Nitrile Acid Hydrolysis

Nitrile Reactions: Acid Hydrolysis to Carboxylic Acid

Treatment of a nitrile (R-CN) with aqueous acid and heat converts the C≡N triple bond completely to a carboxylic acid (R-COOH) plus ammonium ion (NH4+). The mechanism proceeds through two sequential addition-elimination sequences: first, water adds to the protonated nitrile to form an amide intermediate; then, a second water molecule adds to the protonated amide, which collapses to release ammonia and produce the carboxylic acid. This is a reliable, high-yielding transformation used to convert cyano groups installed via nucleophilic substitution into carboxylic acids.


Key Emphasis (Teaching Pivots)

  • Full hydrolysis requires heat. Unlike milder conditions that stop at the amide, acid + heat drives the reaction all the way to the carboxylic acid.
  • Amide is an intermediate. The mechanism passes through a protonated amide (imidic acid → amide → tetrahedral intermediate → carboxylic acid). This two-stage hydrolysis is key to understanding the full mechanism.
  • Nitrogen leaves as NH4+. The nitrile nitrogen is released as ammonia, which is immediately protonated to ammonium ion under acidic conditions.
  • Compare to base hydrolysis. OH-/heat also hydrolyzes nitriles to carboxylic acids (as carboxylate salts), but the mechanism differs: base attacks directly rather than requiring protonation first.

Quick Summary

FeatureDetails
TransformsR-CN → R-COOH
ReagentsH3O+, heat (or conc. H2SO4/H2O, reflux)
ProductCarboxylic acid + NH4+
Key featureAmide intermediate; two hydrolysis stages
  • Reagents/conditions: Dilute or concentrated aqueous acid (HCl, H2SO4), reflux/heat.
  • Outcome: R-CN + 2 H2O + H+ → R-COOH + NH4+. The nitrile is fully hydrolyzed.
  • Intermediate: The reaction passes through an amide stage, but under acidic heat conditions this is not isolated.
  • Comparison: NaOH/heat also works (gives carboxylate salt); DIBAL-H stops at aldehyde; LiAlH4 gives primary amine.

Mechanism - Two-Stage Hydrolysis (7 Steps)

The mechanism involves two nucleophilic addition-elimination sequences. First, water adds to the protonated nitrile to form an amide. Then, water adds to the protonated amide, which collapses to give the carboxylic acid.

Step 1: H3O+ protonates nitrile nitrogen
Step 1 - Protonate nitrile nitrogen. H3O+ protonates the nitrile nitrogen, placing a positive charge on N and making the nitrile carbon highly electrophilic.
Step 2: Water attacks electrophilic nitrile carbon
Step 2 - Water attacks nitrile carbon. A water molecule attacks the electrophilic nitrile carbon. One pi bond shifts to nitrogen, forming a C=N single bond and an oxonium intermediate.
Step 3: Proton transfer gives amide
Step 3 - Proton transfer (tautomerization). Proton transfer from oxygen to nitrogen, mediated by water, converts the imidic acid tautomer to the more stable amide form (R-C(=O)-NH2).
Step 4: Water attacks protonated amide carbonyl
Step 4 - Water attacks protonated amide. H2O attacks the electrophilic carbonyl carbon of the protonated amide. The pi bond shifts to oxygen, forming a tetrahedral intermediate.
Step 5: C-N bond breaks, NH3 leaves
Step 5 - C-N bond breaks; NH3 leaves. The tetrahedral intermediate collapses: C-N bond breaks as NH3 leaves (protonated to NH4+ in solution), and C=O reforms to give the protonated carboxylic acid.
Step 6: Deprotonation of protonated carbonyl
Step 6 - Deprotonation. Water deprotonates the protonated carbonyl oxygen, neutralizing the positive charge and forming the carboxylic acid.
Step 7: Final product - carboxylic acid
Step 7 - Product. The final carboxylic acid product (R-COOH).

