Chapter 23: Amines 

Contents

23.1 Introduction
23.2 Biologically Important Amines
23.3 Basicity of Amines
23.4 Synthesis of Amines
     23.4.1 Reductive Amination
     23.4.2 Alkylation of Ammonia
     23.4.3 Gabriel Synthesis of 1° Amines
     23.4.4 Formation and Reduction of Azides and Nitriles
23.5 Reactions of Amines
     23.5.1 Reactions of Heterocyclic Amines
     23.5.2 Hofmann Elimination
     23.5.3 Cope Elimination
     23.5.4 Reactions with Acid Chlorides
     23.5.5 Reactions with Sulfonyl Chlorides
     23.5.6 Reactions with Nitrous Acid
     23.5.7 Reactions of Arene Diazonium Salts
23.6 Chapter Summary
   23.6.1 Summary of key reactions

Learning Objectives

• Differentiate between primary, secondary, tertiary, and quaternary ammonium salts.
• Know some biologically important amines. 
• Know about heterocyclic amines such as pyridine and pyrrole.
• Predict the basicity of amines based on the concepts of resonance, hybridization and aromaticity.
• Know the methods for synthesis of amines using the techniques of reductive amination, nucleophilic substitution and reduction.
• Know about reactions and mechanisms of the reaction of amines with acid chlorides, alkyl halides and nitrous acid.
• Know about the reactions of arene diazonium salts.

23.1 Introduction

Amines are organic derivatives of ammonia, or ammonia itself. They are typically classified as primary (1°), secondary (2°), or tertiary (3°) according to the number of alkyl or aryl groups bonded to nitrogen. 

Amines are weak bases and their chemistry is dominated by the lone pair of electrons on the N atom. When four alkyl or aryl groups are attached to a nitrogen atom, a quaternary ammonium salt is produced. These are ionic compounds and are much more soluble in water than the equivalent amine. Some examples are shown in Figure 23.1b.

23.2 Biologically Important Amines

Naturally occurring nitrogen heterocycles that are derived from plant sources are called alkaloids. Some biologically active alkaloids include quinine (an antimalarial drug), nicotine (found in tobacco leaves), morphine (painkiller), and cocaine (stimulant of the central nervous system). These are shown in Figure 23.2. 

Histamine is another biologically active amine that dilates blood vessels and is released where an injury or infection occurs to increase blood flow. Histamines also cause allergies. A number of physiologically active compounds are derived from phenylethylamine including adrenaline (a hormone secreted in response to stress), noradrenaline (a neurotransmitter) and methamphetamine (addictive stimulant). These are shown in Figure 23.3.

23.3 Basicity of Amines

The basicity of amines is determined by the availability of lone pair electrons on nitrogen. The more readily available the lone pair of electrons, the more basic the amine (also see Section 2.8 for additional discussion). Most organic chemists use pK_a values to compare the acidity of different compounds. The basicity of different amines can be compared by looking at the pK_a values of their conjugate acids.

The pK_a’s of the conjugate acids of several amines are shown Table 23.1.

Any factor that increases the electron density on the nitrogen increases the basicity of the amine. Thus, electron donating groups such as alkyl groups increase the basicity of the amine. However, as seen in the trend in Table 23.1, the pK_a of the tertiary amine trimethylamine is smaller than the secondary amine, diethylamine. Remember, the weaker the conjugate acid (larger pK_a) the stronger the base. The reason for this is solvent effects. Tertiary amines are typically less basic than secondary amines because increasing the number of alkyl groups decreases the ability of the solvent to solubilize the conjugate acid (ammonium ion) and shifts the equilibrium to the amine. For a more detailed discussion, see Section 4.3. This trend can also be seen in Figure 23.5. Methylamine is more basic than ammonia because the CH₃ decreases the ability of the solvent to solubilize the conjugate acid and, as seen in Figure 23.5, increasing the chain length decreases the ability of the solvent to stabilize the positively charged conjugate acid.

Question 23.1 (Review section 4.10 Electron Donating and Solvent Effects)

Any factor that decreases the electron density on the nitrogen decreases the basicity of the amine. Aryl amines are much weaker bases than aliphatic amines because the electron pair on nitrogen is delocalized into the benzene ring, which decreases electron density on the nitrogen. Since the nitrogen’s lone pair is delocalized throughout the aromatic ring, they become stabilized and, thus, less reactive and less available to an acid. This is shown in Figure 23.6. The basicity of substituted anilines depends on whether the substituent is electron-donating or electron-withdrawing as shown in Table 23.2. 

