohol and carbonyl parts acted together. The acidic nature of carboxylic acids was limited to the O–H bond.
In Section 7.7, we saw how the reactions of the carbonyl group were mostly started by nucleophilic attack to give addition products. Nucleophilic attack is also the major reaction of acyl derivatives. However, instead of overall addition, the reaction leads to substitution products as shown in Figure 7.37.
7.8.1 Nucleophilic Acyl Substitution
The change from addition to substitution is because of the potential leaving group Y in Figure 7.37. In aldehydes and ketones, there is no simple leaving group. Only hydride or carbanions are possible. Because these are both very strong nucleo- philes, they are very poor leaving groups. Acyl derivatives such as acyl halides, acid anhydrides, esters, carboxylic acids, and amides have better leaving groups.
These include halide, carboxylate, alkoxide, hydroxide, and amine anion.
The overall substitution reactions give the same result as the one-step SN2 reac- tions in Section 7.5.2. However, they occur by a different mechanism. Figure 7.37 shows nucleophilic acyl substitution as a two-step process which goes through an intermediate oxyanion.
The relative reactivity of acyl derivatives in substitution is controlled by the polarization in each derivative. The higher the polarity of the C–Y bond, the FIGURE 7.37
Nucleophilic addition versus acyl substitution.
more reactive the acyl derivative. Figure 7.38 lists the acyl derivative reactivity as acyl halides > acid anhydrides > esters > amides.
All the acyl derivatives can be prepared from the carboxylic acid. Because direct conversion needs the substitution of a hydroxyl group, these are done under acidic conditions to improve the leaving group. This method of using acid catal- ysis is the same as we saw for alcohols in Section 7.6.3 and for hydrates in Sec- tion 7.7.1.4.
Alternatively, all acyl derivatives can be made from the very reactive acyl halides.
These most reactive members are prepared from the acid with the reagents PCl3 or SOCl2. Any acyl derivative can be prepared by nucleophilic acyl substitution of an acyl derivative of higher reactivity.
Figure 7.38 also shows a link between primary amides and nitriles. This link is the elimination of water, and completes the circle of interconversions. In Section 7.7.1.1 it was shown how nitriles can be hydrolyzed to give carboxylic acids.
This is a useful reaction because it is easy to put a –CN group into a molecule by nucleophilic substitution. The –CN group is hydrolyzed to give a –CO2H group.
From this, all acyl derivatives can be easily prepared.
7.8.2 Esters
Esters are an important class of compounds. Because of their importance, we will look at the mechanism of their preparation. Figure 7.39 shows one way to make esters by the acid-catalyzed reaction of esterification. This uses a carboxylic acid and an alcohol, along with an acid catalyst. During this reaction a molecule of water is formed.
FIGURE 7.38
Acyl substitution reactivity order.
This equation shows the overall forward reaction. However, the acid-catalyzed process is actually an equilibrium. As Figure 7.40 shows, this equilibrium can be shifted by having different reagents in excess.
To understand this, you need to study the mechanisms of esterification and reverse hydrolysis in Figure 7.41. This clearly shows there are several equilibrium steps in the overall process.
The hydrolysis of an ester to give a carboxylic acid and an alcohol can also be done under basic conditions. This alternative reaction is by a standard nucleo- philic acyl substitution.
7.8.3 Amides
As shown in Figure 7.38, amides can be formed by substitution reactions of the acyl derivatives above them in the reactivity chart. Chapter 2 showed how amides are classified as 1°, 2°, and 3° amides depending on the substitution at FIGURE 7.39
Preparation of esters.
FIGURE 7.40
The reversibility of esterification.
FIGURE 7.41
Mechanism of acid-catalyzed esterification.
the nitrogen. The amide bond is important in many natural products of biologi- cal importance, such as peptides and proteins. Figure 7.42 shows why the bond- ing in an amide makes it special.
The nitrogen lone pair is easily delocalized into the carbonyl group. The result of delocalization is best drawn as a resonance hybrid. This gives partial C]N character to the amide bond, and a planar sp2-hybridized state to the nitrogen.
This stops free rotation around the C–N bond and can cause possible cis/trans isomers.
Proof of this limited rotation is seen in the fixed conformations in amides.
Amides also have a shorter C–N bond length than amines, ±132 pm compared with ±147 pm. This delocalization in amides also explains their non-basic char- acter compared with amines. This is because the lone pair is no longer free to act as a Lewis base.
7.8.4 Nitriles
In Section 7.5.2, we saw that nitriles are easily made and can be hydrolyzed to carboxylic acids. See Figure 7.43. In Section 7.8.5, you can see that a nitrile can be reduced. However, the key feature is that the formation of a nitrile and any subsequent change adds one carbon to the chain.
7.8.5 Reduction
As you can see in Figure 7.44, reduction is a major reaction of all acyl deriva- tives. This can be done with metal hydride reagents, such as LiAlH4. With acyl halides, anhydrides, acids, and esters, reduction gives alcohols as the products.
For amides and nitriles, reduction gives amines as the products.
FIGURE 7.43
Nitrile chain lengthening sequence.
FIGURE 7.42 The amide bond.