Mechanistic Checklist (Exam Focus)

  • Protonate first. Under acidic conditions, always show protonation of the nitrile nitrogen before water attacks.
  • Show the amide intermediate. The mechanism passes through an amide; recognize this as the halfway point.
  • Protonate the amide. The second hydrolysis requires protonation of the amide carbonyl oxygen.
  • Track nitrogen fate. NH2 becomes NH3+ (good leaving group) and departs as NH3, immediately protonated to NH4+ in acid.
  • Two addition-elimination sequences. First: nitrile → amide. Second: amide → carboxylic acid.

Worked Examples

Example A - Propanenitrile → Propanoic acid. Refluxing propanenitrile (CH3CH2CN) with dilute H2SO4 gives propanoic acid.
Example A reactant: propanenitrile
Reactant
Reagent: H3O+ heat
Reagent
Example A product: propanoic acid
Product
Example B - Benzonitrile → Benzoic acid. Benzonitrile hydrolysis gives benzoic acid. The aromatic ring is unaffected.
Example B reactant: benzonitrile
Reactant
Reagent: H3O+ heat
Reagent
Example B product: benzoic acid
Product
Example C - Mandelonitrile → Mandelic acid. The alpha-hydroxy nitrile (cyanohydrin) hydrolyzes to an alpha-hydroxy acid. The OH group survives acid conditions.
Example C reactant: mandelonitrile
Reactant
Reagent: H3O+ heat
Reagent
Example C product: mandelic acid
Product

Scope & Limitations

  • Works well: Simple alkyl nitriles, aryl nitriles, cyanohydrins (give alpha-hydroxy acids).
  • Functional groups tolerated: Aromatic rings, ethers, halogens (unless they undergo competing hydrolysis), alcohols.
  • Sensitive groups: Acetals, epoxides, and other acid-labile groups will be cleaved under these conditions.
  • Stereochemistry: Chiral centers alpha to the nitrile are generally retained (no epimerization at the alpha carbon).
  • Alternative: Base hydrolysis (NaOH/heat) also works and gives the carboxylate salt directly.

Edge Cases & Exam Traps

  • Stopping at amide: Milder conditions (lower temperature, shorter time) can stop at the amide. Full conversion to carboxylic acid requires prolonged heating.
  • Cyanohydrin trap: Cyanohydrins (alpha-hydroxy nitriles) can revert to aldehyde + HCN under certain conditions. Under acidic hydrolysis with heat, they typically give alpha-hydroxy acids.
  • Base vs acid: NaOH/heat gives the carboxylate (requires acid workup for neutral carboxylic acid). H3O+/heat gives the carboxylic acid directly.
  • DIBAL-H confusion: DIBAL-H at -78 C stops at aldehyde. LiAlH4 gives primary amine. Only H3O+/heat or OH-/heat gives carboxylic acid.
  • Two-step synthesis: Alkyl halide + NaCN → nitrile; then H3O+/heat → carboxylic acid. This is a common one-carbon homologation sequence.

Practical Tips

  • Full conversion: Reflux for several hours in dilute H2SO4 or HCl to ensure complete hydrolysis past the amide stage.
  • Product isolation: The carboxylic acid can be extracted into organic solvent after neutralizing the reaction mixture.
  • Monitor by TLC: The amide intermediate can be detected; continue heating until it disappears.
  • Scale considerations: Large-scale reactions may require longer reflux times due to heat transfer limitations.

Exam-Style Summary

R-CN + H3O+/heat → R-COOH + NH4+. The mechanism involves two addition-elimination sequences: first converting the nitrile to an amide, then converting the amide to the carboxylic acid. Key intermediates are the protonated nitrile, imidic acid/amide, and tetrahedral intermediate. Nitrogen is expelled as ammonia (protonated to NH4+).


Interactive Toolbox

  • Mechanism Solver - Enter any nitrile and see the full 7-step mechanism for acid hydrolysis to carboxylic acid.
  • Reaction Solver - Provide a nitrile and predict the carboxylic acid product.
  • IUPAC Namer - Name the carboxylic acid products.