Electron-withdrawing groups draw electron density into the aromatic ring and reduce the electron density on the -NH₂ group. This decreases the basicity of the amine with respect to aniline. Electron-donating groups increase the electron density of the aromatic ring. Thus decreasing the ability of the amine’s electrons to be delocalized into the aromatic ring. Compared to aniline, EDGs increase the electron density on the NH₂ group and thus increases its basicity.

To compare the basicity of heterocyclic amines we can also consider the hybridization of the nitrogen atom. In piperidine, for example, the N atom is sp³-hybridized, whereas in pyridine it is sp²-hybridized. Electrons in orbitals with more s character are held more tightly, therefore, pyridine is less basic than piperidine and acetonitrile is the least basic. This is shown in Figure 23.7.

Given the discussion of aromatic compounds in Chapter 20, consider the basicity of the following molecules.

From the answer given for the above question you should have noticed that pyrrole is not protonated by a strong acid on the nitrogen. This is because the most stable conjugate acid occurs when protonation occurs on the carbons adjacent to nitrogen.

Unlike pyrrole, pyridine is protonated on the nitrogen because the lone pair on the nitrogen is not part of the aromatic system; thus, protonation of the nitrogen does not de-aromatize the compound. Protonation occurs on the sp²-hybridized nitrogen atom. The resonance structures shown in Figure 23.8 include charge-separated structures not normally considered for benzene. The greater electronegativity of nitrogen (relative to carbon) suggests that such resonance structures should be considered. Indeed, pyridine has a larger dipole moment.

The above example with pyrrole shows that when nitrogen’s lone pair is part of an aromatic system they are very stable and unreactive. Conversely, stabilization of the conjugate acid through resonance can increase the basicity of a compound. For example, guanidine is one of the strongest organic bases known. This enhanced basicity is due to the resonance stabilization of the cation.

23.4 Synthesis of Amines

There are several methods available for synthesizing amines. The three main types of reactions are (i) reductive amination (ii) nucleophilic substitution, and (iii) reduction.

23.4.1 Reductive Amination

All classes of amines, 1°, 2°, and 3°, can be prepared using this two-step process that converts a carbonyl compound to an imine or enamine by C−N bond formation and reduction. This is shown in Figure 23.11. (See 22.5.7 Reactions with 1° amines, for the mechanism of the synthesis of imines.)

To prepare either 2° or 3° amines, 1° or 2° amines, respectively, are used as the starting material. Sodium cyanoborohydride (NaBH₃CN) is a commonly used reducing agent. This is shown in Figure 23.12.

Reductive Amination

Reductive amination is used to make a number of legal drugs. Regrettably, it is also a common process in the synthesis of illegal substances, including methamphetamine.

"Breaking Bad" fans may recall the dramatic scene where Walter White (Bryan Cranston) and his co-workers, needing methylamine for this purpose, steal the highly regulated substance from a cargo train. 

Nature’s Alternative to Reductive Amination

In Nature, enzymes called ‘transaminases’ can be used for the similar transformation of a ketone to an amine.

How is the conversion of carbonyls to amines important in our bodies?

One example involves pyridoxamine phosphate (PMP), which is an essential cofactor for multiple enzymatic processes including transamination.

PMP is produced in our bodies from vitamin B6, which is obtained from foods such as nuts, beans, and meats. Shown below is the transamination reaction used to convert PLP (the active form of vitamin B6) to PMP in our bodies (aldehyde to ketone).

Once pyridoxamine phosphate (PMP) is formed, it can be used to facilitate a transamination process for the conversion of α-ketoglutarate to glutamate (ketone to amine). This process is important because it is used in the synthesis of the amino acid glutamine and in the metabolism of glucose.

Although glutamate plays important functions in our bodies, excess glutamate has been associated with Amyotrophic Lateral Sclerosis (ALS). ALS is a neurodegenerative disease that progressively reduces the number of neurons, which in turn decreases the brain’s ability to control muscle movement and eventually paralyzes patients.

Have you heard of the Ice Bucket challenge? In 2014, The Ice Bucket Challenge took over social media and the news, as more than 2 million people posted videos of themselves pouring ice cold water on their heads, and then challenging others to do the same. The initiative raised awareness and funds for ALS research. 

Watch this video compilation of celebrities doing the challenge! 

23.4.2 Alkylation of Ammonia

Nitrogen-containing compounds are nucleophiles and can react with alkyl halides in S_N2 reactions. When ammonia is used as a nucleophile it must be added in excess to decrease the amount of polyalkylation.

As stated, one of the limitations of this method is that the 1° amine produced is itself a nucleophile and polyalkylation occurs to produce a mixture of 1°, 2°, 3° amines, and quaternary ammonium salts as shown in Figure 23.13.

