Synthesis of Amines - Named Reactions and Mechanism

In this article we will learn about synthesis of amine compounds. We will discuss few Named reactions and mechanism.

Amines are the organic compounds and they are derivatives of ammonia. In this article we will discuss about various synthesis methods for preparation of amines. 

Key words: Amine, Organic Synthesis, Reactions of Amine, Name Reaction.

Table of Contents

1. Introduction
2. Common methods for the synthesis of amine
3. Conclusion

1. Introduction

Amine compounds are derivatives of ammonia with basic nitrogen atom. We have studied nomenclature of amine compounds in separate article. Please the article for more details (Link). In this article we will learn various reaction by which amine compounds can be synthesized. Also we will cover some of the important name reactions which are used by researchers to produce amine derivatives. The amine can be synthesized from alkyl halides, alkyl azides , amides, aldehyde / ketones and nitro compounds. 

2. Common methods for the synthesis amine

Some of the important reactions are listed here for the synthesis of amine compounds. 

1. Alkylation of ammonia or amine by alkyl halides

2. Reduction of alkylazides

3. Reduction of amide

4. Reduction of nitriles

5. Reduction of nitrocompounds

6. Reductive amination of aldehyhde / ketones

7. Hofmann rearrangement (Rearrangement of primary amides)

8. Curtius rearrangement (Rearrangement acyl azide)

9. Gabriel synthesis

We will see each method in detail;

1. Alkylation of ammonia or amine by alkyl halides

Alkylation of ammonia by alkyl halides gives primary alkyl halide. But the reaction doesn’t stop here and primary amine further gets alkylated to secondary/ tertiary amines. Therefore this reaction always offers mixture of compounds.

Figure 1: Synthesis of methanamine

Alkylation of primary amines gives secondary amines.

Figure 2: Synthesis of dimethylamine

Alkylation of secondary amines gives tertiary amines.

Figure 3: Synthesis of trimethylamine

In similar way, alkylation of tertiary amine gives quaternary ammonium salt.

Figure 4: tetramethylammonium chloride

2.  Reduction of alkylazides

Reduction of alkyl azide by using hydrogen gas with Pa/C catalyst gives amine product. Lithium aluminium hydride (LiAlH₄) also can be used for the synthesis of amine starting from alkyl azides.

Figure 5: Synthesis of cyclopentyl amine

Staudinger Reduction

The azides are converted in to amine by using triphenylphosphene. It is a mild reaction condition for azide to amine synthesis. In this reaction first step is reaction of triphenylphosphene with azide to form an iminophosphorane. Further aqueous work up provides amine and phosphine oxide as by-product.

Figure 6: Mechanism of Staudinger reduction

3.  Reduction of amide

The amides are used in reduction reaction with lithium aluminium hydride to synthesize amine. 

Figure 7: Reduction of amide by lithium aluminium hydride

Mechanism

Figure 8: Mechanism of reduction of amide  

Figure 9: Synthesis of N-ethyl-N-methyl aniline

4.  Reduction of nitriles

Synthesis of amines from alkyl / aryl nitriles is done by reduction reaction using hydrogen and metal catalyst. The reduction of nitriles gives primary amines.  

Figure 10: Reduction of nitriles by hydrogen and metal catalyst

Similar conversion can also be done by reducing agent like lithium aluminium hydride (LiAlH₄). The mechanism of reduction of nitriles to amine by using lithium aluminium hydride is shown below.

Figure 11: Reduction of nitriles by lithium aluminium hydride

5.  Reduction of nitrocompounds

Nitroaromatic compounds are reduced to amine derivatives by using tin metal and conc. HCl. For example; nitrobenzene undergoes reduction reaction to form aniline. 

Figure 12: Reduction of nitro-compound by Sn/HCl

Nitrocompounds also can be reduced by hydrogen gas with metal catalyst.

6.  Reductive amination of aldehyhde / ketones

The amines are synthesized from aldehydes / ketones by reductive amination. It is two step method; in the first step primary / secondary amine reacts with carbonyl compound in presence of acid catalyst to form imine intermediate. Then in the second step reduction of imine takes place to produce secondary / tertiary amine compound. 

Figure 13: Reductive amination

7.  Hofmann rearrangement (Rearrangement of primary amides)

It is also known as Hoffmann degradation. It is reaction of primary amide with bromine in strong basic condition to form primary amine. 

Figure 14: Hofmann rearrangment

Mechanism

1. Base abstract acidic proton of amine to form anion.

2. The anion attack on bromine to give N-bromamide.

3. Again base abstract acidic proton of N-bromamide to form anion.

4. The anion rearranges by migration of R group to nitrogen atom to form isocyanate  intermediate.

5. Water molecule attack on isocyanate intermediate to yield carbamic acid.

6. The carbamic acid looses carbondioxide molecule to produce amine.

Figure 15: Mechanism of Hofmann rearrangment

Example

Figure 16: Hofmann reduction reaction of benzamide

8.  Curtius rearrangement (Rearrangement acyl azide)

It is a rearrangement reaction of acyl azide to produce amines. It is two steps synthesis. 

Figure 17: Curtius rearrangment reaction

Mechanism

1. In the first step under heating condition acyl azide looses nitrogen molecule to yield isocyanate intermediate.

2. The second step consists of nucleophilic attack of water molecule on isocyanate produces carbamic acid.

3. Further decarboxylation gives amine compound. 

Figure 18: Mechanism of Curtius rearrangment reaction

Example

Figure 19: Curtius rearrangment of acyl azide

9.  Gabriel synthesis

The Gabriel synthesis is two steps chemical reaction. In the first step potassium pthalimide is used for N-alkylation by using alkyl halide. The second step is reaction of N-alkylated pthalimide and hydrazine to yield primary amine along with by-product phthalhydrazide. 

Figure 20: Gabriel sythesis of amines

Example

Figure 21: Gabriel synthesis 

3. Conclusion

To summarize this topic we have discussed various methods available for the synthesis of amines starting from alkyl halide, azide, amide and nitriles. 

The alkyl halides are used for N-alkylation of amines but this method offers mixture of products. 

Reduction of azides, primary amides, aromatic nitro-compounds and nitriles gives primary amines as final product. 

Reductive amination of aldehyde/ ketones gives secondary or tertiary amines. 

Hoffman rearrangement of primary amide yields primary amine. 

Curtius rearrangment of acyl azide gives primary amine. 

Gabriel synthesis for amines is often used in organic chemistry. The method uses potassium pthalimide as starting material and then it is subjected to N-alkylation by alkyl halide. Then hydrazinolysis offers primary amine as final product.

That's all for this topic. If you have any questions please feel free to ask me in the comment box. Thank you..!