Organic Chemistry · Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions
Chemistry of Amides
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An amide Carboxylic acid derivative RCONR′₂, a carbonyl bonded to nitrogen Full entry → is a carboxylic acid derivative in which the –OH of the acid is replaced by an amino group (–NR₂), giving the general formula RCONR′₂. Acetamide (CH3CONH2) is the simplest primary amide; replacing one or both N–H hydrogens gives secondary (RCONHR′) and tertiary (RCONR′₂) amides.
Amides sit at the bottom of the acyl-substitution reactivity ladder — acid chlorides and anhydrides react quickly, esters moderately, amides slowly — which is why the amide (peptide) bond can serve as the stable repeating linkage of proteins. This topic covers amide structure and resonance Delocalization of the N lone pair into the carbonyl π system Full entry →, the properties that follow (planarity, low basicity, hydrogen bonding), preparative routes, and key reactions: hydrolysis, LiAlH₄ reduction Amide → amine (RCH2NH2) Full entry →, dehydration, and the Hofmann rearrangement RCONH2 + Br2/NaOH → RNH2 with loss of one carbon Full entry →.
Why this matters
- Proteins are polyamides. The peptide bond The amide linkage between amino acid residues Full entry → joining amino acids is an amide bond (RCONH); its planarity and restricted rotation set the geometry that lets chains fold into α-helices and β-sheets.
- Drug design leans on amide stability. Acetaminophen, lidocaine, and the penicillins contain amide bonds, chosen partly because amides survive stomach acid and circulating esterases better than esters do.
- Industrial materials. Nylon and Kevlar are polyamides (Topic 9); their strength comes from amide hydrogen bonding between chains.
- Exam relevance. Reactivity rankings (acyl chloride > anhydride > ester > amide) and the amide-versus-amine basicity trap are classic test items.
The college version
Core Concepts
Structure, resonance, and the planar amide bond
In a simple amide, the nitrogen lone pair is conjugated with the carbonyl π bond. Picture the curved arrows: a curved arrow from the nitrogen lone pair toward the carbonyl carbon forms a C=N⁺ bond, and a second curved arrow from the C=O π bond moves onto oxygen, giving it a negative charge.
The consequences are geometric: the C–N bond has substantial double-bond character, so the amide group is planar and rotation about C–N is restricted (barriers of 60–90 kJ/mol). Amide rotamers (cis/trans forms) are observable in NMR, and protein backbones are locked into defined shapes.
Properties that follow from resonance
- Low basicity. The nitrogen lone pair is delocalized into the carbonyl, so amide nitrogens are nearly nonbasic: protonation occurs on oxygen, and the conjugate acid has pKa near −1. Amines, by contrast, have conjugate acids with pKa near 10 — a difference of more than ten orders of magnitude.
- Hydrogen bonding. Amide N–H groups donate hydrogen bonds; amide C=O groups accept them. Small amides are water-soluble (formamide, acetamide), boiling points are high, and the N–H···O=C pattern stitches protein strands into sheets and helices.
- A less electrophilic carbonyl. Resonance donation partially neutralizes the positive character at carbon, making amides the slowest common derivative in acyl substitution.
Preparing amides
Three standard routes, all nucleophilic acyl substitutions on the carbonyl:
- Acid chloride + amine: RCOCl + 2 R′NH2 → RCONHR′ + R′NH3⁺Cl⁻ (extra amine or a base neutralizes the HCl).
- Acid anhydride + amine: (RCO)2O + R′NH2 → RCONHR′ + RCOOH. The industrial route to acetaminophen.
- Acid + amine with a coupling agent (e.g., DCC): RCOOH + R′NH2 → RCONHR′ + H2O; the agent activates the acid so the amine can attack — the basis of peptide synthesis.
Reactions of amides
- Hydrolysis (slow; needs strong acid or base plus heat). Acid: RCONH2 + H2O + H⁺ → RCOOH + NH4⁺; base: RCONH2 + OH⁻ → RCOO⁻ + NH3. Proteases do the same selectively in biology.
- Reduction: LiAlH₄ converts amides to amines: RCONH2 → RCH2NH2. Esters under the same conditions give alcohols.
- Dehydration: P2O5 (or POCl3, SOCl2) with heat: RCONH2 → RCN + H2O.
- Hofmann rearrangement: RCONH2 + Br2 + 4 NaOH → RNH2 + 2 NaBr + Na2CO3 + 2 H2O, via an isocyanate (R–N=C=O); the amine product has one fewer carbon.
How It Works / Step-by-Step Process
Acid-catalyzed hydrolysis of an amide, step by step:
- Protonation of the carbonyl oxygen (a curved arrow from an oxygen lone pair to H⁺) makes the carbonyl carbon more electrophilic.
- Water attacks the carbon, forming a tetrahedral intermediate bearing –OH and –NH2.
- A proton transfers from the bound water oxygen to the nitrogen, converting –NH2 into the better leaving group –NH3⁺.
- The C–N bond breaks: the bond electrons move onto the nitrogen, expelling ammonia.
- Deprotonation of the carbonyl oxygen gives the carboxylic acid.
General lab-safety principle: reactions with strong acids, bases, or reactive reducing agents such as LiAlH₄ must follow your institution's chemical hygiene plan — appropriate PPE, fume hood use, and review of hazard data before starting.
