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Chapter: Organic Chemistry: Carboxylic acids and carboxylic acid derivatives

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Reactions of Carboxylic acids and carboxylic acid derivatives

Carboxylic acids form water soluble carboxylate salts when treated with a base.

REACTIONS

Key Notes

Acid–base reactions

Carboxylic acids form water soluble carboxylate salts when treated with a base.

Interconversion of acid derivatives

Reactive acid derivatives can be converted to less reactive acid derivatives. Acid chlorides can be converted to acid anhydrides, esters, or amides; acid anhydrides can be converted to esters or amides; and esters can be con-verted to amides. Transesterification is also possible by dissolving an ester into an excess of alcohol in the presence of an acid catalyst.

Hydrolysis

Acid chlorides and acid anhydrides are sufficiently reactive to be hydrolyzed by water to their constituent carboxylic acids. Heating under basic or acidic conditions is preferable for the hydrolysis of less reactive esters and amides. The reaction is another example of nucleophilic substi-tution. Under neutral or acidic conditions, the nucleophile is water. Under basic conditions, the nucleophile is the hydroxide ion and the reaction is driven by the irreversible formation of the carboxylate ion. Amides can also be effectively hydrolyzed under acid conditions due to the formation of an ammonium salt. In contrast, the acid-catalyzed hydrolysis of esters is an equilibrium reaction.

Friedel–Crafts acylation

Aromatic rings can be treated with acid chlorides in the presence of a Lewis acid to give an aromatic ketone.

Grignard reaction

Acid chlorides and esters react twice with Grignard reagents to form ter-tiary alcohols, with the introduction of two alkyl substituents. Carboxylic acids and Grignard reagents react together in an acid–base reaction which serves no synthetic value.

Organolithium reactions

Esters react with organolithium reagents to produce tertiary alcohols in a similar process to that described for Grignard reagents. Carboxylic acids have to be protected to prevent destruction of the organolithium reagent in an acid–base reaction.

Organocuprate reactions

Acid chlorides can be treated  with an organocuprate reagent to give ketones. The reaction mechanism is radical based and is not a nucleophilic substitution.

Reduction

Lithium aluminum hydride (LiAlH4) is used to convert carboxylic acids, acid chlorides, acid anhydrides, and esters to primary alcohols. Amides are reduced to amines. Hindered hydride reagents are less reactive and can be used to convert acid chlorides or esters to aldehydes. Borane can be used to reduce carboxylic acids to primary alcohols when nitro groups are present.

Sodium borohydride does not reduce carboxylic acids or their derivatives and can be used to reduce aldehydes and ketones without affecting car-boxylic acids or acid derivatives.

Dehydration of primary amides

Primary amides are dehydrated to nitriles on treatment with a dehydrating agent such as thionyl chloride.

 

Acid–base reactions

Since carboxylic acids have an acidic proton (CO2H), they form water soluble carboxylate salts on treatment with a base (e.g. sodium hydroxide or sodium bicarbonate).


Interconversion of acid derivatives

Reactive acid derivatives can be converted to less reactive acid derivatives by nucleophilic substitution. This means that acid chlorides can be converted to acid anhydrides, esters, and amides (Fig. 2). Hydrochloric acid is released in these reactions and this may lead to side reactions. As a result, pyridine or sodium hydroxide may be added in order to mop up the hydrochloric acid (Fig. 3).



Acid anhydrides can be converted to esters and amides but not to acid chlorides (Fig. 4).

Esters can be converted to amides but not to acid chlorides or acid anhydrides (Fig. 5).


Esters can also be converted by nucleophilic substitution from one type of ester to another – a process called transesterification. For example, a methyl ester could be dissolved in ethanol in the presence of an acid catalyst and converted to an ethyl ester (Fig. 6). The reaction is an equilibrium reaction, but if the alcohol to be introduced is used as solvent, it is in large excess and the equilibrium is shifted to the desired ester. Furthermore, if the alcohol to be replaced has a low boiling point, it can be distilled from the reaction as it is substituted, thus shifting the equilibrium to the desired product.

Amides are the least reactive of the acid derivatives and cannot be converted to acid chlorides, acid anhydrides, or esters.


