Carboxylic Acid Derivatives – Acid Anhydrides, Amides, Nitriles | Organic Chemistry 3

Additional reactions of carboxylic acid derivatives are studied in this chapter: chemistry of acid anhydrides: preparation and reactions, chemistry of amides: preparation, hydrolysis and reactions, nomenclature and properties of nitriles, chemistry of nitriles: preparation, hydrolysis and reactions.

Preparation of Acid Anhydrides

Synthesis of acid anhydrides from acid chlorides:
 


Conversion of an acid chloride into an acid anhydride via an SN2 process with a carboxylate ion.

Mechanism:

  1. Nucleophilic attack of the carboxylate ion on the acid chloride.
  2. Loss of the leaving group, a chloride anion, to form an acid anhydride.


     

This method can be used to prepare symmetrical or unsymmetrical anhydrides.

 

Synthesis of acid anhydrides from carboxylic acid (dehydration):
 


Conversion of a carboxylic acid into an acid anhydride by dehydration.

This method requires excessive heating (800 oC) or the use of a dehydrating agent such as P2O5. However, it is only practical for acetic acid or dicarboxylic acids (to form cyclic anhydrides), as most other acids are not compatible with high temperatures or cannot form anhydrides with P2O5.

Reactions of Acid Anhydrides

General reactivity:

  • Analogous to the reactivity of the acid chloride. The only difference is the nature of the leaving group, a carboxylate ion for the acid anhydrides vs. a chloride ion for the acid chlorides ⇒ it is not necessary to use pyridine in reactions with acid anhydrides because HCl is not produced.
  • The use of anhydrides involves the loss of half of the starting material (the leaving carboxylate ion), which is inefficient and unsustainable ⇒ acid chlorides are more widely used than acid anhydrides.

 

Nucleophilic acyl substitution of acid anhydrides:
 


Mechanism:

Addition-elimination process similar to nucleophilic acyl substitution of acid chlorides.

 

Acetylation with acetic anhydride:
 


Mechanism:

Often a base such as pyridine is added to act as a catalyst.

  1. Nucleophilic attack of the alcohol or amine on the acetic anhydride to form a tetrahedral intermediate.
  2. Loss of the leaving group, an acetate ion, to re-form the carbonyl group.
  3. Deprotonation to form the final acetyl ester or acetylamide.

 

Reduction of acid anhydrides

  • With lithium aluminium hydride:
     


Mechanism:

Reduction similar to the lithium aluminium hydride reduction of acid chlorides.

 

  • With organometallic reagents:
     


Mechanism:

Reduction similar to the reduction of acid chlorides with organometallic reagents.

Preparation of Amides

From carboxylic acid derivatives:

Amides can be prepared from any carboxylic acid derivatives (acid halides, anhydrides, esters). They are best prepared from acid chlorides:
 

Mechanism:

  1. Nucleophilic attack of the amine on the carbonyl to form a tetrahedral intermediate.
  2. Loss of the leaving group, a chloride ion, to re-form the carbonyl group.
  3. Loss of a proton at the nitrogen to form an amide.

2 equivalents of amines are required: one for the nucleophilic attack of the carbonyl group, the other to neutralize the HCl formed.

 

From carboxylic acids:

Direct conversion of a carboxylic acid to an amide is very difficult: carboxylic acids undergo an acid-base reaction in the presence of NH3 or amines to form an ammonium and a carboxylate salt.
 

An additional reagent, a dehydrating agent such as dicyclohexylcarbodiimide (DCC), is used to promote amide formation by converting the carboxy OH group into a better leaving group. DCC is converted to the by-product dicyclohexylurea, with H2O added to the DCC.

 

Mechanism:

  1. Nucleophilic attack of the OH of the carboxylic acid on the carbodiimide.
  2. Proton transfer to form a neutral activated carboxy group.


