Amines

Classification and Structure of Amines

Amines are organic derivatives of ammonia, $NH_3$, in which one or more hydrogen atoms are replaced by organic groups (alkyl, aryl, or others). Their general formulas are based on the idea of substituting $H$ in $NH_3$ by organic residues $R$ or $Ar$.

Primary, Secondary, and Tertiary Amines

According to how many hydrogens in $NH_3$ are replaced, we distinguish:

• Primary (1°) amines: one $H$ is replaced
  $$\text{R–NH}_2 \quad \text{or} \quad \text{Ar–NH}_2$$
  Examples:
• Methylamine, $CH_3NH_2$
• Aniline, $C_6H_5NH_2$ (an aromatic amine)
• Secondary (2°) amines: two $H$ are replaced
  $$\text{R}_2\text{NH},\ \text{R–NH–R}',\ \text{R–NH–Ar},\ \text{Ar–NH–Ar}'$$
  Examples:
• Dimethylamine, $(CH_3)_2NH$
• Ethylmethylamine, $CH_3CH_2NHCH_3$
• Tertiary (3°) amines: all three $H$ are replaced
  $$\text{R}_3\text{N},\ \text{R}_2\text{N–Ar},\ \text{R–N(Ar)}_2,\ \text{Ar}_3\text{N}$$
  Example:
• Trimethylamine, $(CH_3)_3N$

The classification is made according to the number of carbon substituents on nitrogen, not by how many $NH$ groups are present in the molecule as a whole.

Aliphatic versus Aromatic Amines

• Aliphatic amines: nitrogen is directly bonded only to aliphatic (non-aromatic) carbon atoms.
  Example: propylamine, $CH_3CH_2CH_2NH_2$.
• Aromatic amines: nitrogen is directly attached to an aromatic ring.
  Example: aniline, $C_6H_5NH_2$.

A molecule can contain both aliphatic and aromatic substituents at nitrogen (e.g. $C_6H_5NHCH_3$).

The Amino Group and Lone Pair

The functional group of amines is the amino group, usually written as $–NH_2$, $–NHR$, or $–NR_2$.

The nitrogen atom carries a lone pair of electrons. This lone pair:

• Gives the nitrogen approximately pyramidal geometry (for non-quaternary amines).
• Is responsible for the basicity and nucleophilicity of amines (ability to accept a proton or attack electrophiles).

In simple aliphatic amines, nitrogen is approximately sp³-hybridized, with three $\sigma$ bonds and one lone pair.

Quaternary Ammonium Compounds (Overview)

If a tertiary amine accepts a proton or reacts with an alkylating agent, nitrogen can become quaternary, bearing four carbon substituents and a positive charge:

$$\text{R}_3\text{N} + \text{R'–X} \rightarrow \text{R}_3\text{N}^+\text{R'}\ \text{X}^-$$

Quaternary ammonium ions are not amines (they have no lone pair), but they are closely related and are often discussed together with amines because they are formed from them.

Nomenclature of Amines

Amines can be named using common names or systematic (IUPAC) names. Both are widely used, especially for simple compounds.

Common Names (Alkylamine Names)

In common nomenclature, you name the alkyl groups attached to nitrogen followed by the word “amine”.

• $CH_3NH_2$: methylamine
• $(CH_3)_2NH$: dimethylamine
• $CH_3CH_2NHCH_3$: ethylmethylamine

For aromatic amines, traditional names are used:

• $C_6H_5NH_2$: aniline
• $C_6H_5NHCH_3$: N-methylaniline

If more than one substituent is attached to nitrogen, use N- to specify substitution on nitrogen rather than on the carbon chain:

• $C_6H_5N(CH_3)_2$: N,N-dimethylaniline

IUPAC Names

Two common systematic approaches are used:

1. Amino-substituted hydrocarbons
   The parent is the hydrocarbon, and the $–NH_2$ group is named as a substituent: amino.
• $CH_3NH_2$: methanamine (formal), often called methylamine
• $CH_3CH_2CH_2NH_2$: propan-1-amine (or 1-aminopropane)
• $CH_3CH(NH_2)CH_3$: propan-2-amine (or 2-aminopropane)
2. Alkylalkylamine naming with N-substitution
   Especially for secondary and tertiary amines, the parent is often the longest alkyl chain attached to nitrogen, and other groups attached to nitrogen are indicated with N-.
• $CH_3CH_2NHCH_3$: N-methylethanamine
• $(CH_3)_2NCH_2CH_3$: N,N-dimethylethanamine

The choice between common or IUPAC names depends on context; both are frequently encountered.

