Preparation and Reactions of Amines

Preparation of Amines

Amines can be prepared through a variety of methods.

An amine is an organic compound that is a derivative of ammonia (NH3), in which one or more hydrogen atoms are replaced by alkyl or aryl units (R), forming NR {\rm{N{-}R}} single bonds. Most methods involve the reduction of another functional group, such as reductive amination of aldehydes or ketones, or the reduction of nitrobenzene, nitriles, oximes, or amides. Amination is the process of adding an amine group to a compound. Most of these reduction methods employ a metal hydride, such as lithium aluminum hydride, as the reducing agent. Reduction is a reaction that involves the addition of an electron to an atom. Reductive amination adds an amine group through the conversion of an amine to an imine followed by reduction of the double bond of the imine. An imine is an organic compound containing the C=NH {\rm {C{=}NH}} group or its substituted form, NR, that is derived from ammonia by replacement of two hydrogen atoms by a hydrocarbon group or other nonacid organic group.

Other methods for the preparation of primary amines rely on direct alkylation or alkylation through an intermediate. Direct alkylation is a difficult process to control and often leads to overalkylation of the amine, so alkylation through an intermediate is often preferred in a laboratory setting. While there are a variety of reactions available for the synthesis of primary amines, there are only two reactions that reliably generate secondary and tertiary amines: reductive amination of aldehydes and ketones and the reduction of amides, both of which involve the reduction of a carbonyl (C=O{\rm{C{=}O}}) group.

Alkylation of Ammonia, Gabriel Synthesis, or Azide Synthesis

Primary amines can be prepared by adding ammonia to an alkyl halide, using the Gabriel synthesis with an alkyl halide, or using a nucleophilic substitution reaction to produce an alkyl azide and then reducing the azide group.
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.

Direct Alkylation of Amines

It is possible to synthesize primary amines through direct alkylation (i.e., adding ammonia to an alkyl halide). It is a simple nucleophile substitution reaction; however, it is prone to polyalkylation.
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 NH{-}{\rm{NH}} group between two C=O {\rm{C{=}O}} groups, making the NH{-}{\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 (RX{\rm{R{-}X}}) through an SN2 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.

Gabriel Synthesis Mechanism

The Gabriel synthesis is a reaction where alkyl halides are treated with phthalimide and a strong base followed by the addition of hydrazine, which yields a primary amine. Potassium phthalimide is a molecule that contains an imide group, which is a nitrogen atom bonded between two carbonyl (C=O{\rm{C{=}O}} ) groups.
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.

Amine Synthesis via Alkylation through an Azide Intermediate

An azide is a compound containing the group N3 combined with an element or a radical. 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 alcohol or lithium aluminum hydride (LAH).

Reductive Amination and Other Reductions

Amines can be prepared by the reductive amination of a ketone or aldehyde with an amine (NH3, RNH2, or R2NH2), acid catalyst (H+), and NaBH3CN. Amines can also be prepared through the reduction of their respective amide, nitrobenzenes, nitriles, or oximes.

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 (C=NH{\rm{C{=}NH}}) or an oxime (C=NOH\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.

Reductive Amination Synthesis

Reductive amination is a two-step process involving the conversion of a carbonyl group to an amine through an imine or an oxime intermediate. This method is preferable to direct alkylation, as there is more control afforded over the carbon-nitrogen bond formation and there is no need to isolate any intermediates. The reducing agent of choice for this reaction is sodium cyanoborohydride (NaBH3CN).
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 (C=O{\rm{C{=}O}}) linked to a nitrogen atom through a CN{\rm{C{-}N}} bond. It has a general RC(=O)NRR {\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 σ\sigma bond between the hydrogen and the carbon and elimination of a π \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 π \pi bond and causes the breakage of the carbon-oxygen σ \sigma -bond formed in the first step of the reaction. The formation of the new π \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.

General LAH Reduction of Amide to Amine

The reduction of amides to their respective amines using lithium aluminum hydride (LAH) is a method for the synthesis of amines. An amide is an organic compound that contains a carbonyl (C=O{\rm{C{=}O}} ) linked to nitrogen atoms through a carbon nitrogen (CN{\rm{C{-}N}} ) bond with the general (RC(=O)NRR{ \rm{RC(=O)NRR}}') stoichiometry.
Primary amines can be prepared by reducing aromatic nitro (NO2{-}{\rm{NO}}_2) compounds such as nitrobenzene. These amines are generally prepared by nitrating the aromatic ring, adding NO2{-}{\rm{NO}}_2 via an electrophilic aromatic substitution reaction. The NO2{-}{\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 C=NOH {\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 π \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.

Hofmann Rearrangement and Curtius Rearrangement

Primary amines can be prepared by the Hofmann rearrangement of primary amides or the Curtius rearrangement of acyl azides.

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 RN=C=O {\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 NH {\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 π\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 π\pi bond with the carbon which causes it to break its σ\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.

Hofmann Rearrangement Mechanism

The Hofmann rearrangement is a reaction where primary amides are treated with a halogen and a base and rearranged into an isocyanate intermediate, which then converts into a primary amine following the loss of carbon dioxide in the presence of water.
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.

Curtius Rearrangement Mechanism

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.