Preparation and Reactions of Amines

Reactions of Amines

The reactions of amines include acylation, Hofmann elimination, and diazonium reactions.
The acylation reaction forms an amide from an amine. The Hofmann elimination generates an alkene from a primary amine. The Sandmeyer reaction converts aromatic amines to a variety of other compounds, such as aryl halides, phenols, and aryl nitriles, by way of an aryl diazonium ion intermediate.

Acylation Reactions and the Hofmann Elimination Reaction

Acylation of amines occurs via the addition of an acid chloride to an amine. The Hofmann elimination occurs when a primary amine is treated with excess methyl iodide (CH3I) followed by silver oxide (Ag2O), water (H2O), pressure, and heat. The product is the least substituted alkene (the Hofmann product).

The acylation of amines can be used as a means of both converting an amine to an amide and adding a protecting group to a molecule. Acylation is the process of adding an acyl group to a compound. Both primary amines (RNH2) and secondary amines (R2NH) will react with acid chlorides to form amides through a nucleophilic substitution mechanism. The nitrogen (the nucleophile) of the amine donates its electrons to the carbon (the electrophile) of the carbonyl group. This donation causes the π\pi bond between the carbon and the oxygen to break, which results in the shared electrons moving to the oxygen of the carbonyl and the formation of a tetrahedral intermediate. The negatively charged oxygen of the tetrahedral intermediate donates its electrons to the carbon, re-forming the π\pi bond and expelling the chlorine atom as a chloride ion. This ion then deprotonates the nitrogen to yield the neutral amide product. Because the acid (HCl) is a by-product of this reaction, a base such as pyridine or sodium hydroxide (NaOH) is often added to neutralize it.

Amides are less basic and less nucleophilic than their amine counterparts; therefore, conversion of amines to amides can be used advantageously in electrophilic aromatic substitution reactions. For example, the amino group of aniline (C₆H₅NH₂) can be converted to an amide group. This conversion will reduce the activity of the nitrogen and allow the aromatic ring to be subjected to other procedures, such as nitration.

Acylation of Amines

Both primary and secondary amines will react with acid chlorides to form amides. This reaction proceeds through a nucleophilic substitution mechanism. Since the acid (HCl) is a by-product of this reaction, a base such as pyridine or sodium hydroxide (NaOH) is often added to neutralize it.
With most elimination reactions, the major alkene product is generally the more substituted alkene. By contrast, the product derived from the Hofmann elimination is the least substituted alkene. In the Hofmann elimination reaction, a primary amine is treated with excess methyl iodide (CH3I), and then the resultant ammonium salt is distilled under pressure with silver oxide (Ag2O), yielding the least substituted alkene. In the first step of the reaction, the nitrogen donates its electrons to the carbon of the methyl iodide, creating a new σ\sigma bond between the nitrogen and the carbon and elimination of the σ\sigma bond between the carbon and the iodine, leaving a positively charged nitrogen and an iodine anion. The amine is then deprotonated, and the process repeats until the nitrogen does not have any more hydrogens to give up. The first step of this reaction is also known as exhaustive methylation. The ammonium salt produced by this step is then heated under pressure with silver oxide (a strong base). This base removes a hydrogen from the alpha carbon to the ammonium group, and the subsequent formation of a π\rm\pi bond between the alpha carbon and the carbon the ammonium group is attached to promotes the breakage of the σ\sigma bond between the nitrogen and carbon and the leaving of the ammonium group.

Hofmann Elimination Mechanism

The Hofmann elimination occurs when a primary amine is treated with excess methyl iodide (CH3I) followed by silver oxide (Ag2O), water (H2O), pressure, and heat. The product is the least substituted alkene (the Hofmann product).
The bulkiness of the ammonium group determines which alpha carbon loses a hydrogen and whether the more substituted or the less substituted alkene is formed. The elimination reaction requires an antiperiplanar arrangement of the carbon-hydrogen and carbon-ammonium bonds. The less substituted alkene is preferentially formed because of steric hindrance between the alignment of the carbon-hydrogen and carbon-ammonium bonds that would produce the more substituted alkene.

