7.5.4 Nucleophilic Addition–Elimination

Nucleophilic addition–elimination reactions are a type of reaction in which a nucleophile attacks an electrophilic carbonyl carbon, leading to addition and then elimination of a leaving group. Ammonia and primary amines can undergo nucleophilic addition–elimination reactions with acyl chlorides and acid anhydrides to form amides. This process is commonly used to synthesize non-substituted and substituted amides.

Reactivity of Acyl Chlorides and Acid Anhydrides

• Acyl Chlorides: The structure of acyl chlorides ($RCOCl$) includes a highly polar $C=O$ and$C–Cl$ bond. Chlorine, being highly electronegative, pulls electron density away from the carbonyl carbon, creating a stronger positive dipole on the carbonyl carbon. This makes acyl chlorides highly reactive and more susceptible to nucleophilic attack.
• Acid Anhydrides: Acid anhydrides ($RCOOCOR'$) are also reactive but less so than acyl chlorides. This is because the oxygen bridge in acid anhydrides is less electronegative than chlorine, resulting in a less positive carbonyl carbon.

Mechanism of Nucleophilic Addition–Elimination Reactions

In nucleophilic addition–elimination reactions, the carbonyl carbon ($C=O$) in the acyl chloride or acid anhydride is attacked by a nucleophile (such as ammonia or a primary amine), which donates a lone pair of electrons. The reaction proceeds through a two-step mechanism involving addition and then elimination.

Step-by-Step Mechanism with Acyl Chlorides

1. Nucleophilic Attack:

• The lone pair on the nitrogen atom in ammonia (NH₃) or the primary amine (R'NH₂) attacks the delta-positive carbonyl carbon in the acyl chloride.
• This leads to the formation of a tetrahedral intermediate, where the carbonyl double bond ($C=O$) temporarily breaks, and a single bond forms between the carbon and the nucleophile $(NH₃$ or $R'NH₂$).

2. Elimination of HCl:

• The tetrahedral intermediate then collapses, reforming the $C=O$ bond and eliminating a chloride ion ($Cl⁻$).
• The result is an amide ($RCONH₂$ for ammonia or $RCONHR$' for a primary amine) and hydrogen chloride ($HCl$).

3. Formation of Ammonium Salt:

• The $HCl$ produced in the reaction reacts with a second molecule of ammonia or amine (which are basic) to form an ammonium salt:

• With ammonia: $HCl$ reacts to form ammonium chloride ($NH₄Cl$).

• With a primary amine: $HCl$ reacts to form an organic ammonium salt ($R'NH₃Cl$). The overall reactions can be summarized as follows:

• With Ammonia:

$${RCOCl} + 2\text{NH}_3 \rightarrow \text{RCONH}_2 + \text{NH}_4\text{Cl}$$

Product: Non-substituted amide ($RCONH₂$) and ammonium chloride ($NH₄Cl$).

• With Primary Amine:

$${RCOCl} + 2\text{R'NH}_2 \rightarrow \text{RCONHR'} + \text{R'NH}_3\text{Cl}$$

Product: Substituted amide ($RCONHR$') and organic ammonium salt ($R'NH₃Cl$).

Reactions with Acid Anhydrides

The reactions of acid anhydrides with ammonia or amines follow a similar nucleophilic addition–elimination mechanism, but the products differ slightly:

4. Nucleophilic Attack and Intermediate Formation:

• The nucleophile ($NH₃$ or $R'NH₂$) attacks one of the carbonyl carbons in the acid anhydride, forming a tetrahedral intermediate.

5. Elimination of Carboxylate Ion:

• The intermediate collapses, reforming the $C=O$ bond and eliminating a c****arboxylate ion ($RCOO⁻$) instead of a chloride ion.

6. Formation of Carboxylic Acid:

• The carboxylate ion combines with a hydrogen ion (H⁺) to form a carboxylic acid ($RCOOH$). The overall reactions are:

• With Ammonia:

$${(RCO)}_2\text{O} + \text{NH}_3 \rightarrow \text{RCONH}_2 + \text{RCOOH}$$

Product: Non-substituted amide (RCONH₂) and carboxylic acid (RCOOH).

• With Primary Amine:

$${(RCO)}_2\text{O} + \text{R'NH}_2 \rightarrow \text{RCONHR'} + \text{RCOOH}$$

Product: Substituted amide ($RCONHR$') and carboxylic acid ($RCOOH$).

Key Observations

1. Ammonia with Acyl Chlorides:

• Produces non-substituted amides.
• White fumes of ammonium chloride ($NH₄Cl$) are often observed as a by-product.

2. Primary Amines with Acyl Chlorides:

• Produces substituted amides.
• The HCl formed in the reaction reacts with the primary amine to form a white organic ammonium salt (e.g.,$R'NH₃Cl$).

3. Reactivity Differences:

• Reactions with acyl chlorides are generally more vigorous due to the highly polarized $C–Cl$ bond, which makes the carbonyl carbon more electrophilic.
• Reactions with acid anhydrides are less vigorous and produce a carboxylic acid as a by-product instead of $HCl$.

Preparation of amines - Comparing the different methods

• Reacting ammonia with haloalkanes is hugely complicated

• Any amine produced reacts with more haloalkanes, undergoing further substitution.

• This leaves you with a mixture of different classifications of amines, this method is not generally used for preparing primary amines as the mixture of amines and ammonium salts produced would have to be separated. There are 2 other methods used to prepare primary amines: - Reduction of nitriles - this is used to prepare aliphatic amines (straight carbon chains).

• Reduction of nitrobenzene compounds - this is used to prepare aromatic amines (Cyclic compounds, like benzene)

By Reduction of Nitriles

• Primary aliphatic amines can be prepared by the reduction of nitriles. This is done in 2 steps:

4. A nitrile compound is produced from a haloalkane.
5. The nitrile compound is then reduced: • Conditions: hydrogen gas with a nickel catalyst high temp. and high pressure. Equation: $R-CN + 2H2 → R-CH2-NH2$ This method has 2 major advantages over reaction of ammonia with haloalkanes:

• Much better yield.
• No other products.

By Reduction of Nitro Compounds

• Aromatic amines (used in the manufacture of dyes) can be prepared by the reduction of nitro compounds. This is done in 2 steps as well:

6. A nitro compound is produced by the nitration of benzene.
7. The nitro compound is reduced • Conditions: hydrogen gas with a nickel catalyst, high temp. + pressure.

Equation: $R-NO2 + 3H2 → R-NH2 + 2H2O$

Skills Development and Mechanism Outlining

Understanding Mechanisms:

• Mechanism Outlining: Students should practice drawing out and explaining the nucleophilic addition–elimination mechanism for reactions of ammonia and primary amines with acyl chlorides and acid anhydrides. This includes:

  • Identifying the nucleophilic attack by nitrogen's lone pair on the carbonyl carbon.
  • Detailing the formation and collapse of the tetrahedral intermediate.
  • Showing the elimination of the leaving group ($Cl⁻$or $RCOO⁻$) and formation of by-products ($HCl$or carboxylic acid). Comparing Reactivity:

• Comparing the reactivity of acyl chlorides and acid anhydrides helps students understand the impact of electronegativity and the nature of leaving groups on reaction rates. Practical Observation:

• Observing the white fumes or organic salts produced in these reactions provides insights into the products formed, especially when dealing with volatile acyl chlorides.