Preparation of Amines

Primary amines can be synthesized through direct alkylation, i.e., adding ammonia (NH₃) to an alkyl halide (RX). The reaction is a simple nucleophile substitution; however, it is prone to polyalkylation. Polyalkylation is a reaction that occurs when multiple alkyl groups are added instead of just the desired one alkyl group. This occurs because the product is also nucleophilic and it competes with the starting material to react with the alkyl halide. Using a large excess of the starting material will generally prevent a mixture of mono- and polyalkylated amine products. An alternative method of alkylation is the Gabriel synthesis. The Gabriel synthesis is a reaction in which alkyl halides are treated with phthalimide and a strong base, followed by the addition of hydrazine, yielding a primary amine. Potassium phthalimide contains an ${-}{\rm{NH}}$ group between two ${\rm{C{=}O}}$ groups, making the ${-}{\rm{NH}}$ group very acidic because of resonance stabilization. When it is combined with a strong base, it readily gives up its hydrogen, forming a nucleophilic anion. The nucleophilic nitrogen of the phthalimide anion then attacks the alkyl halide (${\rm{R{-}X}}$) through an S_N2 reaction, and the reaction stops there. The addition of hydrazine (NH₂NH₂) is required to free the amine-alkyl group and give the final product. The hydrazine does this by adding to the carbonyl carbons and displacing the amine-alkyl group as the primary amine product. The final method for synthesizing primary amines via alkylation is through an azide intermediate. Azides are compounds containing the N₃ group. The alkyl halide can be converted to an alkyl azide by a nucleophilic substitution reaction, and then the azide group can be reduced to the primary amine using sodium and methanol or lithium aluminum hydride (LAH). Alkyl azides are explosive and should be reduced without purification. As a general rule, the lower-molecular-weight azides are more explosive. For example, sodium azide was the explosive compound used in the early design of airbags that enabled them to deploy quickly during a crash.

The most common method for the synthesis of amines is reductive amination. Reductive amination is a two-step form of amination that involves the conversion of a carbonyl group to an amine through an imine (${\rm{C{=}NH}}$) or an oxime ($\rm{C{=}NOH}$) intermediate. This method is preferable to direct alkylation because it is easier to control the carbon-nitrogen bond formation and there is no need to isolate intermediates.

The most effective reducing agent for reductive amination is sodium cyanoborohydride (NaBH₃CN). While sodium borohydride (NaBH₄) can also be used as a reducing agent, the product yield is often lower than with NaBH₃CN. NaBH₄ may also reduce the aldehyde or the ketone before it can react, thus reducing the amount of starting material available for conversion to the amine. Sodium cyanoborohydride is a weaker reducing agent and will only react with the iminium ion, converting it to the amine. The reduction of amides to their respective amine using lithium aluminum hydride (LAH) is another method for the synthesis of amines. An amide is an organic compound that contains a carbonyl (${\rm{C{=}O}}$) linked to a nitrogen atom through a ${\rm{C{-}N}}$ bond. It has a general ${\rm{RC({=}O)NRR'}}$ stoichiometry. In all of these reductions, the first step of the reaction has a nucleophilic hydride donating electrons to the electrophilic carbon of the carbonyl group. This results in formation of a new $\sigma$ bond between the hydrogen and the carbon and elimination of a $\pi$-bond between the carbon and the oxygen. The oxygen then interacts with the reducing agent, creating an unstable metal alkoxide intermediate. The donation of the nitrogen's lone pair to the carbon creates a new $\pi$ bond and causes the breakage of the carbon-oxygen $\sigma$-bond formed in the first step of the reaction. The formation of the new $\pi$ bond results in the loss of the metal alkoxide group and the formation of a new iminium ion intermediate. This ion also undergoes reduction to yield the final amine. Primary amines can be prepared by reducing aromatic nitro (${-}{\rm{NO}}_2$) compounds such as nitrobenzene. These amines are generally prepared by nitrating the aromatic ring, adding ${-}{\rm{NO}}_2$ via an electrophilic aromatic substitution reaction. The ${-}{\rm{NO}}_2$ is then reduced to an amino group. There are several methods for the reduction of the nitro group. The method selection is made based upon what other groups are present on the molecule. Catalytic hydrogenation with platinum (H₂/Pt) or palladium on carbon (Pd/C) is one of the most frequently chosen methods; however, catalytic hydrogenation will also react with a variety of other functional groups (e.g., aldehydes, ketones, alkenes).

