ChemTalk

Amination Reactions

Core Concepts

This article covers amination reactions, the addition of an amine group to an organic molecule, with examples. These amine groups can be either primary, secondary, or an azanide, depending on the requriments for each reaction, and on the molecules present in solution. Amination reactions may occur due to reductive amination with a reducing agent, hydroamination in the presence of water, acid-catalyzed hydroamination in an acidic solution, base-catalyzed hydroamination in a basic solution, metal-catalyzed hydroamination, or through electrophilic amination. Amination reactions are needed as amine groups are weak nucleophiles for substitution reactions.

Reductive Amination

Reductive amination, also known as reductive alkylation, converts a carbonyl group to an amine in the presence of a reducing agent with an intermediate of an imine. The first step in the process is to add a primary(terminal) or secondary amine(enamine) to an aldehyde or ketone (carbonyl) group to form an imine through a condensation reaction. If a ketone is used, a tertiary amine is formed. As shown below, if an aldehyde is used then a secondary amine is formed. Cyclic or aromatic amines are made only when the reductive amination is intramolecular. An indirect reductive amination approach isolates the imine, extracts it, and then reduces it to an amine. In a direct reductive amination, the reactions use the formation of imine to come to equilibrium with the preceding steps, as shown below. By Le Chatelier’s Principle, the imine is in equilibrium with the iminium ion(protonated imine) and will react with a reducing agent, such as sodium cyanoborohydride or hydrogenation, to reduce or eliminate the double bond, shifting the equilibrium. Additionally, an acidic solution may be used to speed up the reaction by similar principles. This process may also be achieved by hydrogenation using a metal catalyst and hydrogen gas for syn-addition.

Hydroamination

These types of reactions add an amine across an alkene or alkyne with the use of a light(an energy source) or a catalyst to create an amine which is more highly substituted (ex. primary to secondary). It is worth noting that alkynes are better than alkenes at undergoing hydroamination. The markovnikov product is usually favored, and it is more difficult to create the anti-markovnikov product.

Acid-catalyzed Hydroamination

Acid-catalyzed hydroamination adds an amino group and hydrogen to an alkene or alkyne typically in the presence of a strong acid. The acid protonates the substrate, making it more succeptible to a nucleophilic attack by an amine. This reaction is regioselective, following the Markovnikov rule and is simialr to an SN1 reaction. Acids are not generally used due to the nitrogen being found in a basic state, which creates nitrogen containing salts, however when used with homogeneous and heterogeneous catalysts the desired product can be created. Consequently, the more basic the amine, the slower the reaction rate. Electron-withdrawing substitutents on the nitrogen containing compound increase the rate of reaction, as does having a less stable carbenium ion intermediate forming. Chiral acids can be used to produce heterocyclic amine products.

Base-catalyzed Hydroamination

Base-catalyzed hydroamination occurs through deprotonation of the amine group creating a nucelophilic amine and then a proton transfer from the other reactant. These steps occur simultanously; this is a concerted mechanism similar to an SN2 reaction. This reaction occurs via These usually occur at high termperatures and pressures. The base facilitates the nucleophilic attack of the nitrogen. The stereoselectivity of these products is time dependent as the Z isomer is kinetically stable and the E isomer is thermodynamically stable.

Metal Catalyzed Hydroamination

Reactions catalyzed by alkali metals are anti-Markovnikov. Lanthanide or rare-earth metal catalysts create anti-Markovnikov products. Rare-earth metal catalysts are great catalysts for intramolecular hydroamination but not as good at intermolecular processses, but they may still be used such that a ring is formed and then the compound goes through protonolysis to release the catalyst. Group 4 and 5 metal catalysts have products similar to lanthanide, though with different rate-determining steps.

Electrophilic Amination

Electrophilic amination involves reacting a nucleophilic carbanion with an electrophilic nitrogen through substitution or addition. These electrophilic nitrogens come from various speciies such as nitrous acid or diazonium salts. The product of these reactions is mostly anime, though not always. Nitrogen does not have a full octet and is highly electrophilic in such reactants, as it is near an electron-donating group. If the nucleophilic species contains a leaving group, then a substitution results. If the nitrogen is added across the electron-rich double or triple bond, then a nucleophilic addition results.

Citations

https://www.masterorganicchemistry.com/2017/09/01/reductive-amination/
https://pubs.acs.org/doi/10.1021/cr0306788
https://pubs.acs.org/doi/full/10.1021/acs.accounts.6b00449
https://www.sciencedirect.com/topics/chemical-engineering/hydroamination
https://reagents.acsgcipr.org/reagent-guides/reductive-amination/

Topics Covered in Other Articles

https://chemistrytalk.org/alcohol-reactions/
https://chemistrytalk.org/radical-reaction/
https://chemistrytalk.org/carboxylic-acid-derivative-reactions/
https://chemistrytalk.org/cycloaddition-reactions/
https://chemistrytalk.org/organometallic-chemistry-compounds-reactions/