Source: Organic Chemistry, The Ohio State University
Tags: amide hydrolysis, amide reduction, lactam, nitrile preparation, nitrile hydrolysis, nitrile reduction, Grignard addition to nitrile, thiol ester, acetyl CoA, peptide bond, dehydration, SN2 cyanide displacement, DIBAH nitrile reduction, imine intermediate
Difficulty: Intermediate Prerequisites: Parts 1 and 2 of these notes, acid-base chemistry, SN2 reactions, LiAlH4 reduction basics.
Amides are the least reactive carboxylic acid derivatives because nitrogen donates electron density into the carbonyl through resonance, and the amide nitrogen anion (R2N⁻) is a very poor leaving group. This low reactivity is exactly what makes them the backbone linkage in proteins (peptide bonds). Nitriles (R–C≡N) are not technically carboxylic acid derivatives, but they sit at the same oxidation level and are easily converted into acids, amides, aldehydes, ketones, and amines, so they are covered in the same chapter. Thiol esters round out the picture as biologically critical derivatives whose reactivity falls between anhydrides and oxygen esters.
Amides require harsh conditions (strong acid or base with heat) for hydrolysis and are reduced by LiAlH4 to amines, not alcohols. Nitriles can be prepared by SN2 displacement with cyanide or by dehydration of amides, and they react with water (hydrolysis to acids), LiAlH4 (amines), DIBAH (aldehydes), and Grignard reagents (ketones). Thiol esters are important in biochemistry, with acetyl coenzyme A being the prime example.
Amide (carboxamide)
RC(=O)NR'2. The least reactive carboxylic acid derivative due to strong N-to-C=O resonance donation and the poor leaving-group ability of R2N⁻. In simple terms, nitrogen shares its lone pair so generously with the carbonyl that the C=O is much less electrophilic than in other derivatives.
Peptide bond
The amide linkage (–C(=O)–NH–) that connects amino acids in proteins. Its stability under physiological conditions is precisely because amides resist hydrolysis without enzyme catalysis.
Lactam
A cyclic amide. Reduced by LiAlH4 to a cyclic amine, with the ring intact. Think of it as the nitrogen analogue of a lactone.
Nitrile (R–C≡N)
A functional group with a carbon-nitrogen triple bond. The carbon is electrophilic (δ+) and the nitrogen is nucleophilic and basic (δ−). Nitriles sit at the same oxidation level as carboxylic acids and can be hydrolysed to them.
Imine
R2C=NR'. An intermediate formed during nitrile reduction (DIBAH or Grignard) or amide reduction (LiAlH4). Imines hydrolyse to carbonyls in the presence of water.
Thiol ester (thioester)
RC(=O)–SR'. The sulfur analogue of an oxygen ester. More reactive than oxygen esters because RS⁻ is a better leaving group (pKa of RSH is around 10, compared to around 16 for ROH).
Acetyl coenzyme A (acetyl CoA)
A thiol ester that serves as the primary acetylating agent in biological systems. It transfers acetyl groups in metabolic pathways including the citric acid cycle and fatty acid synthesis.
Amides are the least reactive carboxylic acid derivatives. The nitrogen lone pair delocalises strongly into the carbonyl (resonance), which reduces the electrophilicity of the carbonyl carbon and makes R2N⁻ a very poor leaving group (pKa of NH3 is around 33, compared to around 16 for H2O and around −7 for HCl).
1. Hydrolysis to carboxylic acids
(a) Acidic hydrolysis:
RC(=O)NH2 + H3O⁺, heat → RCO2H + NH4⁺
Conditions are more severe than for esters: prolonged heating with strong acid is required. The mechanism follows the same general pattern (protonation of carbonyl oxygen, nucleophilic attack by water, proton transfers, loss of amine), but extra proton-transfer steps are needed because the nitrogen must be fully protonated to become a good enough leaving group (NH3 rather than NH2⁻). The released ammonia is protonated by the acidic medium to give NH4⁺.
(b) Basic hydrolysis:
RC(=O)NH2 + NaOH, H2O, heat → RCO2⁻ + NH3, then H3O⁺ workup → RCO2H
Hydroxide attacks the carbonyl carbon, forming a tetrahedral intermediate. The amide nitrogen departs as NH2⁻, which is immediately protonated to NH3. The carboxylic acid formed is deprotonated by the basic medium to the carboxylate anion, driving the equilibrium to completion.
Both pathways require heat because the amide C–N bond is strong and the leaving group is poor.
2. Reduction to amines (LiAlH4)
RC(=O)NH2 + LiAlH4, then H2O → RCH2NH2 (a primary amine)
This is a distinctive reaction: LiAlH4 reduces an amide to an amine, not an alcohol. The reason is that RO⁻ is a far better leaving group than R2N⁻. In the tetrahedral intermediate, the C–O bond breaks preferentially (the oxygen leaves as part of an aluminium alkoxide complex), and the nitrogen stays bonded to carbon. A second hydride delivery then reduces the resulting imine to the amine.