If the reduction of groups other than the nitro group is a concern, acid and a metal can be used instead. Typical metals for this reduction include iron (Fe), zinc (Zn), and tin (Sn). The acid and metal reagent combination is a milder reducing agent and will generally reduce the nitro group while leaving other groups untouched.

Primary amines can also be prepared through the reduction of nitriles, azides, or oximes. A nitrile is an organic compound that has a carbon triple bonded to a nitrogen with RCN stoichiometry, also called a cyano group. An azide is a compound containing the group N₃ combined with an element or a radical. An oxime is an organic compound containing the divalent group ${\rm{C{=}NOH}}$ and obtained mainly by the action of hydroxylamine on aldehydes and ketones.

The reduction of nitriles, azides, and oximes to obtain a primary amine can be achieved through the use of the reducing agent lithium aluminum hydride (LAH). The reduction of these groups with a metal hydride proceeds through the same general mechanism. The hydride adds to the carbon adjacent to the nitrogen group. If a $\pi$ bond exists between the nitrogen and the carbon, then the addition of the hydrogen to the carbon causes this bond to break and the electrons to move to nitrogen as a lone pair of electrons. The negative charge on the nitrogen is stabilized by the aluminum hydride complex until it is protonated by the addition of water.

Primary amines can also be prepared by two different rearrangement reactions: Hofmann rearrangement and Curtius rearrangement. These reactions share a common intermediate and mechanistic step: the formation of an isocyanate intermediate and the subsequent hydration and decarboxylation of the intermediate to yield the final primary amine. An isocyanate is a highly reactive, low-molecular-weight organic compound with the formula ${\rm{R{-}N{=}C{=}O}}$.

The Hofmann rearrangement is a reaction in which primary amides are treated with a halogen and a base and rearrange into an isocyanate intermediate that then converts into a primary amine following the loss of carbon dioxide in the presence of water. In the first step of the reaction, the nitrogen of the primary amide donates its electron pair to a halogen (e.g., Br₂), which creates a nitrogen cation. The base then donates its electrons to one of the amide's hydrogens, breaking an ${\rm{N{-}H}}$ bond and resulting in an N-halide amide.

The next step in the reaction is the rearrangement step. A carbon atom migrates to the adjacent nitrogen, displacing a halogen atom as a result. During this process, a carbon-carbon bond and a nitrogen-halogen bond break, and a new carbon-nitrogen bond forms, yielding a carbocation between a nitrogen and an oxygen.

The isocyanate is formed through the donation of nitrogen's lone pair to the carbon to form a double bond and the subsequent deprotonation of the nitrogen with the base to give the neutral isocyanate intermediate.

Once the isocyanate is formed, it can be converted to an amine through a hydration and decarboxylation step. In this step, the oxygen of the water molecule donates its electron pair to the carbon of the isocyanate; this causes the $\pi$ bond between the carbon and the nitrogen to break, resulting in a negatively charged nitrogen and a positively charged oxygen. Then a series of proton transfers from the oxygen to the nitrogen follows, which results in a fully protonated nitrogen that is positively charged and a deprotonated oxygen that is negatively charged. The negatively charged oxygen forms a $\pi$ bond with the carbon which causes it to break its $\sigma$ bond with the nitrogen. This bond breaking results in the formation of the final primary amine product and the carbon dioxide side product. Mechanistic studies have shown that the rearrangement and isocyanate formation occur in a single step. The Curtius rearrangement is a reaction that involves the thermal decomposition of acyl azides to produce an isocyanate intermediate, which is then hydrated and decarboxylated to form a primary amine. Unlike the Hofmann rearrangement, the first step in the Curtius rearrangement is the key rearrangement step that precedes the formation of the isocyanate intermediate. In this step, a carbon atom migrates to the adjacent nitrogen, displacing a nitrogen gas molecule (N₂) as a result. During this process, a carbon-carbon bond and a nitrogen-nitrogen bond break, and a new carbon-nitrogen bond forms. The intermediate is a carbocation between a nitrogen and an oxygen. The isocyanate is formed through the donation of nitrogen's lone pair to the carbon to form a double bond, giving the neutral isocyanate intermediate. Deprotonation is not necessary, as there is no hydrogen attached to the nitrogen. Instead, the nitrogen is negatively charged while the carbon is positively charged. Once the isocyanate is formed, it can be converted to an amine through a hydration and decarboxylation step just like in the Hofmann rearrangement.