Preparation of Amines: Definition, Types, Structure, Preparation and Properties

Amines are part of many chemical processes and products encountered in our lives. Pharmaceuticals treat a host of health conditions, from agrochemicals, which enhance agricultural productivity to their core amines. Take, for instance, the antibiotics and antidepressants in such wide application—many of which are synthesized through reactions involving amines. Equally important in agriculture are amines in the production of fertilizers and pesticides that sustain food production.

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This Story also Contains

1. Amines
2. Gabriel Phthalimide Synthesis
3. Hoffmann Bromamide Reaction
4. Special Case of Hoffmann Bromamide Reaction
5. Relevance and Applications
6. Some Solved Examples
7. Summary

A proper understanding of the procedures to prepare such versatile compounds is what every chemist and industrialist would like to have. Thus, this paper shall explore three famous procedures that have been used in the preparation of amines: Gabriel Phthalimide Synthesis, Hoffmann Bromamide Reaction, and one special case of Hoffmann Bromamide Reaction. One of the classic methods for the selective formation of primary amines, of high relevance for pharmaceutical industries, is Gabriel Phthalimide Synthesis.

Amines

Amines are any of the class of organic compounds produced from ammonia NH₃ by replacement of one or more hydrogen atoms with either alkyl or aryl groups. They are classified into three categories: primary, secondary, and tertiary amines. Primary amines have one alkyl or aryl group attached to the nitrogen, secondary amines have two, and tertiary amines have three. General formula for amines$\mathbb{R}-\mathrm{NH}_2, \mathrm{R}_2 \mathrm{NH}$, or $\mathrm{R}{ }_3 \mathrm{~N}$, where $\mathrm{R}=$ alkyl or aryl group. Amines have basicity due to the lone pair on the nitrogen atom. This makes it a proton acceptor, hence very reactive and useful in a wide range of chemical reactions. Amines are also known for their typical smells, ranging from the nauseating odor of plain amines like putrescine to those that have far more pleasant odors among the complex amines used in perfumery. Putting such sensational properties aside, amines join the long list of compounds that make up other compounds, from drugs and agrochemicals to dyes. Knowing the preparation of amines is therefore of paramount importance in the research of new chemical entities and also the development of such processes for efficiency.

Curtius Reaction

The Acid azides on heating in a non-polar solvent give alkyl isocyanate via acylnitrene formation, which on hydrolysis gives 1^o amine. The reaction occurs as follows:

Schmidt Reaction

Carboxylic acid on reaction with hydrazoic acid in the presence of acid$\left.\mathrm{H}_2 \mathrm{SO}_4\right)$gives acid azide which on heating gives alkyl isocyanate followed by hydrolysis to give 1^o amine. The reaction occurs as follows:

Lossen Reaction

Hydroxamic acid in a basic medium rearranges to give alkyl isocyanate via acyl nitrene formation, which on hydrolysis gives 1^o amine. The reaction occurs as follows:

Reduction of Nitroalkanes

Nitro compounds are reduced to amines by reduction with metals$=\left(\mathrm{Fe}_2 \mathrm{Sn}\right.$ or Zn$)$ in dil. HCl or $\mathrm{SnCl}_2$ in HCl or by passing $\mathrm{H}_2$ gas in the presence of finely divided $\mathrm{Ni}, \mathrm{Pt}$, or Pd. Reduction with Fe scrap and HCl is preferred because the $\mathrm{FeCl}_2$ formed gets hydrolyzed to give HClduring the reaction, and thus only a small amount of HCl is required for the initiation of the reaction. The reactions occur as follows:

Gabriel Phthalimide Synthesis

Gabriel Phthalimide Synthesis Gabriel Phthalimide Synthesis is a general method for the preparation of primary amines. The reaction starts with phthalimide and potassium hydroxide, which is converted into potassium phthalimide.
This will then react to an alkyl halide to form N-alkylphthalimide. In this last step, this obtained N-alkyl phthalimide is hydrolyzed either under acidic or basic conditions to get the primary amine while regenerating back phthalic acid. More importantly, the method is much valued since the primary amines can be formed without the creation of secondary and tertiary amines. As a result of high selectivity and efficiency, it has become one of the supporting aspects for organic synthesis, mostly when a pure primary amine is required.

This reaction is used for the preparation of 1^o aliphatic amine and 1^o aromatic amine. Phthalimide on treatment with ethanolic KOH forms potassium salt of phthalimide which on heating with RX followed by either alkaline hydrolysis or hydrazinolysis with hydrazine(H₂N.NH₂) produces the corresponding 1^o amine. 1^o aromatic amine cannot be synthesized by this method because ArX does not undergo SN reaction with an anion formed by phthalimide. The reaction occurs as follows:

Hoffmann Bromamide Reaction

Hoffmann Bromamide Reaction Another important process for primary amine synthesis is the Hoffmann Bromamide Reaction. It involves treating an amide with bromine and an aqueous or alcoholic solution of sodium hydroxide to form an isocyanate intermediate.

Then, this undergoes hydrolysis to finally yield the primary amine and carbon dioxide. Another interesting aspect is that the Hoffmann Bromamide Reaction can be used for converting higher amides into primary amines with one fewer carbon atom. The reaction is quite useful because it is simple and efficient; it very often becomes one of the methods of choice for a great many organic transformations.