23.4.3 Gabriel Synthesis of 1° Amines

The Gabriel synthesis avoids the formation of 2° and 3° amines because the product does not contain a nucleophilic N atom that can further react (Figure 23.14). 

The reaction occurs in two stages: nucleophilic substitution followed by hydrolysis. The negatively charged N atom of the potassium salt of phthalimide acts as a nucleophile toward 1° alkyl halides in an S_N2 process. These steps are shown in Figure 23.15.

23.4.4 Formation and Reduction of Azides and Nitriles

Other nucleophiles besides phthalimide can be used to synthesize 1° amines. The azide ion, N₃⁻ converts the alkyl halide to an alkyl azide and is then reduced with the loss of N₂ to a 1° amine. A similar reaction also occurs with nitriles as shown in Figure 23.16.

23.5 Reactions of Amines

The main properties of amines are their basicity and nucleophilicity, which are both due to the lone pair of electrons on the N atom.

The reactions of amines that have been shown in previous chapters are shown in Figure 23.17.

23.5.1 Reactions of Heterocyclic Amines

Electrophilic aromatic substitution is significantly more difficult for pyridine than for benzene because the aromatic ring is electron-deficient as seen in Figure 23.18. When pyridine does react, substitution occurs at the 3-position and not the 2- or 4-position because in both cases in the resulting sigma complex, the positive charge delocalizes onto the N atom which is not desired as N is more electronegative than C. This is shown in Figure 23.18 for the reaction of pyridine with KNO₃ at 330°C.

Fo pyridine,  nucleophilic aromatic substitution occurs more readily than electrophilic substitution because the nitrogen atom makes the ring electron-deficient and susceptible to attack by a nucleophile. Attack happens at either the 2- or 4-position because as the following addition–elimination mechanism shows, the intermediate is stabilized by delocalization of the negative charge onto the more electronegative N atom. Nucleophilic substitution does not occur at the 3-position. This is shown in Figure 23.19.

In the substitution reaction of pyridine, when pyridine has a good leaving group, the leaving group leaves and is replaced with the new substituent. This is shown in Figure 23.20.

23.5.2 Hofmann Elimination

Amines are poor leaving groups because the amide ion NH₂⁻ is a very strong base. To convert the amino group into a good leaving group, it is first converted into a quaternary ammonium salt. The reaction consists of three steps and these are shown in Figure 23.21. The last step in the reaction is an E2 reaction and because of the steric interaction of the quaternary ammonium salt, the less substituted Hoffman product will form (see Section 7.5.1).

23.5.3 Cope Elimination

The Cope elimination is the name given to a reaction that occurs when an amine oxide is heated and converted to an alkene. Like the Hofmann elimination, the product is the least substituted alkene. The reaction proceeds through a cyclic transition state. This is shown in Figure 23.22.

23.5.4 Reactions with Acid Chlorides

A primary or secondary amine will react with acid chlorides to form amides. This is shown in Figure 23.23. The HCl generated will react with the amine, therefore, a base such as NaOH or pyridine is added to neutralize it. (See 25.2.2 Acid Chlorides: Preparation and Nucleophilic Acyl Substitution, for the mechanism)

23.5.5 Reactions with Sulfonyl Chlorides

When a 1° or 2° amine reacts with sulfonyl chloride, the chloride ion is displaced and a sulfonamide is produced. A sulfonamide is an amide of sulfonic acid. This reaction is shown in Figure 23.24.

23.5.6 Reactions with Nitrous Acid

When sodium nitrite is mixed with HCl, a number of species are formed that act as sources of the nitrosonium ion. This ion acts as a reactive intermediate in the reaction with amines. This is shown in Figure 23.25.

Reaction with 1° amines: This reaction called diazotization reaction, forms diazonium salts. The reaction begins with nucleophilic attack of the amine on the nitrosonium ion that forms N-nitrosamine. There is then a loss of H₂O to form the diazonium salt. The mechanism is shown in Figure 23.26. The alkyl diazonium salt that is formed is unstable and decomposes to nitrogen and carbocations. Arene diazonium salts are partially stabilized by the adjacent aromatic π cloud and are relatively stable, which makes them useful synthetic intermediates (Figure 23.27). At temperatures greater than 50°C, nitrogen is lost to form the very reactive phenyl cation, which then forms phenols in an aqueous solution.

Reaction with 2° amines: Secondary amines react with the nitrosonium ion to form secondary N-nitrosamines. Many of these compounds are carcinogens. The reaction is shown in Figure 23.28.

23.5.7 Reactions of Arene Diazonium Salts

As mentioned in the previous section, arene diazonium salts are relatively stable and are formed by diazotizing an aniline. The diazo group can be replaced by many other functional groups. This is shown in Figure 23.29.