The key comparison: esters reduced with LiAlH4 give alcohols (oxygen stays, alkoxide leaves). Amides reduced with LiAlH4 give amines (nitrogen stays, oxygen leaves). This difference comes down to leaving-group ability.
3. Cyclic amides: lactams
Lactams are reduced by LiAlH4 to cyclic amines with the ring intact.
Example: a five-membered lactam treated with LiAlH4 then H2O gives a five-membered cyclic amine (pyrrolidine derivative), where the former C=O becomes a CH2 group.
1. SN2 displacement with cyanide
R–X + NaCN, Et2O → R–C≡N + NaX
Cyanide ion (C≡N⁻) is a good nucleophile. It displaces a halide from an alkyl halide via SN2. The usual SN2 limitations apply: works best with primary and methyl substrates, fails with tertiary substrates (elimination dominates), and proceeds with inversion of configuration at the carbon bearing the leaving group.
This reaction extends the carbon chain by one carbon, which is useful in synthesis planning.
2. Dehydration of amides
RC(=O)NH2 + SOCl2, benzene, 80 °C → R–C≡N + SO2 + 2 HCl
The amide loses water (in the form of SO2 and HCl by-products) to form the nitrile. SOCl2 activates the oxygen of the amide as a good leaving group, and after loss of a proton the nitrogen forms the triple bond to carbon.
Other dehydrating agents that work: P2O5, POCl3, and Ac2O.
This method is very general because amides are easy to make from acid chlorides and amines.
The C≡N bond is polarised: carbon is δ+ (electrophilic) and nitrogen is δ− (nucleophilic/basic). Nucleophiles attack the carbon; electrophiles (including protons) attack the nitrogen.
1. Hydrolysis to carboxylic acids
(a) Acidic hydrolysis:
R–C≡N + H3O⁺, heat → (goes through amide intermediate) → RCO2H + NH4⁺
H⁺ protonates the nitrogen, activating the carbon for water attack. After several proton-transfer and tautomerisation steps, an amide is formed as an intermediate, which is then hydrolysed further to the carboxylic acid under the same acidic conditions.
(b) Basic hydrolysis:
R–C≡N + NaOH, H2O, heat, then H3O⁺ → RCO2H
Hydroxide attacks the electrophilic carbon. After proton transfers and tautomerisation, the nitrile passes through an amide intermediate and is ultimately hydrolysed to the carboxylate, which is protonated during acidic workup.
In both cases the nitrile passes through an amide on its way to the carboxylic acid.
2. Reduction to amines (LiAlH4)
R–C≡N + LiAlH4, then H2O → RCH2NH2
LiAlH4 delivers H⁻ to the electrophilic carbon of the nitrile. The first equivalent reduces the triple bond to a double bond (forming an imine-aluminium complex). A second H⁻ then reduces the C=N to a C–N single bond. Aqueous workup releases the free primary amine.
This is a two-carbon-to-nitrogen reduction, converting a C≡N all the way down to CH2–NH2.
3. Selective reduction to aldehyde (DIBAH)
R–C≡N + DIBAH, then H2O → RCHO
DIBAH delivers only one H⁻, reducing the triple bond to a double bond (imine). On aqueous workup, the imine hydrolyses to the aldehyde plus ammonia. The carbonyl group is thermodynamically favoured over the imine at equilibrium, so the product is the aldehyde.
4. Grignard addition to nitrile
R–C≡N + R'MgBr, then H2O → RC(=O)R' (ketone)
The Grignard reagent adds R' to the electrophilic carbon of the nitrile, forming an imine salt (with MgBr as counterion). Aqueous workup hydrolyses the imine to the ketone.
This is an alternative to Friedel-Crafts acylation for making ketones. Only one equivalent of Grignard is needed because the imine intermediate is not reactive enough toward a second Grignard addition under these conditions.
Structure: RC(=O)–SR'
Thiol esters are more reactive than oxygen esters because RS⁻ is a better leaving group than RO⁻. The pKa of RSH is around 10 (thiols are more acidic than alcohols), so RS⁻ is more stable and departs more readily.
Their reactivity sits between anhydrides and oxygen esters in the overall hierarchy.
Biological importance:
Acetyl coenzyme A (acetyl CoA) is the most important thiol ester in biochemistry. It acts as an acetyl-group donor in the citric acid cycle, fatty acid biosynthesis, and many other metabolic pathways.
The thiol ester linkage is reactive enough for enzyme-catalysed acyl transfer yet stable enough to survive the aqueous cellular environment without spontaneous hydrolysis.
Amide → acid (acidic): H3O⁺, heat
Amide → acid (basic): NaOH, H2O, heat, then H3O⁺
Amide → amine: LiAlH4, then H2O
Lactam → cyclic amine: LiAlH4, then H2O
Amide → nitrile: SOCl2, 80 °C (or P2O5, POCl3, Ac2O)
Nitrile preparation: R–X + NaCN (SN2)
Nitrile → acid (acidic): H3O⁺, heat
Nitrile → acid (basic): NaOH, H2O, then H3O⁺
Nitrile → amine: LiAlH4, then H2O
Nitrile → aldehyde: DIBAH, then H2O
Nitrile → ketone: R'MgBr, then H2O
Every peptide bond in every protein in your body is an amide linkage. The fact that amides resist hydrolysis under mild conditions is what keeps proteins stable at body temperature; breaking them requires either enzymes (proteases) or harsh lab conditions. Nitrile chemistry is central to the industrial production of nylon (adiponitrile is a key precursor) and many pharmaceutical intermediates. Acetyl CoA sits at the crossroads of metabolism, connecting carbohydrate, fat, and protein energy pathways.