Physical Properties of Amines

Intermolecular Forces and Hydrogen Bonding

Amines can form hydrogen bonds because nitrogen is relatively electronegative and is bonded to hydrogen (for primary and secondary amines) and carries a lone pair.

• Primary and secondary amines form hydrogen bonds among themselves (N–H···N), leading to relatively higher boiling points than nonpolar molecules of similar molar mass.
• Tertiary amines cannot donate hydrogen bonds (no N–H), but can accept hydrogen bonds (via the lone pair). Their boiling points are typically lower than those of corresponding primary and secondary amines with similar molar mass.

The hydrogen bonding in amines is generally weaker than in alcohols, because O–H bonds are more polar than N–H bonds.

Boiling Points and Volatility

For a given molar mass:

• Boiling point order (rough trend):
  $$\text{alcohol} > \text{primary amine} \gtrsim \text{secondary amine} > \text{tertiary amine} > \text{hydrocarbon}$$

Lower-mass aliphatic amines (e.g. methylamine, ethylamine) are gases or volatile liquids with strong fishy or ammonia-like odors.

Solubility in Water

• Low-molar-mass amines (both aliphatic and small aromatic) are generally miscible or quite soluble in water, due to hydrogen bonding and the polar $C–N$ bond.
• As the hydrophobic carbon chain length increases, water solubility decreases.
• The conjugate acids of amines (ammonium salts, e.g. $RNH_3^+Cl^-$) are usually much more water-soluble than the neutral amines.

This difference in solubility between the free amine and its salt is widely used in separations and purification.

Basicity of Amines

Amines as Brønsted Bases

Amines are bases because the lone pair on nitrogen can accept a proton:

$$\text{RNH}_2 + \text{H}^+ \rightleftharpoons \text{RNH}_3^+$$

In aqueous solution, this is observed as:

$$\text{RNH}_2 + \text{H}_2\text{O} \rightleftharpoons \text{RNH}_3^+ + \text{OH}^-$$

Here, the amine increases the concentration of $OH^-$ in solution by removing $H^+$ from water.

• The equilibrium constant that describes this is the base dissociation constant $K_b$, or more commonly its negative logarithm $pK_b$.
• The corresponding conjugate acid has an acid dissociation constant $K_a$; for a given conjugate acid–base pair in water, $pK_a + pK_b = 14.0$ at 25 °C.

Influence of Structure on Basicity (Qualitative Ideas)

Several structural aspects influence the basicity of amines:

• Alkyl substitution (inductive effect)
  Alkyl groups can donate electron density toward nitrogen, making the lone pair more available, which can increase basicity in many aliphatic amines.
• Resonance and aromaticity
  In aromatic amines like aniline, the lone pair can be delocalized into the aromatic ring, reducing its availability for protonation and generally lowering basicity relative to corresponding aliphatic amines.
• Steric effects and solvation
  Bulky substituents around nitrogen can hinder solvation of the protonated amine and can affect basicity.

A complete quantitative comparison requires thermodynamic considerations, but these qualitative effects are central for understanding trends in basicity among different amines.

Amines as Nucleophiles (Overview)

Because the nitrogen lone pair is electron-rich, amines act not only as bases but also as nucleophiles in many organic reactions. This nucleophilicity is closely connected to their basicity, but it also depends on steric hindrance and reaction conditions.

Preparation of Amines (Overview)

Amines can be obtained by different synthetic methods. Only a brief overview is given here; detailed reaction mechanisms and stoichiometry are treated elsewhere.

Alkylation of Ammonia and Amines (N-Alkylation)

Ammonia or a primary/secondary amine can react with an alkyl halide to give a more substituted amine:

$$\text{R–X} + NH_3 \rightarrow \text{RNH}_2 + HX$$

Further reaction is possible:

• Primary amine $\rightarrow$ secondary amine
• Secondary amine $\rightarrow$ tertiary amine
• Tertiary amine $\rightarrow$ quaternary ammonium salt

In practice, mixtures of products can form because each new amine is also nucleophilic. Conditions and stoichiometry are chosen to favor a particular product where possible.

Reduction of Nitrogen-Containing Precursors

Amines can be obtained by reduction of more highly oxidized nitrogen compounds. Important examples include:

• Reduction of nitriles, $R–C \equiv N$, to primary amines, $RCH_2NH_2$.
• Reduction of nitro compounds, $Ar–NO_2$, to aromatic amines, $Ar–NH_2$ (e.g. synthesis of aniline from nitrobenzene).
• Reduction of amides, $RCONH_2$ or $RCONHR'$, to the corresponding amines.

Various reducing agents (e.g. metal/acid systems, catalytic hydrogenation, or hydride reagents) can be employed, depending on the substrate and functional groups present.