Reactions with Nitrous Acid, Aryl Diazonium Salts, and Azo Coupling

Amines react with nitrous acid to form diazonium salts, N-nitroso amines, or aryl diazonium salts. The aryl diazonium ion formed when aniline is treated with sodium nitrate and hydrochloric acid can be converted to a variety of other groups (Br, Cl, I, Cn, OH, H, or F). Aryl diazonium salts can also couple with other aromatic compounds to form azo compounds that are often used as organic dyes.

The reaction of primary amines with nitrous acid will generate diazonium salts through a procedure called diazotization, the process of converting a primary amine into its diazonium salt. While alkyl diazonium salts are unstable even at low temperatures—they decompose by losing nitrogen to produce complex mixtures of products—aryl diazonium salts are relatively more stable and are very useful intermediates. An aryl diazonium salt is one of a group of salts of the general formula ArN2X, where Ar is an aryl group and X is an anion, such as benzenediazonium chloride (C6H5N(N)Cl).

Nitrous acid (HON=O{\rm{H{-}O{-}N{=}O}} ) is unstable and must be generated in the reaction mixture by reacting sodium nitrite (NaNO2) with cold, dilute hydrochloric acid. In the acidic solution, the nitrous acid can protonate and split into water and a nitrosonium ion, which is the reactive intermediate in these reactions between nitrous acid and amines. Nitrous acid reacts with amines to form a variety of products, such as diazonium salts, N-nitrosoamines, and aryldiazonium salts.

The reaction of secondary alkyl and aryl amines with nitrous acid produces N-nitrosoamines. These compounds will separate from the reaction mixture as oily yellow liquids and are often carcinogenic. The different ways in which these amines react with nitrous acid can be used as a qualitative test to determine if an amine is alkyl, aryl, primary, secondary, or tertiary.

Reaction of Amines with Nitrous Acid

Nitrous acid reacts with amines to form a variety of products, such as diazonium salts, N-nitrosoamines, and aryl diazonium salts. The different ways in which these amines react with nitrous acid can be used as a qualitative test to determine if an amine is alkyl, aryl, primary, secondary, or tertiary.
Aryl diazonium salts are formed from the treatment of primary aromatic amines with nitrous acid. Once formed, these intermediates can be converted into a variety of other groups, such as bromine, chlorine, iodine, nitrile, alcohol, hydrogen, or fluorine, with various reagents. In almost all cases, it is not necessary to isolate the diazonium salt before proceeding to the conversion step. Rather, the replacement reagent is simply added to the cold solution containing the diazonium salt, and the mixture is slowly warmed. The replacement of the diazonium ion will occur along with the production of nitrogen gas as a by-product.

A Sandmeyer reaction is a replacement reaction that occurs via copper reagents (e.g., CuCl, CuBr, CuCN). The copper reagents are known as Sandmeyer reagents. The mechanism for this reaction is not fully understood, but it is believed to be radical rather than ionic in nature.

Aryl diazonium salts can also react with phenols or tertiary aryl amines under slightly basic conditions in an azo coupling reaction to form products known as azo compounds. An azo coupling is an electrophilic aromatic substitution reaction between an aryl diazonium salt and another aromatic compound that produces an azo compound. An azo compound is an organic compound bearing the functional group diazenyl, RN=NR {\rm{R{-}N{=}N{-}R}}', in which R and R′ can be either aryl or alkyl. These compounds are often brightly colored and used as organic dyes. This is because the azo bond (N=N{-}{\rm{N{=}N}}{-}) brings the two aromatic ring systems into conjugation, which gives the new molecule an extended delocalized π\pi system and allows for the absorption of light in the visible spectrum.

Mechanism of Azo Coupling

Aryl diazonium salts can also react with phenols or tertiary aryl amines under slightly basic conditions in a coupling reaction to form products known as azo compounds. These compounds are often brightly colored and used as organic dyes.