3.5. Synthesizing Primary, Secondary, and Tertiary Amines
The previous methods exclusively form primary amines. It is not possible to use those approaches to form secondary or tertiary amines. Other methods were developed that allowed access to a wider array of amines, including primary, secondary and tertiary.
3.5.1. Reaction: Amine Synthesis Using Reduction of Imine/Iminium
It is possible to selectively synthesize a primary, secondary, or tertiary amine by forming and then reducing an iminium (Scheme 3.8). An aldehyde or ketone and an amine combine to form an iminium, typically through acid catalysis. Afterwards, the iminium is reduced into an amine using a weak reducing compound such as sodium cyanoborohydride (NaBH3CN). Reduction using sodium cyanoborohydride requires quenching with a weak base to generate the final product. The reaction is often depicted as three steps to indicate this. This sequence of steps is sometimes called Reductive Amination.
Scheme 3.8 – Generalized Reaction Equation for Amine Synthesis Using Reductive Amination.
For the strong acid catalyst, it is possible to use acids such as sulfuric acid (H2SO4), phosphoric acid (H3PO4), or nitric acid (HNO3) but it is much more common to use hydrochloric acid (HCl). Like sulfuric acid, phosphoric and nitric acid always contain at least some water. This water inhibits imine/iminium formation (water is a product and the reaction is in equilibrium). However, it is possible to generate hydrochloric acid without any water in it (sometimes referred to as anhydrous hydrochloric acid).
There are several variations of reductive amination with different reaction conditions. Some variants form an imine rather than an iminium. This requires modified conditions for each step of the reaction sequence. Examples like this will not feature in this text but may be encountered in other sources.
Adding multiple groups is not possible; the nitrogen of the starting amine cannot combine with multiple equivalents of aldehyde/ketone. The overall sequence adds one alkyl group to the nitrogen. Whether a primary, secondary, or tertiary amine is generated depends on the starting amine used for the reaction (Figure 3.18): ammonia (NH3) becomes a primary amine; a primary amine becomes a secondary amine; a secondary amine becomes a tertiary amine.
Figure 3.18 – Examples of Syntheses of a Primary, Secondary, and Tertiary Amine Using Reductive Amination.
It is possible to use this method to synthesize amines with different alkyl groups sequentially (Scheme 3.9). Each group is added one-by-one until the desired product is obtained.
Scheme 3.9 – Example of Synthesis of a Tertiary Amine Using Three Sequential Reductive Aminations.
This occurs in three main parts (Scheme 3.10). Two of the three are standard mechanisms from introductory organic chemistry. The first part, formation of the iminium, follows the same sequence of steps as acid-catalyzed hemiacetal/acetal formation (see Catalysis of Addition Reactions) but with additional steps.
First, acid-catalyzed iminium formation occurs. The strong acid reacts with the solvent to form an oxonium (cationic oxygen; not shown). This is the active catalyst. The electrophile (carbonyl) gets activated by the catalyst. This greatly increases its electrophilicity. Then, the amine (nucleophile) attacks activated carbonyl (electrophile). This forms a new bond and adds a lone pair to the oxygen. The solvent then removes a proton from the nitrogen (the former nucleophile) and places it on the oxygen. This greatly increases its leaving group ability. These steps may be viewed as regeneration of the catalyst and another acid-catalyzed activation. Then the lone pair of the nitrogen forms a new π bond with the carbon, ejecting the leaving group (water). Although the solvent does remove a proton, forming the imine and regenerating the catalyst, this is in equilibrium. The iminium is favoured.
Second, hydride reduction occurs. The nucleophile (hydride) attacks the electrophile (carbon of the iminium). This forms a new bond and adds a lone pair to the nitrogen. Then the lone pair forms a new bond with the boron.
Third, after the reaction is complete water and a weak base is added to quench, forming the final product (no mechanism shown).
Scheme 3.10 – Reaction Mechanism for Amine Synthesis Using Reductive Amination of Propan-2-one (Acetone) and Ethylamine.
It is possible for a stereocentre to be formed during the reduction step (Scheme 3.11). These differ from previous cases because the stereocentre is formed from a reaction with a single possible mechanism (hydride attack) rather than a reactivity continuum (SN1 and SN2).
Scheme 3.11 – Example of formation of a Stereocentre During Reductive Amination.