Other Methods (Brief Mention)

Additional routes include:

• Gabriel synthesis: specifically for primary aliphatic amines, using phthalimide as a protected nitrogen source.
• Reductive amination: formation of amines from carbonyl compounds (aldehydes, ketones) and ammonia/amine in the presence of reducing agents.

Details of these reaction types and mechanisms are discussed in the relevant reaction chapters.

Chemical Reactions of Amines

Amines participate in a variety of reactions, most of which are closely related to the presence of the nitrogen lone pair and their basic character.

Protonation and Salt Formation

In the presence of acids, amines form ammonium salts, which are often crystalline and have high melting points:

$$\text{RNH}_2 + \text{HCl} \rightarrow \text{RNH}_3^+\text{Cl}^-$$

Similarly, secondary and tertiary amines give the corresponding dialkyl- or trialkylammonium salts.

This acid–base reaction is reversible. Treatment of the ammonium salt with a strong base (e.g. $NaOH$) regenerates the free amine:

$$\text{RNH}_3^+\text{Cl}^- + \text{OH}^- \rightarrow \text{RNH}_2 + \text{H}_2\text{O} + \text{Cl}^-$$

The conversion between free amine and salt is widely used in purification, extraction, and pharmaceutical formulation (where the salt form is often more water-soluble).

Nucleophilic Substitution at Carbon (Alkylation and Acylation)

Alkylation (C–N Bond Formation)

As nucleophiles, amines can attack electrophilic carbons, such as those in alkyl halides:

$$\text{R–X} + \text{R'NH}_2 \rightarrow \text{R'RNH} + HX$$

This leads to the formation of new C–N bonds. The extent of alkylation and the formation of mixed or quaternary products are practical issues in synthetic planning.

Acylation (Formation of Amides)

Primary and secondary amines react with acylating agents (e.g. acyl chlorides, anhydrides) to give amides:

$$\text{RCOCl} + \text{R'NH}_2 \rightarrow \text{RCONHR'} + \text{HCl}$$

Tertiary amines, lacking an N–H bond, do not form amides in this simple way, though they can participate as bases or catalysts in such reactions.

Acylation reduces the basicity of nitrogen significantly because the amide nitrogen lone pair is delocalized (resonance) with the carbonyl group.

Reaction with Nitrous Acid (Overview)

The reaction of amines with nitrous acid ($HNO_2$) is particularly important:

• Primary aliphatic amines: often give unstable diazonium ions that decompose, releasing nitrogen gas and forming mixtures of products (e.g. alcohols, alkenes, etc.).
• Primary aromatic amines: give stable diazonium salts at low temperature in solution, which are key intermediates in the preparation of azo dyes and many aromatic substitution products.
• Secondary amines: typically form N-nitrosamines.
• Tertiary amines: can form nitrosated products or salts depending on the conditions.

The behavior depends strongly on whether the amine is aliphatic or aromatic and on its degree of substitution.

Oxidation (Brief Overview)

• Aliphatic amines can be oxidized by strong oxidizing agents to various products (nitriles, nitroso compounds, or even fragmentation products).
• Aromatic amines can be oxidized to azo compounds, quinone imines, or other derivatives, depending on reagents and conditions.

Because many oxidation products are reactive and sometimes toxic, such reactions are important both synthetically and in environmental/health contexts.

Biological and Practical Significance of Amines

Amines in Biological Systems

Amines are widespread in biology, often in protonated (ammonium) form at physiological pH:

• Amino acids contain a primary amino group (–$NH_2$ or –$NH_3^+$ in physiological conditions).
• Biogenic amines (e.g. dopamine, histamine, serotonin) are derived from amino acids and function as neurotransmitters and signaling molecules.
• Many vitamins and coenzymes contain amino groups or are related to amine chemistry.

In biological environments, the protonation state of amines (whether they exist predominantly as free bases or as ammonium ions) is strongly influenced by pH and local microenvironment, which in turn affects structure and function.

Industrial and Everyday Importance

Some important roles of amines in daily life and industry include:

• Dyes and pigments: Aromatic amines are key starting materials for the synthesis of azo dyes and other colorants.
• Pharmaceuticals: A large fraction of drugs contain basic nitrogen atoms; the amine functionality influences solubility, binding to biological targets, and metabolic behavior.
• Polymers and materials: Amines serve as monomers (e.g. in polyamides and polyurethanes), curing agents for epoxy resins, and stabilizers.
• Corrosion inhibitors, flotation agents, and surfactants: Amines and especially quaternary ammonium compounds are used in a variety of technical applications.

Because of their reactivity and biological activity, safety considerations (toxicity, handling, environmental effects) are important when working with amines, particularly aromatic amines and nitrosamine-forming systems.