Students often assume LiAlH4 reduces amides to alcohols, by analogy with esters. It does not. Amides give amines because the oxygen leaves (as an aluminium alkoxide), not the nitrogen. The nitrogen stays bonded to carbon throughout.
Nitrile hydrolysis passes through an amide intermediate. Students sometimes draw a direct one-step conversion of nitrile to acid, skipping the amide. Examiners may ask you to show or identify the intermediate.
Students confuse DIBAH reduction of a nitrile (gives aldehyde) with LiAlH4 reduction of a nitrile (gives amine). DIBAH stops at the imine/aldehyde level; LiAlH4 pushes through to the amine.
Tertiary amines (R3N) cannot form amides from acid chlorides because they lack an N–H proton. Students sometimes forget this restriction when planning a synthesis.
⚠️ "LiAlH4 + amide → amine" is one of the most commonly tested reductions. Be prepared to explain why the nitrogen stays (RO⁻ is a better leaving group than R2N⁻, based on pKa values: H2O around 16, NH3 around 33).
⚠️ Know that nitrile hydrolysis goes through an amide intermediate, regardless of whether conditions are acidic or basic. This is a frequent short-answer question.
⚠️ Grignard addition to a nitrile produces a ketone (via imine hydrolysis). This is distinct from Grignard addition to an acid chloride, which gives a tertiary alcohol (two equivalents add).
⚠️ Nitrile preparation via SN2 with NaCN extends the carbon chain by one. Synthesis problems often use this to build a longer chain.
⚠️ The dehydration of an amide to a nitrile (SOCl2 or P2O5) is the reverse conceptual pathway to nitrile hydrolysis. Being able to move in both directions is useful in retrosynthetic analysis.
True or False: LiAlH4 reduces an amide to an alcohol.
Fill in the blank: Nitrile hydrolysis proceeds through a(n) ________ intermediate before reaching the carboxylic acid.
True or False: DIBAH reduces a nitrile to a primary amine.
Fill in the blank: Acetyl CoA is an example of a ________ ester.
True or False: Treating a nitrile with R'MgBr followed by aqueous workup gives a tertiary alcohol.
Answers: 1. False (it gives an amine). 2. Amide. 3. False (DIBAH gives an aldehyde via imine hydrolysis). 4. Thiol. 5. False (it gives a ketone; only one R' group adds).
Q: Why does LiAlH4 reduction of an amide give an amine rather than an alcohol?
A: In the tetrahedral intermediate, the C–O bond breaks preferentially because RO⁻ (as an aluminium alkoxide) is a far better leaving group than R2N⁻. The nitrogen remains bonded to carbon throughout, and the resulting imine is reduced by a second hydride to give the amine.
Q: Write the overall equation for acidic hydrolysis of benzamide (C6H5CONH2).
A: C6H5CONH2 + H3O⁺ (heat) → C6H5CO2H + NH4⁺
Q: A student needs to convert toluene (C6H5CH3) into phenylacetic acid (C6H5CH2CO2H). Propose a two-step synthesis using a nitrile intermediate.
A: Step 1, treat benzyl bromide (C6H5CH2Br, obtained by benzylic bromination of toluene) with NaCN to give phenylacetonitrile (C6H5CH2CN) via SN2. Step 2, hydrolyse the nitrile with H3O⁺ and heat (or NaOH/H2O then H3O⁺) to give phenylacetic acid.
Q: What is the product of treating cyclohexanecarbonitrile with DIBAH followed by aqueous workup?
A: Cyclohexanecarbaldehyde (the nitrile is reduced to an aldehyde).
Q: Why are thiol esters more reactive than oxygen esters?
A: RS⁻ is a better leaving group than RO⁻ because thiols (pKa around 10) are more acidic than alcohols (pKa around 16), so the thiolate anion is more stable. This makes the carbonyl carbon of a thiol ester more susceptible to nucleophilic attack.
Q: A lactam is treated with LiAlH4 followed by aqueous workup. What functional group does the product contain?
A: A cyclic amine. The carbonyl oxygen is removed and replaced by two hydrogens (CH2), and the ring nitrogen is retained.
Amide hydrolysis connects to biochemistry: protease enzymes catalyse the cleavage of peptide (amide) bonds that would otherwise be too stable to break under physiological conditions. Nitrile chemistry links back to SN2 reactions (Ch. 7/8) for preparation and to carbonyl chemistry (Ch. 19) for the imine intermediates seen in reductions and Grignard additions. Thiol esters bridge organic chemistry and metabolism, appearing in nearly every biochemistry course when the citric acid cycle and fatty acid synthesis are covered.
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