Amide

Amides, also known as organic amides or carboxamides, are a major class of organic compounds characterised by a carbonyl group directly bonded to a nitrogen atom. Represented by the general formula R–CO–NR′R″, they form a central structural motif in biological macromolecules, industrial polymers, pharmaceuticals, and a wide range of synthetic materials. Their properties derive from a combination of resonance, restricted rotation, and the ability to participate in hydrogen bonding, making amides among the most significant functional groups in organic chemistry.

Structure, Bonding, and Classification

An amide can be viewed as a derivative of a carboxylic acid, where the hydroxyl group has been replaced by an amino group. The resulting C–N linkage is known as a peptide bond when found in proteins or an isopeptide bond when formed through amino acid side chains such as those of asparagine or glutamine.
Amides are classified according to the substitution on the nitrogen atom:

• Primary amides: R–CO–NH₂
• Secondary amides: R–CO–NHR′
• Tertiary amides: R–CO–NR′R″

Cyclic amides are called lactams, which act as secondary or tertiary amides due to intrinsic ring structure.
Because of the delocalisation of the nitrogen lone pair into the carbonyl group, the amide bond has significant partial double-bond character. This resonance leads to:

• Planarity around the amide group
• Restricted rotation about the C–N bond
• A shortened C=O bond relative to ketones and esters
• A lengthened C–N bond relative to simple amines

The C–N–C–O framework is essentially planar, and the amide group exists as a resonance hybrid between a neutral form and a zwitterionic form. Infrared spectra typically show a strong C=O absorption around 1650 cm⁻¹, lower than that of aldehydes or esters due to resonance stabilisation.

Nomenclature

Amides are named by replacing the suffix –ic acid or –oic acid of the parent carboxylic acid with –amide. For example:

• CH₃CONH₂ is acetamide (IUPAC: ethanamide).
• Substituents on nitrogen are denoted using N- prefixes, such as in N,N-dimethylacetamide.

Physical Properties and Hydrogen Bonding

Amides are highly polar molecules.Primary and secondary amides can both donate and accept hydrogen bonds, leading to:

• Higher solubility in water than hydrocarbons of comparable size
• Strong intermolecular interactions
• Significant influence on protein secondary structure (e.g., α-helices and β-sheets)

Tertiary amides cannot donate hydrogen bonds and are generally less water-soluble, with notable exceptions such as dimethylformamide (DMF).

Basicity and Acid–Base Behaviour

Amides are very weak bases compared to amines. The conjugate acid of an amide typically has a pKₐ around –0.5, whereas amine conjugate acids have pKₐ values near 9.5. This reduced basicity results from electron withdrawal by the adjacent carbonyl group and resonance that delocalises charge away from nitrogen.
Under strongly acidic conditions, protonation occurs at the oxygen atom (pKₐ ≈ –1), although nitrogen protonation is also possible.

Reactions of Amides

Amides are among the most stable carbonyl derivatives. They are far less reactive than esters, anhydrides, or acid chlorides.
1. HydrolysisAmides undergo hydrolysis only under harsh conditions:

• Acidic hydrolysis forms a carboxylic acid and an ammonium salt.
• Basic hydrolysis yields a carboxylate salt and ammonia or an amine.

This resistance is biologically crucial: the peptide bond is stable in aqueous environments but can be cleaved enzymatically by peptidases.
2. Reaction with carbon nucleophilesPrimary and secondary amides are generally deprotonated by strong organometallic reagents rather than forming addition products. Tertiary amides react to give ketones after workup.
A key example is the formylation of aromatic compounds using DMF and organolithium reagents, resulting in aromatic aldehydes upon hydrolysis.
3. Other electrophilic reactionsElectrophiles preferentially attack the carbonyl oxygen in amides, often preceding hydrolysis. Lewis acids and Brønsted acids can catalyse these transformations.

Synthesis

Amides can be synthesised through several approaches:
From Carboxylic AcidsDirect condensation of a carboxylic acid with an amine requires high temperatures. More efficient alternatives use activated derivatives:

• Acid chlorides (Schotten–Baumann conditions)
• Acid anhydrides
• Esters
• Coupling reagents in peptide synthesis, e.g. HATU, PyBOP, or hydroxybenzotriazole

From NitrilesHydrolysis of nitriles provides amides as intermediates en route to carboxylic acids. This reaction is widely used industrially, especially in the production of fatty amides.
Specialty MethodsMany reagents have been developed for specific synthetic challenges, including boron-based catalysts and modern peptide-coupling auxiliaries.

Applications

Amides are central to the chemistry of life and materials:

• Proteins: peptide bonds link amino acids in all living organisms.
• Industrial polymers: polyamides such as nylon, Kevlar, and Twaron derive strength and durability from amide linkages.
• Pharmaceuticals: many drugs contain amide groups (e.g., paracetamol, penicillin, and LSD).
• Solvents: low-molecular-weight amides such as DMF and dimethylacetamide are valuable polar aprotic solvents.