08 Amines and Nitrogen-Containing Functional Groups

Structure and classification

Amines are derivatives of ammonia in which carbon groups replace one or more hydrogen atoms. Their classification depends on how many carbon groups are attached to nitrogen:

• A primary amine has one carbon group, represented as $\mathrm{RNH_2}$.

• A secondary amine has two carbon groups, represented as $\mathrm{R_2NH}$.

• A tertiary amine has three carbon groups, represented as $\mathrm{R_3N}$.

• A quaternary ammonium ion has four carbon groups and a permanent positive charge, represented as $\mathrm{R_4N^+}$.

These labels count carbon groups bonded to nitrogen—not the number of hydrogen atoms. In a typical amine, nitrogen is approximately trigonal pyramidal and has a lone pair. This lone pair explains much of amine chemistry: it can accept a proton or donate an electron pair to form a bond.

Amides are a distinct functional group. In an amide, the nitrogen lone pair is delocalized into the carbonyl, making it less available than the lone pair in an amine. As a result, amides are much less basic and nucleophilic than typical amines.

Basicity and salt formation

An amine acts as a Brønsted–Lowry base by accepting a proton from water. For example, a primary amine can establish this equilibrium:

A useful comparison is the $\mathrm{p}K_\mathrm{a}$ of the amine’s conjugate acid: a higher conjugate-acid $\mathrm{p}K_\mathrm{a}$ generally corresponds to a stronger amine base. Alkyl groups often increase electron density at nitrogen, while resonance delocalization reduces the availability of its lone pair. For this reason, aniline is less basic than a typical alkylamine: its lone pair can delocalize into the aromatic ring.

There is no universal basicity ranking of primary, secondary, and tertiary amines in water. Solvation and steric effects also influence how well the resulting ammonium ion is stabilized.

Protonation also provides a practical separation strategy. An amine reacts with aqueous acid to form a water-soluble ammonium salt. After separating the aqueous layer, adding base regenerates the neutral amine, which can then be separated from the water.

Takeaway: Basicity depends on how available the nitrogen lone pair is and how well the protonated form is stabilized; the surrounding solvent matters too.

Preparing amines

Choose a preparation based on the desired substitution pattern and which carbon–nitrogen bond must be formed. Planning backward from the target helps identify a suitable precursor and avoid unwanted overalkylation.

• Reductive amination uses an aldehyde or ketone and ammonia or an amine to form an imine or iminium intermediate, which is then reduced. Ammonia can give a primary amine; a primary amine can give a secondary amine; and a secondary amine can give a tertiary amine. For example, cyclohexanone plus ammonia followed by reduction gives cyclohexylamine. The new carbon–nitrogen bond forms at the former carbonyl carbon.

• Gabriel synthesis uses alkylated phthalimide, followed by cleavage of the imide, to obtain a primary amine. It helps avoid mixtures that can result when ammonia undergoes repeated alkylation.

• Reduction of nitriles gives primary amines. This route adds a carbon to the chain relative to the alkyl halide used to make the nitrile. Reduction of nitro groups also gives amines; for example, reducing nitrobenzene gives aniline.

• Direct alkylation lets ammonia or an amine displace a leaving group on a suitable alkyl substrate. Further alkylation may occur, so this approach requires care when a single substitution level is needed.

Takeaway: Match the method to the target amine, and consider whether the reaction controls how many carbon groups become attached to nitrogen.

Reactions and functional-group transformations

The nitrogen lone pair lets amines form bonds with electrophiles as well as accept protons. These reactions can convert an amine into a new functional group or use it as an intermediate.

• Alkylation: An amine attacks an alkyl electrophile by substitution, forming a new $\mathrm{C-N}$ bond. Repeated alkylation can produce a quaternary ammonium salt, so primary and secondary amines may be prone to overalkylation.

• Acylation: Primary and secondary amines react with acid chlorides or acid anhydrides by nucleophilic acyl substitution to form amides. For example, aniline reacting with an acetylating reagent gives acetanilide. The amide product is less nucleophilic than the starting amine because its lone pair is delocalized into the carbonyl.

• Condensation with carbonyl compounds: A primary amine reacts with an aldehyde or ketone, typically under mild acid catalysis with water removed, to form an imine. A secondary amine can form an enamine when the carbonyl compound has an $\alpha$-hydrogen. These reversible reactions connect amine chemistry with carbonyl chemistry; imines also serve as intermediates in reductive amination.

• Formation of aromatic diazonium salts: A primary aromatic amine such as aniline can be converted with nitrous acid under cold acidic conditions into an arenediazonium salt. The diazonium group can then be replaced by groups such as chlorine, bromine, iodine, cyanide, hydroxyl, or hydrogen. This strategy is useful when direct substitution on an aromatic ring is difficult or gives an unwanted pattern.

• Hofmann elimination: Exhaustive alkylation first converts an amine into a quaternary ammonium salt. Treatment with base and heat can then eliminate an alkene, often favoring the less substituted alkene. Changing nitrogen into a good leaving group makes this elimination possible.

Takeaway: The lone pair is the key to many amine reactions, while protonation, acylation, and exhaustive alkylation change how nitrogen behaves.

• diazonium salt