     
  3. Nucleophilic attack of the amine on the carbonyl to form a tetrahedral intermediate.
  4. Loss of the leaving group, the dicyclohexylurea, to re-form the carbonyl group.
  5. Proton transfer to form an amide and a urea.

Hydrolysis and Reactions of Amides

Hydrolysis of amides (carboxylic acid formation):

  • Acid-catalyzed hydrolysis:
     

Mechanism:

Hydrolysis similar to the acid-catalyzed hydrolysis of esters.

  1. Protonation of the carbonyl group to make it even more electrophilic.
  2. Nucleophilic attack of water on the carbonyl.
  3. Deprotonation to form a neutral tetrahedral intermediate.
  4. Protonation of the amino group to make it a better leaving group.
  5. Loss of the leaving group, the ammonia or an amine, to re-form the carbonyl group.
  6. Deprotonation to form a carboxylic acid.

Due to the high pKa of the ammonium ion (NH4+) formed (pKa = 9.2) compared to H3O+, the equilibrium strongly favors product formation ⇒ unlike esters, acid-catalyzed hydrolysis of amides is irreversible.

 

  • Base-catalyzed hydration:
     

Mechanism:

Hydrolysis similar to the saponification of esters.

  1. Nucleophilic attack of the hydroxide on the carbonyl group.
  2. Loss of the leaving group, an amide ion, to re-form the carbonyl.
  3. Deprotonation of the carboxylic acid with the amide ion to form a carboxylate ion (shifting the equilibrium in favor of product formation).
  4. After the reaction is complete, protonation of the carboxylate ion in the presence of an acid.

 

Reduction of amides (amine formation):
 

Mechanism:

Treatment with lithium aluminium hydride (LiAlH4) converts amides into amines.

  1. Nucleophilic attack of a hydride ion on the amide carbonyl group.
  2. Loss of the leaving group, an aluminate anion, to form an iminium ion intermediate.
  3. Second nucleophilic attack of a hydride ion to form an amine.


     

This reaction is effective with both acyclic and cyclic amides, or lactams, and is a good method for preparing cyclic amines.

 

Hofmann rearrangement:
 

Mechanism:

  1. Amidate formation:


     
  2. Halogenation:


     
  3. N-haloamidate formation:


     
  4. Rearrangement with halide elimination:


     
  5. Carbamic acid hydration and decomposition:

Nomenclature and Properties of Nitriles

Nomenclature:

The ​​​-ic acid ending of the corresponding carboxylic acid is replaced by -nitrile. Nitrile takes precedence over aldehyde, ketone, amine, alkene, alkyne. The -CN substituent is called cyano. A cycloalkane with a cyano group attached to the ring is called a cycloalkanecarbonitrile.

 

 

Properties:

  • Polarity: The nitrile bond (C≡N) is short, strong and polar due to the electronegativity difference between carbon and nitrogen ⇒ significant dipole-dipole interactions.
  • Geometry: The carbon of the C≡N bond of nitrile is sp hybridized ⇒ linear geometry.

 

Absorption spectroscopy:

  • 13C NMR: δ ~ 115-130 ppm.
    Upfield signal compared to other carboxylic acid derivatives due to sp hybridization. Farther downfield signal compared to signal of alkynes (65-100 ppm).
  • IR absorption: ~ 2250 cm-1 (C≡N stretching).

Preparation of Nitriles

Preparation via SN2 reactions:
 

Mechanism:

Nucleophilic attack of a cyanide ion to an alkyl halide in an SN2 process to form the desired nitrile. Tertiary halides do not react due to steric hindrance.

 

Preparation via dehydration of amides:
 

Mechanism:

  1. Nucleophilic attack of the amide on thionyl chloride.
  2. Loss of the leaving group, a chloride ion.
  3. Deprotonation of one of the hydrogens on the nitrogen atom.
  4. Deprotonation of the second hydrogen on the nitrogen atom and loss of SO2 to form a nitrile.

This process is useful for preparing tertiary nitriles, which cannot be prepared via an SN2 process.

