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 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 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 () group.
Alkylation of Ammonia, Gabriel Synthesis, or Azide Synthesis
Direct Alkylation of Amines
Gabriel Synthesis Mechanism
Amine Synthesis via Alkylation through an Azide Intermediate
Reductive Amination and Other Reductions
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 () or an oxime () 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
General LAH Reduction of Amide to Amine
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 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 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 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 .
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 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 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 bond with the carbon which causes it to break its 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.