Amination Reactions

Core Concepts

In this article we will talk about amines and their respective properties, with a focus on the different types of amination reactions that they can participate in.

Topics Covered in Other Articles

Amine Functional Group

Friedel Crafts Acylation and Alkylation

Acid Chloride Functional Group

Introduction to Amines

An amine is a compound or functional group that contains at least a singular Nitrogen atom with a lone pair. Amines are derivatives of ammonia (NH₃) where one or more of the Hydrogen atoms are replaced with another group. Depending on how many Hydrogens are replaced determines whether an amine is classified as primary, secondary, or tertiary.

Primary Amines

Primary (1°) amines are amines in which the amino group is directly bonded to one carbon of any given hybridization, but is not a carbonyl group carbon. In other words, any R group bonded to an NH₂ as shown below.

Secondary Amines

Secondary (2°) amines are amines in which the amino group is bonded to two carbons of any hybridization, but once again this carbon cannot be a carbonyl group carbon. In other words, two R groups are now attached to the Nitrogen, while one Hydrogen remains as shown below.

Tertiary Amines

Tertiary (3°) amines are amines in which the amino group is bonded to three carbons of any hybridization, once again not a carbonyl group carbon. In tertiary amines, three R groups are attached to the Nitrogen atom, removing all 3 Hydrogens from it as shown below.

Quaternary Ammonium Salts

Quaternary (4°) ammonium salts, also known as quaternary ammonium cations, is an amine in which the amino group is bonded to four carbons of any hybridization. Since Nitrogen can only bond to three other molecules, this creates a positive charge on the amine group which is typically coupled with the ionization of the leaving group. In the example below, the chlorine ion if left with a negative charge.

Synthesis of Amines via Reductive Amination

Reductive Amination allows for ketones and aldehydes to be converted into primary, secondary, or tertiary amines. These reactions occur in two steps. First, an imine is produced by reacting the aldehyde or ketone with an amine. Whether the reactant amine is primary, secondary, or tertiary later on determines which of the three the final product will be. This imine can then be reduced to an amine via a reducing agent, the most common one being sodium cyanoborohydride.

In the following example, the amine molecule has two R groups attached, therefore yielding a tertiary amine as the final product of reduction.

Synthesis of Amines via Amide Reduction

In this type of reduction, amines are synthesized by the reduction of amides via a hydride reagent, typically LiAlH. This mechanism involves three steps. First, the Hydrogen of the reagent binds to the carbonyl carbon of the starting ester, creating an intermediate compound. The attached Oxygen becomes a metal alkoxide leaving group, while the Nitrogen provides the Carbon with the now missing electrons, forming a double bond between the two. Finally, rapid reduction occurs by the hydride reagent as another Hydrogen group is added to the electrophilic C. Electrons from the C=N double bond move back to the original Nitrogen, neutralizing the overall charge and yielding an amine product. 

Syntheses Limited to Primary Amines

Synthesizing amines via a traditional Sn2 reaction is not always possible as exhaustive alkylation or methylation (as discussed in later sections) will continue the forward reaction until a quaternary structure is formed. One way to avoid this is through the use of specific reactions like Gabriel Synthesis.

Gabriel Synthesis

Gabriel Synthesis is a reaction that easily synthesizes amines. The catch: it only works in creating primary amines. Gabriel Synthesis works in three steps. First, phthalimide is deprotonated using a strong base.

Next, an alkyl halide is added. This causes an Sn2 reaction allowing for an C-N bond to form. What sets Gabriel Synthesis apart from other reactions is that the Nitrogen is now attached to two electron withdrawing groups, reducing its nucleophilicity. This stops the reaction from becoming exhaustive! After the Sn2 reaction, NH₂NH₂ and heat are introduced, allowing the amine to release from the compound, thus yielding both a new primary amine and the byproduct, in this case phthalhydrazide.

Alkylation of Amines via Alkyl Halides

Amine alkylation (also known as amino-dehalogenation) is a reaction between an amine/ammonia and an alkyl halide. The reaction proceeds in an Sn2 fashion, producing a higher substituted amine as the product. In the alkylation of amines, it is typically hard to control the products that result, however, two specific types of amine alkylation reactions are known to produce good yields of alkylated products. These are: Exhaustive Alkylation and Excess Alkylation.

Exhaustive Alkylation

Exhaustive Alkylation is a reaction in which an excess of alkyl halide is reacted with a primary, tertiary, or quaternary amine in order to convert it into a quaternary ammonium salt. This is a positively charged nitrogen with four substituents. In the example below, the charge is balanced by iodide ions. Alkylation with iodomethane is shown below, but many other alkyl halides can be used.

Excess Alkylation

The other alkylation reaction that provides good yield of desired alkylated products is the Excess Alkylation reaction. In this reaction, an excess of ammonia is reacted with an alkyl halide in order to aminate the alkyl halide. The Nitrogen in ammonia acts as the nucleophile, attacking the electrophilic carbon in the alkyl halide, thus creating a N-C bond and causing the leaving group to leave, in this example a Bromide group (This is essentially an SN2 reaction). An acid/base reaction follows, where the excess ammonia deprotonates the Nitrogen center, yielding the alkylation product (a primary amine).

Amines as Leaving Groups: Hofmann Elimination

Amines rarely act as leaving groups in both substitution and elimination reactions, however, amino groups can be converted into quite useful leaving groups. In Hofmann Elimination, an amine behaves as the leaving group causing the least substituted alkene to become the major product. In a typical Hofmann Elimination, excess methyl is added to the reactant containing an amine. The amine acts as the nucleophile and proceeds in an Sn2 fashion, causing the displacement of a methyl halide. (This is exhaustive methylation!) This reaction repeats until a quaternary ammonium is produced, hence the term exhaustive.

Next, the addition of a metal oxide facilitates an anion exchange. In this example, the Iodine Ion is precipitated as AgI while a hydroxide group replaces the I ion. This hydroxide will act as the strong base in the elimination step.

Finally, a simple E2 elimination takes place. Since a less substituted carbanion is more stable than a more substituted counterpart, elimination occurs with the less substituted beta carbon. The Hofmann product then becomes the less substituted alkene as shown below.

Oxidation of Amines: The Cope Elimination

The Cope Elimination is an elimination reaction for tertiary amines in which the major product is an alkene. In this type of elimination, the leaving group is a hydroxyl amine resulting in a Hofmann product. Unlike Hofmann Elimination, the Cope Elimination occurs in only two steps. First, a tertiary amine is oxidized into an amide oxide, usually by treatment of hydrogen peroxide.

Then, the amine oxide produced in the first step undergoes a classic E2 elimination in which the oxide portion in the leaving group also serves as the base involved in the reaction.