Recall that when two orbitals overlap constructively they form a covalent bond (σ or π). However, when they overlap deconstructively they form an anti-bonding orbital (σ* or π*). Usually, in order to break a covalent bond electron density must be put into its corresponding anti-bonding orbital. During the reduction step the covalent bond being broken is the carbon-nitrogen π-bond, which is broken by putting electron density from the nucleophile (hydride) into the corresponding anti-bonding π* orbital.
The carbon and nitrogen of an iminium are sp2 hybridized and trigonal planar. The p orbitals which make up the electrophilic π bond are located both above and below the iminium. This is also true for the corresponding anti-bonding orbitals (π*), which simply point in the opposite directions (Figure 3.19).
Figure 3.19 – Representations of Pi (π) Bonding and Pi* (π*) Anti-Bonding Orbitals for Methaniminium.
Assuming there are no pre-existing stereocentres in the starting materials, the nucleophilic attack (hydride attacks iminium) will not be stereoselective as attacking from above the iminium is sterically and electronically equivalent to attacking from below the iminium (Figure 3.20). If a new stereocentre is formed during this step, it will be formed as an equal mixture of both (R) and (S). This step is not stereoselective. This is true regardless of the E/Z configuration of the iminium.
Figure 3.20 – Comparison of Products from Nucleophilic Attacks from Above and Below N-(Butan-2-ylidene)methanaminium.
If another stereocentre (or multiple stereocentres) exists then the resulting products will be diastereomers. Because there is a steric and/or electronic difference between attacking from above or below in these cases, the two stereoisomers are NOT formed equally and the product is a non-one-to-one mixture of diastereomers. In these cases, it is important only to recognize that the product will be formed as a mixture of diastereomers. Predicting which diastereomer should be favoured is not required.
3.5.2. Reaction: Amine Synthesis Using Reduction of Amides
Recall that the reduction of amides follows a slightly different path than reduction of other carbonyl-containing functional groups such as esters. Instead of the nitrogen-containing group becoming the leaving group, the oxygen of the carbonyl leaves. This is another route to synthesize amines.
It is possible to selectively synthesize a primary, secondary, or tertiary amine by reducing an amide (Scheme 3.8). The amide can be synthesized through any of the standard routes (see Converting Acid Halides to Amides, Converting Anhydrides to Amides, and Converting Carboxylic Acids/Esters to Amides). Afterwards, the amide is reduced into an amine using a strong reducing compound such as lithium aluminum hydride (LiAlH4). Because this is done using aluminum hydride it requires a polar aprotic solvent, typically tetrahydrofuran (THF). Reduction using lithium aluminum hydride normally requires quenching. Unlike most aluminum hydride reductions these do not require a quench to generate the final product.
Scheme 3.12 – Generalized Reaction Equation for Amine Synthesis Using Reduction of Amides.
Recall that nitrogen atoms have unusual properties. A consequence of this is that anionic nitrogen atoms are extremely poor leaving groups (because they are very strong bases). This affects the reactivity of amides with hydride sources.
No groups are being added to the nitrogen. Whether a primary, secondary, or tertiary amine is generated depends on the starting amide used for the reaction (Figure 3.21).
Figure 3.21 – Examples of Syntheses of a Primary, Secondary, and Tertiary Amine Using Reduction of an Amide.
For convenience the following mechanism will show a different molecule of aluminum hydride delivering each hydride, but this is not likely to be accurate. The mechanism for this reaction is straightforward but time consuming to draw. Many sources do not keep track of all compounds in the reaction, adding or removing them as needed. At an introductory level this is acceptable but discouraged.
First, aluminum hydride (nucleophile) attacks the carbonyl (electrophile; Scheme 3.13). This forms a new bond and adds a lone pair to the oxygen. Instead of returning and ejecting an anionic nitrogen leaving group, the anionic oxygen (nucleophile) attacks the aluminum (electrophile). This significantly increases its leaving group ability. Then the lone pair of the nitrogen forms a π bond with the carbon, ejecting the leaving group and forming an iminium. Finally, another hydride (nucleophile) attacks the iminium (electrophile), generating the final product.
Scheme 3.13 – Reaction Mechanism for Addition-Elimination Followed by Addition of N,N-Dimethylethanamide with Lithium Aluminum Hydride.