Hydrolysis

Reactive acid derivatives (i.e. acid chlorides and acid anhydrides) are hydrolysed by water to give the constituent carboxylic acids (Fig. 7). The reaction is another example  of  nucleophilic  substitution  where  water  acts  as  the  nucleophile. Hydrochloric acid is a byproduct from the hydrolysis of an acid chloride, so pyridine is often added to the reaction mixture to mop it up (Fig. 3).


Esters and amides are less reactive and so the hydrolysis requires more forcing conditions using aqueous sodium hydroxide or aqueous acid with heating (Fig. 8).


Under basic conditions, the hydroxide ion acts as the nucleophile by the normal mechanism for nucleophilic substitution. For example, the mechanism of hydrolysis of ethyl acetate is as shown (Fig. 9). However, the mechanism does not stop here. The carboxylic acid which is formed reacts with sodium hydroxide to form a water soluble carboxylate ion (Fig. 10a). Furthermore, the ethoxide ion which is lost from the molecule is a stronger base than water and undergoes proto-nation (Fig. 10b). The basic hydrolysis of an ester is also known as saponification and produces a water soluble carboxylate ion.


The same mechanism is involved in the basic hydrolysis of an amide and also results in a water soluble carboxylate ion. The leaving group from an amide is initially charged (i.e. R2N: ). However, this is a strong base and reacts with water to form a free amine plus a hydroxide ion.

In the basic hydrolysis of esters and amides, the formation of a carboxylate ion is irreversible and so serves to drive the reaction to completion.

In order to isolate the carboxylic acid rather than the salt, it is necessary to add acid (e.g. dilute HCl) to the aqueous solution. The acid protonates the carboxylate salt to give the carboxylic acid which (in most cases) is no longer soluble in aqueous solution and precipitates out as a solid or as an oil.

The mechanism for acid–catalyzed hydrolysis (Fig. 11) involves water acting as a nucleophile. However, water is a poor nucleophile since it gains an unfavorable positive charge when it forms a bond. Therefore, the carbonyl group has to be activated which occurs when the carbonyl oxygen is protonated by the acid catalyst (Step 1). Nucleophilic attack by water is now favored since it neutralizes the unfavorable positive charge on the carbonyl oxygen (Step 2). The intermediate has a positive charge on the oxygen derived from water, but this is neutralized by losing the attached proton such that the oxygen gains the electrons in the O–H bond (Step 3). Another protonation now takes place (Step 4). This is necessary in order to convert a poor leaving group (the methoxide ion) into a good leaving group (methanol). The π bond can now be reformed (Step 5) with loss of methanol. Finally, water can act as a base to remove the proton from the carbonyl oxygen (Step 6).


The acid-catalyzed hydrolysis of an ester is not as effective as basic hydrolysis since all the steps in the mechanism are reversible and there is no salt formation to pull the reaction through to products. Therefore, it is important to use an excess of water in order to shift the equilibria to the products. In contrast to esters, the hydrolysis of an amide in acid does result in the formation of an ion (Fig. 12). The leaving group here is an amine and since amines are basic, they will react with the acid to form a water soluble aminum ion. This is an irreversible step which pulls the equilibrium through to the products.


In the acid-catalyzed hydrolysis of an ester, only a catalytic amount of acid is required since the protons used during the reaction mechanism are regenerated. However with an amide, at least one equivalent of acid is required due to the ionization of the amine.

Friedel–Crafts acylation

Acid chlorides can react with aromatic rings in the presence of a Lewis acid to give aromatic ketones (Fig. 13). The reaction involves formation of an acylium ion from the acid chloride, followed by electrophilic substitution of the aromatic ring .


Grignard reaction

Acid chlorides and esters react with two equivalents of a Grignard reagent  to produce a tertiary alcohol where two extra alkyl groups are provided by the Grignard reagent (Fig. 14).


There are two reactions involved in this process (Fig. 15). The acid chloride reacts with the first equivalent of Grignard reagent in a typical nucleophilic substitution to produce an intermediate ketone. However, this ketone is also reactive to Grignard reagents and immediately reacts with a second equivalent of Grignard reagent by the nucleophilic addition mechanism described for aldehydes and ketones.


