3.4. Synthesizing Primary Amines
Because all amines, including ammonia, are nucleophilic they can usually be alkylated directly with an alkyl halide (Scheme 3.1). However, the product has one more alkyl group than the starting material and is now more nucleophilic (see Figure 3.14). The amine will undergo alkylation repeatedly until it is a tertiary amine. The tertiary amine is not nucleophilic enough to undergo a fourth alkylation.
Scheme 3.1 – Example of Alkylation of Ammonia with 1-Bromoethane Highlighting the Actual Product Obtained.
It is possible to use a very large excess of ammonia relative to the alkyl halide to inhibit this. In practice, this method produces the desired primary amine as the major product but purification (i.e. removing the small amounts of secondary and tertiary products) tends to be challenging.
Instead, several other approaches were developed to allow the selective synthesis of amines. Note that the examples in this text (Sections 3.4.1-3.5.2) are only some of the more common methods; there are many other reactions or sequences of reactions that may be used to generate amines selectively.
For many of these reactions it is possible to form a stereocentre as part of the transformation. In theory, it is possible to selectively form a stereocentre during the reaction. For example, using conditions to force a stereospecific SN2 mechanism (inversion; Figure 3.17). In practice this is very challenging and usually affords poor stereoselectivity. For all reactions in this chapter assume any stereocentres formed from the reaction are formed with no stereoselectivity; if both enantiomers are possible a racemate is formed, diastereomers are formed as a non-one-to-one mixture.
Figure 3.17 – Example of a Hypothetical Stereospecific Synthesis of a Primary Amine.
3.4.1. Reaction: Primary Amine Synthesis Using Phthalimide
It is possible to selectively synthesize a primary amine using an amide-like nucleophile such as phthalimide (Scheme 3.2). The reduced nucleophilicity requires the use of a strong base (e.g. NaOH, KOH) to form the anion and allow nucleophilic substitution to occur. Afterwards, the “amides” are removed through hydrolysis/saponification. The reaction is often depicted as three steps to indicate this. This sequence of steps is sometimes called Gabriel Synthesis.
Scheme 3.2 – Generalized Reaction Equation for Primary Amine Synthesis Using Phthalimide.
Adding multiple groups is not possible; the product is (much) less nucleophilic and these positions are already occupied.
In reality this method only works well with some alkyl halides, usually primary alkyl bromides, with many others affording poor-to-acceptable results. However, it is not always intuitive whether a given electrophile will work well or poorly for this reaction. Assume any given alkyl halide will work for this reaction unless otherwise indicated.
There are several possible conditions with slightly different mechanisms for the third step (cleavage of the “amides”). A classic example is the use of hydrazine (H2N-NH2) instead of a hydroxide base. Some details of the mechanism change but the general idea is always the same: use a nucleophile to do addition-elimination on the carbonyls and eject the amine as a leaving group.
This occurs in three main parts (Scheme 3.3). All three are standard mechanisms from introductory organic chemistry. The mechanism for this reaction is typically abbreviated due to its length.
First, an acid-base reaction occurs. The base (hydroxide) removes a proton from the acid (phthalimide). This greatly increases its nucleophilicity. Resonance stabilization of the resulting anion (not shown) makes this acid-base reaction favourable/irreversible; this is not base catalysis.
Second, a nucleophilic substitution occurs. This can follow an SN1 or SN2 mechanism depending on the structure of the electrophile. All standard considerations apply (see Determining if a Reaction Follows an SN1 or SN2 Mechanism). An SN2 mechanism is shown for this electrophile. The nucleophile (anionic nitrogen) attacks the electrophile (carbon of the alkyl halide). This forms a new bond and ejects the leaving group, the anionic bromine.
Third, hydrolysis/saponification occurs. The nucleophile (hydroxide) attacks the electrophile (carbonyl). This forms a new bond and adds a lone pair to the oxygen. Then that lone pair comes back and reforms the π bond with the carbon, ejecting the leaving group (anionic nitrogen). The two “products” then react with each other; the base (anionic nitrogen) removes a proton from the acid (carboxylic acid). This occurs again at the other carbonyl (not shown), forming the final product. A quench is not needed to obtain the desired amine.