Hydrolysis and Reactions of Nitriles

Hydrolysis of nitriles (carboxylic acid formation):

  • Acid-catalyzed hydrolysis:
     

Mechanism:

The nitrile is first hydrolyzed to an amide, which is then further hydrolyzed to a carboxylic acid.

  1. Protonation of the nitrile group to make it even more electrophilic.
  2. Nucleophilic attack of water on the protonated nitrile.
  3. Deprotonation to form a neutral intermediate.
  4. Protonation of the nitrogen atom to form a resonance-stabilized intermediate.
  5. Deprotonation to form an amide.
  6. The amide is then further hydrolyzed as seen previously in the acid-catalyzed hydrolysis of amides.

 

  • Base-catalyzed hydrolysis:
     

Mechanism:

Again, the nitrile is first hydrolyzed to an amide, which is then further hydrolyzed to a carboxylic acid.

  1. Nucleophilic attack of the hydroxide on the cyano group.
  2. Protonation of the nitrogen atom to form a neutral intermediate.
  3. Deprotonation of the -OH to form a resonance-stabilized intermediate.
  4. Protonation of the nitrogen atom to form an amide.
  5. The amide is then further hydrolyzed as seen previously in the base-catalyzed hydration of amides.

 

Reduction of nitriles

  • With lithium aluminium hydride (amine formation):
     

Mechanism:

  1. Nucleophilic attack of a hydride ion on the cyano group to form an anion which complexes with the AlH3.
  2. Second nucleophilic attack of a hydride ion on the carbon of the former cyano group to form an anion which complexes with the AlH3.
  3. Hydrolysis with water to protonate the dianion and form an amine.

 

  • With diisobutylaluminium hydride - DIBAL-H (aldehyde formation):
     

Mechanism:

  1. Nucleophilic attack of a hydride ion on the cyano group to form an anion.
  2. Protonation of the anion with water to form an imine.
  3. Hydrolysis of the imine to form an aldehyde.

 

Reactions with organometallic reagents (ketone formation):
 

Mechanism:

  1. Nucleophilic attack by the Grignard reagent to form an anion.
  2. Protonation of the anion with water to form an imine.
  3. Hydrolysis of the imine to form a ketone.

Check your knowledge about this Chapter

Acid anhydrides are prepared by two methods:

  • The most common method involves the reaction of a carboxylic acid with an acyl chloride in the presence of a base, such as pyridine, which acts as a catalyst and a hydrogen chloride scavenger.
  • The second  method involves the dehydration of two carboxylic acids, usually by heating them with a dehydrating agent like phosphorus pentoxide.

The reactivity of the acid anhydrides is similar to that of the acid chloride. The only difference is the nature of the leaving group, a carboxylate ion for the acid anhydrides vs. a chloride ion for the acid chlorides ⇒ it is not necessary to use pyridine in reactions with acid anhydrides because HCl is not produced.

 

Acid anhydrides undergo nucleophilic acyl substitution reactions. Nucleophiles attack the electrophilic carbon in the anhydride, leading to the formation of carboxylic acids or esters, depending on the reaction conditions.

Acetic anhydrides react with alcohols in a process known as acetylation, where the anhydride acts as an acylating agent to transfer an acyl group to the alcohol. The reaction produces an ester and a carboxylic acid as products. Specifically, one of the acyl groups from the anhydride is transferred to the hydroxyl group of the alcohol, forming an ester, while the remaining acyl group is hydrolyzed to form a carboxylic acid.

The reaction between acid anhydrides and amine compounds typically involves the formation of amides. In this reaction, the nucleophilic amine attacks the electrophilic carbonyl carbon of the acid anhydride, leading to the formation of an amide bond. The byproduct of this reaction is a carboxylic acid. 

