Acylation Reactions and the Hofmann Elimination Reaction
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 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 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
Hofmann Elimination Mechanism
Reactions with Nitrous Acid, Aryl Diazonium Salts, and Azo Coupling
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 () 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
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, , 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 () brings the two aromatic ring systems into conjugation, which gives the new molecule an extended delocalized system and allows for the absorption of light in the visible spectrum.