Preparations of carboxylic acid derivatives

PREPARATIONS OF CARBOXYLIC ACID DERIVATIVES

Key Notes

Acid chlorides

Acid chlorides are synthesized by treating carboxylic acids with thionyl chloride, phosphorus trichloride, or oxalyl chloride. The carboxylic acid reacts  with  the  reagent  to  release  a  chloride  ion  which  then  acts  as  a nucleophile with the reaction intermediate to form the acid chloride.

Acid anhydrides

Acid anhydrides are best prepared by treating acid chlorides with a car- boxylate salt. Cyclic anhydrides can be synthesized from acyclic di-acids by heating.

Esters

Esters are prepared by the nucleophilic substitution of acid chlorides or acid anhydrides with alcohols, the nucleophilic substitution of carboxylic acids with alcohol in the presence of a catalytic amount of mineral acid, the SN2 nucleophilic substitution of an alkyl halide with a carboxylate ion, and finally the reaction of carboxylic acids with diazomethane to give methyl esters.

Amides

Acid chlorides can be converted to primary, secondary, and tertiary amides by reaction with ammonia, primary amines, and secondary amines, respec- tively.  Acetic  anhydride  can  be  treated  with  amines  to  synthesize ethanamides. Carboxylic acids and amines react together to form a salt. Some salts can be converted to amides by strong heating to remove water.

Acid chlorides

Acid chlorides can be prepared from carboxylic acids using thionyl chloride (SOCl₂), phosphorus trichloride (PCl₃), or oxalyl chloride (ClCOCOCl Fig. 1).

The mechanism for these reactions is quite involved, but in general involves the OH group of the carboxylic acid acting as a nucleophile to form a bond to the reagent and displacing a chloride ion. This has three important consequences. First of all, the chloride ion can attack the carbonyl group to introduce the required chlorine atom. Secondly, the acidic proton is no longer present and so an acid–base reaction is prevented. Thirdly, the original OH group is converted into a good leaving group and is easily displaced once the chloride ion makes its attack. The reaction of a carboxylic acid with thionyl chloride follows the general pathway shown in Fig. 2.

The leaving group (SO₂Cl) spontaneously fragments to produce hydrochloric acid and sulfur dioxide. The latter is lost as a gas which helps to drive the reaction to completion. The detailed mechanism is shown in Fig. 3.

Acid anhydrides

Acid anhydrides are best prepared by treating acid chlorides with a carboxylate salt . Carboxylic acids are not easily converted to acid anhydrides directly. However five-membered and six-membered cyclic anhydrides can be synthesized from diacids by heating the acyclic structures to eliminate water (Fig. 4).

Esters

There are many different ways in which esters can be synthesized. A very effective method is to react an acid chloride with an alcohol in the presence of pyridine . Acid anhydrides also react with alcohols to give esters, but are less reactive . Furthermore, the reaction is wasteful since half of the acyl content in the acid anhydride is wasted as the leaving group (i.e. the carboxylateion). This is not a problem if the acid anhydride is cheap and readily available. For example, acetic anhydride is useful for the synthesis of a range of acetate esters (Fig. 5).

A very common method of synthesizing simple esters is to treat a carboxylic acid with a simple alcohol in the presence of a catalytic amount of mineral acid (Fig. 6). The acid catalyst is required since there are two difficult steps in the reac-tion mechanism. First of all, the alcohol molecule is not a good nucleophile and so the carbonyl group has to be activated. Secondly, the OH group of the carboxylic acid is not a good leaving group and this has to be converted into a better leaving group. The mechanism (Fig. 7) is another example of nucleophilic substitution. In the first step, the carbonyl oxygen forms a bond to the acidic proton. This results in the carbonyl oxygen gaining a positive charge. This makes the carbonyl carbon more electrophilic and activates it to react with the weakly nucleophilic alcohol. In the second step, the alcohol uses a lone pair of electrons to form a bond to the carbonyl carbon. At the same time, the carbonyl π bond breaks and both electrons move onto the carbonyl oxygen to form a lone pair of electrons and thus neutral-ize the positive charge. Activation of the carbonyl group is important since the incoming alcohol gains an unfavorable positive charge during this step. In the third stage, a proton is transferred from the original alcohol portion to the OH group which we want to remove. By doing so, the latter moiety becomes a much better leaving group. Instead of a hydroxide ion, we can now remove a neutral water molecule. This is achieved in the fourth step where the carbonyl π bond is reformed and the water molecule is expelled.

All the steps in the reaction mechanism are in equilibrium and so it is important to use the alcohol in large excess (i.e. as solvent) in order to drive the equilibrium to products. This is only practical with cheap and readily available alcohols such as methanol and ethanol. On the other hand, if the carboxylic acid is cheap and readily available it could be used in large excess instead.

An excellent method of preparing methyl esters is to treat carboxylic acids with diazomethane (Fig. 8). Good yields are obtained because nitrogen is formed as one of the products and since it is lost from the reaction mixture, the reaction is driven to completion. However, diazomethane is an extremely hazardous chemical which can explode, and strict precautions are necessary when using it.

Lastly, the carboxylic acid can be converted to a carboxylate ion and then treated with an alkyl halide (Fig. 9). The reaction involves the S_N2 nucleophilic substitution of an alkyl halide and so the reaction works best with primary alkyl halides.

Amides

Amides can be prepared from acid chlorides by nucleophilic substitution . Treatment with ammonia gives a primary amide, treatment with a primary amine gives a secondary amide, and treatment with a secondary amine gives a tertiary amide. Tertiary amines cannot be used in this reaction because they do not give a stable product.

Two equivalents of amine are required for the above reactions since one equiv- alent of the amine is used up in forming a salt with the hydrochloric acid which is produced in the reaction. This is clearly wasteful on the amine, especially if the amine is valuable. To avoid this, one equivalent of sodium hydroxide can be added to the reaction in order to neutralize the HCl.

Amides can also be synthesized from acid anhydrides and esters , but in general these reactions offer no advantage over acid chlorides since acid anhydrides and esters are less reactive. Furthermore, with acid anhydrides, half of the parent carboxylic acid is lost as the leaving group. This is wasteful and so acid anhydrides are only used for the synthesis of amides if the acid anhydride is cheap and freely available (e.g. acetic anhydride).

The synthesis of amides directly from carboxylic acids is not easy since the reac-tion of an amine with a carboxylic acid is a typical acid–base reaction resulting in the formation of a salt (Fig. 10). Some salts can be converted to an amide by heat-ing strongly to expel water, but there are better methods available as previously described.