The synthesis of amides from carboxylic acids typically involves the activation of the carboxylic acid to make it more reactive towards nucleophilic substitution. This is usually accomplished by converting the carboxylic acid into an acid chloride using a reagent such as thionyl chloride (SOCl2) or oxalyl chloride (C2O2Cl2), or by activating the carboxy OH group with a carbodiimide such as dicyclohexylcarbodiimide (DCC). The resulting activated carboxylic acid (with a good leaving group) is then treated with an amine to form the corresponding amide. 

Amides typically undergo reactions that include hydrolysis, reduction, and Hofmann rearrangement:

  • Hydrolysis can occur in the presence of acid or base, yielding carboxylic acids and amines. Acid hydrolysis results in a carboxylic acid and an ammonium salt, while base hydrolysis produces a carboxylate ion and an amine.
  • Reduction reactions transform amides into primary amines through catalytic hydrogenation or other reducing agents such as LiAlH4.
  • Hofmann rearrangement of amides involves the conversion of an amide to an amine with one fewer carbon atom, resulting in the migration of an alkyl or aryl group from the carbonyl carbon to the nitrogen atom.
  • The hydrolysis of amides in acidic conditions typically results in the formation of a carboxylic acid and an ammonium ion. Under acidic conditions, the amide nitrogen is protonated, making it a better leaving group, and water acts as a nucleophile to attack the carbonyl carbon, leading to the cleavage of the amide bond.
  • In basic conditions, the products of amide hydrolysis are a carboxylate anion and an amine. The base deprotonates the water molecule, creating a hydroxide ion that is a strong nucleophile which attacks the carbonyl carbon, leading to the formation of the carboxylate anion after the expulsion of the amine group.

Nitriles are organic compounds that contain a cyanide (-C≡N) group attached to an alkyl or aryl group. In naming nitriles, the suffix '-nitrile' is added to the name of the parent alkane from which the nitrile is derived, replacing the '-e' ending. If the nitrile is not the principal functional group, the prefix 'cyano-' is used instead. Additionally, when naming complex molecules, the carbon atom in the CN group is assigned as C-1 in numbering the longest carbon chain while giving the lowest possible number to this moiety.

The main methods to prepare nitriles involve the dehydration of amides or the substitution reaction of alkyl halides with cyanide ions:

  • In the case of amides, a dehydrating agent like SOCl2 is used to remove water and form the corresponding nitrile.
  • When starting from alkyl halides, the halogen atom is replaced by the cyano group (-CN) using a cyanide salt such as sodium cyanide (NaCN) or potassium cyanide (KCN) in a nucleophilic substitution (SN2) reaction.

To convert a carboxylic acid into a nitrile, you would typically use a dehydration reaction. A common method is to first react the carboxylic acid with a dehydrating agent such as thionyl chloride (SOCl2) to form an acid chloride. Then, the acid chloride can be treated with a suitable nitrogen source, like ammonia (NH3), which will substitute the chloride to form the corresponding amide, which is then dehydrated with SOCl2 to form a nitrile.

Nitriles typically undergo reactions that include hydrolysis, reduction, and reactions with Grignard reagents:

  • Hydrolysis of nitriles forms carboxylic acids or their corresponding salts, depending on the conditions.
  • Reduction of nitriles, using hydride reagents, leads to primary amines with LiAlH4 or aldehydes with DIBAL-H.
  • Reactions with Grignard reagents form ketones, where the nitrile carbon becomes part of the carbonyl group.

The hydrolysis of nitriles under acidic conditions involves the addition of water in the presence of an acid catalyst, typically yielding a carboxylic acid and ammonium ion as the end products. The nitrile carbon is electrophilically activated by the acid, allowing water to attack and form an amide intermediate, which is further hydrolyzed to the carboxylic acid.

Under basic conditions, the mechanism involves nucleophilic attack by a hydroxide ion on the carbon of the nitrile group, leading to the formation of a carboxylate anion and ammonia. Upon acidification of the reaction mixture, the carboxylate anion is protonated to give the carboxylic acid.

Both processes convert the triple bond of the nitrile to a carboxylic functional group.