Carboxylic acids react with Grignard reagents in an acid–base reaction resulting in formation of the carboxylate ion and formation of an alkane from the Grignard reagent (Fig. 16). This has no synthetic use and it is important to protect carboxylic acids when carrying out Grignard reactions on another part of the molecule so that the Grignard reagent is not wasted.


Carboxylic acids react with Grignard reagents in an acid–base reaction resulting in formation of the carboxylate ion and formation of an alkane from the Grignard reagent (Fig. 16). This has no synthetic use and it is important to protect carboxylic acids when carrying out Grignard reactions on another part of the molecule so that the Grignard reagent is not wasted.

Organolithium reactions

Esters react with two equivalents of an organolithium reagent to give a tertiary alcohol where two of the alkyl groups are derived from the organolithium reagent (Fig. 17). The mechanism of the reaction is the same as that described in the Grignard reaction, that is, nucleophilic substitution to form a ketone followed by nucleophilic addition. It is necessary to protect any carboxylic acids present when carrying out organolithium reactions since one equivalent of the organo-lithium reagent would be wasted in an acid–base reaction with the carboxylic acid.


Organocuprate reactions

Acid chlorides react with diorganocuprate reagents to form ketones (Fig. 18). Like the Grignard reaction, an alkyl group displaces the chloride ion to produce a ketone. However, unlike the Grignard reaction, the reaction stops at the ketone stage. The mechanism is thought to be radical based rather than a nucle-ophilic substitution. This reaction does not take place with carboxylic acids, acid anhydrides, esters, or amides.


Reduction

Carboxylic acids, acid chlorides, acid anhydrides and esters are reduced to primary alcohols on treatment with lithium aluminum hydride (LiAlH4 ;Fig. 19). The reaction involves nucleophilic substitution by a hydride ion to give an intermediate aldehyde. This cannot be isolated since the aldehyde immediately undergoes a nucleophilic addition reaction with another hydride ion. The detailed mechanism is as shown in Fig. 21.


Amides differ from carboxylic acids and other acid derivatives in their reaction with LiAlH4 . Instead of forming primary alcohols, amides are reduced to amines (Fig. 22). The mechanism (Fig. 23) involves addition of the hydride ion to form an intermediate which is converted to an organoaluminum intermediate. The differ-ence in this mechanism is the intervention of the nitrogen’s lone pair of electrons. These are fed into the electrophilic center to eliminate the oxygen which is then followed by the second hydride addition.


Although acid chlorides and acid anhydrides are converted to tertiary alco-hols with LiAlH4, there is little synthetic advantage in this since the same reac-tion can be achieved on the more readily available esters and carboxylic acids. However, since acid chlorides are more reactive than carboxylic acids, they can be treated with a milder hydride-reducing agent and this allows the synthesis of aldehydes (Fig. 24). The hydride reagent used (lithium tri-tert-butoxyaluminum hydride) contains three bulky alkoxy groups which lowers the reactivity of the remaining hydride ion. This means that the reaction stops after nucleophilic substitution with one hydride ion. Another sterically hindered hydride reagent – diisobutylaluminum hydride (DIBAH) – is used to reduce esters to aldehydes (Fig. 24). Normally low temperatures are needed to avoid over-reduction.


Borane (B2H6) can be used as a reducing agent to convert carboxylic acids to pri-mary alcohols. One advantage of using borane rather than LiAlH4 is the fact that the former does not reduce any nitro groups which might be present. LiAlH4 reduces a nitro group (NO2) to an amino group (NH2).

It is worth noting that carboxylic acids and acid derivatives are not reduced by the milder reducing agent – sodium borohydride (NaBH4). This reagent can there-fore be used to reduce aldehydes and ketones without affecting any carboxylic acids or acid derivatives which might be present.

 

Dehydration

Primary amides are dehydrated to nitriles using a dehydrating agent such as of primary amides thionyl chloride (SOCl2), phosphorus pentoxide (P2O5), phosphoryl trichloride (POCl3), or acetic anhydride (Fig. 25).


The mechanism for the dehydration of an amide with thionyl chloride is shown in Fig. 26. Although the reaction is the equivalent of a dehydration, the mechanism shows that water itself is not eliminated. The reaction is driven by the loss of sulfur dioxide as a gas.

 

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