Common Confusions
| Do not confuse | With | Difference |
|---|---|---|
| Amide nitrogen basicity | Amine basicity | The amide lone pair is delocalized into the C=O (conjugate acid pKa ≈ −1); amine conjugate acids have pKa ≈ 10. |
| Amide | Amine | An amide has a C=O attached to N (RCONR′₂); an amine is R₃N with no carbonyl. |
| Tertiary amide | Tertiary amine | Both have three C–N bonds, but the amide nitrogen is bonded to a carbonyl carbon. |
| Amide hydrolysis speed | Ester hydrolysis speed | Amides need strong acid/base plus heat; esters hydrolyze far more readily. |
| Peptide bond | Disulfide or glycosidic bond | Peptide = amide linkage (C–N); other protein cross-links are different functional groups. |
Eli explains
The same idea, in plain words
Explain it like I’m 10
An amide is like a Lego brick with a special clip: a carbon–oxygen clip (the carbonyl) holding onto a nitrogen piece. The nitrogen shares its extra electron "sticker" with the clip, which makes the whole piece flat and hard to twist — that's why proteins, which are chains of amide bricks, fold into neat shapes instead of tangling. Amides are also the "slow to break" Lego bricks of chemistry, which is why your body uses them to build proteins that need to last.
Worked example
Example 1: How many molecules are in 5.00 g of acetamide?
Acetamide is CH3CONH2 (M = 59.07 g/mol). The amount of substance, n, equals mass divided by molar mass:
n = mM
Substituting:
n = 5.00 g59.07 g/mol = 0.0846 mol
The number of molecules follows from Avogadro's constant:
N = n × NA = 0.0846 mol × 6.022 × 1023 mol-1 = 5.10 × 1022 molecules
Example 2: Theoretical yield from base-promoted hydrolysis
Benzamide (C7H7NO, M = 121.14 g/mol) reacts with aqueous NaOH: C7H7NO + NaOH + H2O → C6H5COO⁻Na⁺ (sodium benzoate) + NH3. How many grams of sodium benzoate (M = 144.10 g/mol) can form from 2.00 g of benzamide?
Step 1 — moles of benzamide:
n = mM = 2.00 g121.14 g/mol = 0.0165 mol
Step 2 — the stoichiometry is 1:1, so moles of sodium benzoate = 0.0165 mol.
Step 3 — mass of product:
m = n × M = 0.0165 mol × 144.10 g/mol = 2.38 g
Dimensional check: g × (mol/g) × (g/mol) = g. The theoretical yield is 2.38 g.
Key takeaways
- Amide = RCONR′₂: primary (RCONH2), secondary (RCONHR′), tertiary (RCONR′₂).
- The amide group is planar with restricted C–N rotation — the basis of peptide-bond geometry.
- Amide nitrogens are essentially nonbasic (conjugate acid pKa ≈ −1); amines are basic (pKa ≈ 10).
- Amides donate and accept hydrogen bonds via N–H and C=O → high boiling points, water solubility, protein structure.
- Reactivity order (fastest → slowest): acyl chloride > anhydride > ester > amide.
- Preparation: acid chloride + amine; anhydride + amine; acid + amine with DCC.
- Reactions: hydrolysis (needs heat), LiAlH₄ → amine, P2O5 → nitrile, Br2/NaOH → Hofmann amine (one carbon less).
Check yourself
5 review questions from the chapter. Try each one, then open the answer.
Write, in words or SMILES, a primary, a secondary, and a tertiary amide.
Show answer
Primary: CH3CONH2 (acetamide); secondary: CH3CONHCH3 (N-methylacetamide); tertiary: CH3CON(CH3)2 (N,N-dimethylacetamide).
Why is the amide group planar, and why does that matter for proteins?
Show answer
The nitrogen lone pair is conjugated with the carbonyl π bond, giving the C–N bond partial double-bond character; the amide is planar with restricted rotation. Proteins need this fixed geometry to fold into helices and sheets.
Which is more basic at nitrogen, an amide or an amine, and what is the pKa-based reason?
Show answer
An amine. An amide's lone pair is delocalized into the carbonyl (conjugate acid pKa ≈ −1), while an amine's lone pair is available for protonation (conjugate acid pKa ≈ 10).
Rank acyl chloride, ester, amide, and anhydride by reactivity toward nucleophilic acyl substitution.
Show answer
Acyl chloride > anhydride > ester > amide (fastest to slowest).
What product forms when a primary amide is treated with (a) LiAlH₄, (b) Br2 in aqueous NaOH, (c) P2O5 with heat?
Show answer
(a) Primary amine RCH2NH2; (b) primary amine RNH2 with one fewer carbon (Hofmann rearrangement, via isocyanate); (c) nitrile RCN.
Study tools & related lessonsKey vocabulary · Related
Key vocabulary
- amide
- Carboxylic acid derivative RCONR′₂, a carbonyl bonded to nitrogen
- primary/secondary/tertiary amide
- Amides with two, one, or zero N–H hydrogens
- resonance
- Delocalization of the N lone pair into the carbonyl π system
- peptide bond
- The amide linkage between amino acid residues
- Hofmann rearrangement
- RCONH2 + Br2/NaOH → RNH2 with loss of one carbon
- LiAlH₄ reduction
- Amide → amine (RCH2NH2)
Sources & references
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