Scheme 3.3 – Reaction Mechanism for Primary Amine Synthesis Using Phthalimide and Bromomethane.
3.4.2. Reaction: Primary Amine Synthesis Using Azide
It is possible to selectively synthesize a primary amine using anionic azide as a nucleophile (Scheme 3.4). Sodium azide (NaN3) is the most commonly used, but other counterions (e.g. LiN3, KN3, etc.) are also possible. Afterwards, the azide is cleaved into an amine and nitrogen gas (N2) using hydrogenation. The overall reaction is normally shown as two steps to indicate this.
Scheme 3.4 – Generalized Reaction Equation for Primary Amine Synthesis Using Azide.
Adding multiple groups is not possible; the nitrogen’s other two bonds are already occupied.
This occurs in two stages (Scheme 3.5). Both are standard “mechanisms” from introductory organic chemistry.
First, a nucleophilic substitution occurs. This can follow an SN1 or SN2 mechanism depending on the structure of the electrophile. All standard considerations apply (see Determining if a Reaction Follows an SN1 or SN2 Mechanism). An SN2 mechanism is shown for this electrophile. The nucleophile (anionic nitrogen) attacks the electrophile (carbon of the alkyl halide). This forms a new bond and ejects the leaving group, the anionic bromine.
Second, hydrogenation breaks one of the N-N double bonds. This releases nitrogen gas (N2) and the amine. The mechanism for hydrogenation is not complex but involves a transition metal (“palladium on carbon”) and contains steps that fall outside of the scope of organic chemistry. As a result, it is typically omitted and instead discussed in-depth in inorganic chemistry courses (no mechanism shown).
Scheme 3.5 – Reaction Mechanism for Primary Amine Synthesis Using Sodium Azide and Bromomethane Followed by Hydrogenation.
3.4.3. Reaction: Primary Amine Synthesis Using Cyanide
It is possible to selectively synthesize a primary amine using anionic cyanide as a nucleophile (Scheme 3.6). Potassium cyanide (KCN) is the most commonly used, but other counterions (e.g. NaCN, LiCN, etc.) are also possible. Afterwards, the nitrile 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 requires quenching with a strong acid or strong base to generate the final product. The overall reaction is normally shown as three steps to indicate this.
Scheme 3.6 – Generalized Reaction Equation for Primary Amine Synthesis Using Cyanide.
This method differs from other approaches in that it adds the amine AND a new carbon (as a CH2) to the electrophile.
Adding multiple groups is not possible; the carbon/nitrogen is not nucleophilic in the product after nucleophilic substitution.
This occurs in three main parts (Scheme 3.7). All three are standard mechanisms from introductory organic chemistry. For convenience the following mechanism will show a single molecule of aluminum hydride delivering both hydrides. The reality is likely a complex mix of hydride sources for each step.
First, a nucleophilic substitution occurs. This can follow an SN1 or SN2 mechanism depending on the structure of the electrophile. All standard considerations apply (see Determining if a Reaction Follows an SN1 or SN2 Mechanism). An SN2 mechanism is shown for this electrophile. The nucleophile (anionic carbon) attacks the electrophile (carbon of the alkyl halide). This forms a new bond and ejects the leaving group, the anionic bromine.
Second, hydride reduction occurs. The nucleophile (hydride) attacks the electrophile (carbon of the nitrile). This forms a new bond and adds a lone pair to the nitrogen. Then the lone pair forms a new bond with the aluminum. These two steps occur again at the same position.
Third, after the reaction is complete water and a strong acid or strong base is added to quench, forming the final product (no mechanism shown).
Scheme 3.7 – Reaction Mechanism for Primary Amine Synthesis Using Potassium Cyanide and Bromomethane.