Sandmeyer Reaction: In this reaction, a copper(I) halide or cyanide salt reacts with the arene diazonium salt to form an aryl halide or aryl cyanide. This is shown in Figure 23.30.

Fluorination: This is called the Schiemann reaction. When fluoroboric acid is added to an aryl diazonium salt an aryl fluoride is formed. This is shown in Figure 23.31.

Substitution by ^-OH: When arene diazonium ions are heated, nitrogen is evolved and a reactive aryl cation is produced, which can then be trapped by water. This is a way to synthesize phenols as seen in Figure 23.32.

Substitution by H (deamination by diazotization): Treatment of an aryl diazonium salt with hydrophosphorous acid yields benzene. This is shown in Figure 23.33.

Another general reaction of diazonium salts is coupling. In this electrophilic aromatic substitution process, a diazonium salt is reacted with an aromatic compound that contains an electron-donating group and the two rings join together to form an azo dye compound. This is shown in Figure 23.34.

The reactions that have just been discussed are summarized in Figure 23.35.

​Deaminization by diazotization allows the synthetic chemist to use an amine as both a directing group and a blocking group. For example, how can you synthesize 1-bromo-3-methylbenzene shown in Figure 23.36? Both the methyl and the bromine groups are ortho-para directors and, yet the groups are meta to each other. Starting with p-toluidine, synthesize N-(p-tolyl)acetamide by reacting the starting material with acetic anhydride. In the next step monbromination, ortho to the amide is expected to be the major product. This is because the acetamide derivative is less reactive than the amine starting material and the para position is occupied. This reaction produces the desired meta substitution between the bromine and the methyl group and all that needs to be done, to complete the synthesis is to remove the amide group. First, hydrolyze the amide to the amine by heating in dilute sulfuric acid to produce 2-bromo-4-methylaniline. The next step produces the diazonium ion intermediate which when reacted with hypophosphorous acid replaces diazo group with a hydrogen atom to produce the desired meta substituted product, 1-bromo-3-methylbenzene.

Diazo coupling Reactions of Aryl Diazonium salts:

Aryl diazonium salts act as an electrophile in electrophilic aromatic substitution reactions. It is a weak electrophile, therefore, we need a highly activated ring that possess electron-donating groups as the nucleophile.

Azo compounds are usually used as industrial dyes because the azo group is a strong chromophore. Diazo compounds produce a variety of colors which depends strongly on the groups attached to the benzene ring. 

23.6 Chapter Summary

Amines are weak bases and their chemistry is dominated by the lone pair of electrons on the N atom.

Amines are typically classified as primary (1°), secondary (2°), or tertiary (3°) according to the number of alkyl or aryl groups bonded to nitrogen. When four alkyl or aryl groups are attached to a nitrogen atom, a quaternary ammonium salt is produced.

Basicity of amines: The basicity of amines is determined by the availability of lone pair electrons on nitrogen. The more readily available the lone pair of electrons, the more basic the amine. The basicity of different amines can be compared by looking at the pKa values of their conjugate acids. In general, the weaker the conjugate acid, the more basic the amine. 

Any factor that increases the electron density on the nitrogen atom increases the basicity of the amine. Thus, electron donating groups such as alkyl groups increase the basicity of the amine.

Any factor that decreases the electron density on the nitrogen atom decreases the basicity of the amine. Aryl amines are much weaker bases than aliphatic amines because the electron pair on nitrogen is delocalized into the benzene ring, which decreases electron density on the nitrogen. Electron-withdrawing groups draw electron density into the aromatic ring and reduce the electron density on the -NH₂ group. This decreases the basicity of the amine.

Tertiary amines are typically less basic than secondary amines because increasing the number of alkyl groups decreases the ability of the solvent to solubilize and stabilize the conjugate acid, shifting the equilibrium to the amine. 

23.6.1 Summary of key reactions

Reductive amination

Alkylation of ammonia

Gabriel Synthesis

Formation and Reduction of Azides and Nitriles

Formation of imines

Formation of enamines

Hofmann Elimination

Cope Elimination

Reaction of amines with acid anhydrides

Reaction of amines with sulfonyl chloride

Reactions of amines with Nitrous Acid

Reactions of 1°amines with nitrosonium ion - formation of diazonium salt

Reactions of 2° amines with nitrosonium ion - formation of N-nitrosamines

Reactions with Arene Diazonium Salts

Sandmeyer Reaction

Fluorination

Substitution by ⁻OH

Coupling reactions of Aryl Diazonium salts

End of Chapter 23

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[1] Image courtesy of ForestWander under CC BY-SA 3.0 US.