Amines and Amides: Organic Nitrogen Compounds

Amines are organic derivatives of ammonia in which one or more hydrogen atoms are replaced by carbon groups, and they are basic; amides contain a carbonyl group bonded to nitrogen (RCONH₂) and are neutral. In brief: methylamine is a stronger base than ammonia (pK_a of the conjugate acid 10.6 against 9.25), a 0.10 M solution has pH 11.8, and the amide link joins amino acids into proteins.

Nitrogen compounds are found in proteins, DNA, vitamins, alkaloids and most drugs. Amines are responsible for the smell of fish and decaying flesh, and amides hold together the molecules of proteins and nylon. This article explains the classification and naming of amines and amides, their basicity, their properties and synthesis, with a table and worked examples.

What are amines?

Amines are classified by the number of carbon groups on nitrogen:

• Primary (1°): RNH₂, for example methylamine, CH₃NH₂, and aniline, C₆H₅NH₂.
• Secondary (2°): R₂NH, for example dimethylamine.
• Tertiary (3°): R₃N, for example trimethylamine.

Note that this classification differs from that of alcohols: it counts the groups attached to nitrogen, not to the carbon. The nitrogen atom is sp³ hybridized with a lone pair, giving a trigonal pyramidal shape. In names, the suffix -amine is added to the alkane name (propan-1-amine) or the alkyl groups are listed before “amine” (propylamine). The –NH₂ group as a substituent is amino-.

Primary and secondary amines form hydrogen bonds with themselves (weaker than those of alcohols, since nitrogen is less electronegative than oxygen), and tertiary amines cannot. Methylamine boils at −6.3 °C, ethylamine at 16.6 °C, propylamine at 48 °C, triethylamine at 89 °C and aniline at 184 °C. The small amines are soluble in water, with a fishy or ammonia-like smell; two diamines, putrescine and cadaverine, have the smell of decaying meat.

How basic are amines?

The lone pair on nitrogen can accept a proton: RNH₂ + H₂O ⇌ RNH₃⁺ + OH⁻. Alkyl groups donate electrons and stabilize the ammonium ion, so alkylamines are stronger bases than ammonia. In water, secondary amines are generally a bit stronger than primary ones, and tertiary amines are not much stronger than ammonia, because the ammonium ion is solvated less well. Aromatic amines are much weaker bases, since the lone pair is delocalized into the benzene ring.

Basicity of amines compared

What are the reactions of amines?

• Reaction with acids: CH₃NH₂ + HCl → CH₃NH₃⁺Cl⁻. The salts are soluble in water and are solids, which is why many amine drugs are sold as hydrochlorides.
• Acylation: primary and secondary amines react with acyl chlorides or anhydrides to form amides: CH₃NH₂ + CH₃COCl → CH₃NHCOCH₃ + HCl.
• Alkylation: amines react with haloalkanes by nucleophilic substitution, which can continue to give secondary, tertiary and quaternary ammonium salts.
• Diazotization: aniline with nitrous acid at 0–5 °C gives a diazonium salt, which is used to prepare azo dyes.
• Preparation: by reduction of nitriles or nitro compounds (nitrobenzene to aniline with tin and HCl), or by the reaction of haloalkanes with excess ammonia.

What are amides?

Amides have the group –CO–NH₂ (primary amides), –CO–NHR (secondary) or –CO–NR₂ (tertiary). They are named by replacing -oic acid with -amide: ethanamide (CH₃CONH₂). The nitrogen lone pair is delocalized into the carbonyl group (resonance), so the C–N bond has partial double-bond character (132 pm, against 147 pm for a C–N single bond), the amide group is planar and rotation around the bond is restricted. For the same reason, the nitrogen is not basic, and amides are neutral. Amides with N–H bonds form strong hydrogen bonds: ethanamide melts at 82 °C and boils at 221 °C, much higher than the corresponding acid or amine.

This planar amide link is the peptide bond of proteins: the hydrogen bonds between amide groups produce the α-helix and β-sheet structures. Nylon-6,6 is a polyamide, and paracetamol is an amide of an aminophenol.

How are amides made and hydrolyzed?

• From acyl chlorides: RCOCl + 2NH₃ → RCONH₂ + NH₄Cl (fast; two equivalents of amine are needed to take up the HCl).
• From carboxylic acids: heating the ammonium salt, RCOO⁻NH₄⁺, or with coupling agents in peptide synthesis.
• Hydrolysis: amides are hydrolyzed more slowly than esters, by heating with strong acid (giving the acid and ammonium salt) or strong base (giving the carboxylate and ammonia or amine). In the body, enzymes (proteases) do this at 37 °C.

Worked examples

Example 1: pH of a methylamine solution

Find the pH of 0.10 M methylamine (K_b = 4.4 × 10⁻⁴). K_b = x² / (0.10 − x) = 4.4 × 10⁻⁴. The ionization is about 6 %, so the small-x approximation is poor; the quadratic gives x = [−4.4 × 10⁻⁴ + √((4.4 × 10⁻⁴)² + 4 × 4.4 × 10⁻⁵)] / 2 = 6.4 × 10⁻³ M = [OH⁻]. pOH = 2.19 and pH = 11.81.

Example 2: classifying amines

(CH₃)₂NH is a secondary amine (two carbon groups on N), while (CH₃)₃N is tertiary. The compound (CH₃)₃C–NH₂ (tert-butylamine) is a primary amine, although its carbon is tertiary, because the nitrogen has only one carbon group.

Example 3: why is aniline a weaker base than cyclohexylamine?

In aniline, the nitrogen lone pair overlaps with the π system of the ring and is delocalized, so it is less available to take up a proton. In cyclohexylamine the lone pair is localized and an alkyl group donates electrons, so it is much more basic (pK_a of the conjugate acid about 10.6 against 4.6).

Example 4: making an amide

Ethanoyl chloride reacts with ethylamine to give N-ethylethanamide, CH₃CONHC₂H₅, and HCl, which is captured by a second molecule of amine as ethylammonium chloride.

Where do these compounds appear in history?

August Wilhelm von Hofmann studied amines in the 1840s and 1850s and developed methods for their preparation and for the degradation of amides that bear his name. William Henry Perkin made the first synthetic dye, mauveine, from impure aniline in 1856, which launched the synthetic dye industry. Wallace Carothers at DuPont made nylon-6,6, a polyamide, in 1935, and it was commercialized in 1938. Emil Fischer proposed the peptide bond theory of protein structure in 1902.

Which mistakes are common?

• Classifying amines like alcohols: count the carbon groups on nitrogen.
• Calling amides basic: the lone pair is delocalized.
• Forgetting that aromatic amines are weak bases: aniline’s pK_a is 4.6.
• Neglecting the second equivalent of amine in acylation: HCl forms.
• Confusing the amine and amide suffixes: -amine for the amino group on carbon, -amide for the –CONH₂ group.