Amides on reaction with Br₂ in alkali give 1^o amine with one C atom less than the parent amide. This is known as the Hofmann bromamide rearrangement or degradation reaction. The reaction occurs as follows:

The mechanism of the reaction is given as

Special Case of Hoffmann Bromamide Reaction

A special case of the Hoffmann Bromamide Reaction is involved when certain functional groups or structural features are present in the amide substrate that alter the mechanism of the reaction.

For example, cyclic amides and substrates bearing bulky groups can change the reaction pathways involved or alter the product distributions.

Knowing these variations is important in the optimization of reaction conditions for the desired results. Special cases such as these could be used by chemists who want to optimize their synthesis procedures, particularly on complex or unusual substrates.

It is only the primary amides that undergo the Hoffmann Bromamide reaction. Secondary amides do not undergo this reaction. However, secondary diamides (also called IMIDES) undergo this reaction to form amino acids. Thus, it is considered a special case of Hoffmann Bromamide reaction. The reaction occurs as follows:

Relevance and Applications

The preparation of amines by techniques such as Gabriel Phthalimide Synthesis and Hoffmann Bromamide Reaction has far-reaching impacts on academic research and industrial applications alike.

These methods are applied in the pharmaceutical industry in the production of active pharmaceutical ingredients APIs that form the basis of many drugs.

Several antibiotics and anti-depressants, among others, apply such types of processes; therefore, their worth in the medical field is immense. In agriculture, amines play a vital role in the manufacture of fertilizers and pesticides to promote the development of crops and protect the crops from pests. Apart from this, amines find their essential applications in the textile industry in the formation of dyes and pigments responsible for the coloration of fabrics and other material targets. Other areas where the functions of amines apply are in the development of new materials and chemical compounds; an example here is in synthesizing polymers and resins applied in coatings and adhesives, among many others.

Mastering various methods for the preparation of amines gives a number of new avenues that a chemist can explore, develop, and perfect the existing ones. Knowledge of such means helps not only in practical applications but also in further advancement in chemical research and technology.

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Some Solved Examples

Example 1 Which of the following is used for the ascent of the amine series?1) Reduction of nitrile with $\mathrm{LiAlH}_4$
2) Reduction with $\mathrm{Sn}+\mathrm{HCl}$
3) Reduction with $\mathrm{Fe}+\mathrm{HCl}$
4) Reduction with $\mathrm{H}_2 \mathrm{Pd}$

Solution:
The ascent of the amine series involves preparing amines with one carbon atom more than the starting amine. The reduction of nitriles with LiAlH₄ is specifically used for this purpose, as it converts nitriles $(\mathrm{R}-\mathrm{C}=\mathrm{N})$ to primary amines ( $\left.\mathrm{R}-\mathrm{CH}_2-\mathrm{NH}_2\right)$.Thus, the correct answer is option (1).

Example 2 Which of the following can be used to get a secondary amine?
1) Reduction of oximes
2) Reduction of amides3) Reduction of nitriles by $\mathrm{LiAlH}_4$
4) Reduction of isocyanides by LiAlH

Solution:
Secondary amines can be prepared by reducing isocyanides using LiAlH₄. This reduction converts the isocyanide group$(\mathrm{R}-\mathrm{N}=\mathrm{C})$ into a secondary amine $\left(\mathrm{R}-\mathrm{NH}-\mathrm{CH}_3\right)$.Therefore, the correct answer is option (4).

Example 3 A solution of m-chloroaniline, m-chlorophenol, and m-chlorobenzene acid in ethyl acetate was extracted initially with a saturated solution of $\mathrm{NaHCO}_3$ to give fraction A. The leftover organic phase was extracted with dilute NaOH solution to give fraction B. The final organic layer was labeled as fraction C. Fractions A, B, and C contain respectively:
1) m-chlorobenzoic acid, m-chloroaniline, and m-chlorophenol
2) m-chlorobenzoic acid, m-chlorophenol, and m-chloroaniline
3) m-chlorophenol, m-chlorobenzoic acid, and m-chloroaniline
4) m-chloroaniline, m-chlorobenzoic acid, and m-chlorophenol

Solution:
Carboxylic acids react with NaHCO to form soluble salts, so m-chlorobenzoic acid would be in fraction A. Phenols react with NaOH to form soluble phenoxide salts, so m-chlorophenol would be in fraction B. The remaining m-chloroaniline, which does not react with $\mathrm{NaHCO}_3$ or $\mathrm{NaOH}_3$ would be in fraction C. Hence, the fractions contain m-chlorobenzoic acid, m-chlorophenol, and m-chloroaniline respectively. The correct answer is option (2).

Summary

The preparation of amines is an integral part of organic chemistry, with very broad applications in several industries. The three general methods for preparing amines taken up in this paper are the Gabriel Phthalimide Synthesis, the Hoffmann Bromamide Reaction, and a special case of the Hoffmann Bromamide Reaction. Such methods are of interest with regard to practical applications in pharmaceuticals, agriculture, and textiles; hence, these methods become important for both industrial and academic applications.