Source: Organic Chemistry, The Ohio State University
Tags: acid chloride reactions, acyl chloride, anhydride reactions, ester reactions, ester hydrolysis, saponification, lactone, Grignard reagent, organocuprate, LiAlH4 reduction, DIBAH, pyridine, acyl substitution, nucleophilic addition
Difficulty: Intermediate Prerequisites: Part 1 of these notes (mechanism and reactivity), Grignard reagents, hydride reductions, acid-base workup procedures.
Acid chlorides sit at the top of the reactivity ladder, so they can be converted into every other derivative (anhydrides, esters, amides) and also reduced to aldehydes or alcohols. Anhydrides are one step down and react with the same nucleophiles but a bit more slowly. Esters are less reactive again, requiring stronger nucleophiles or acid/base catalysis to undergo substitution. This part covers what each class reacts with, what it produces, and the reagent choices that control selectivity (e.g. getting an aldehyde instead of an alcohol from an acid chloride).
Acid chlorides react with water (to give acids), alcohols (esters), amines (amides), LiAlH4 (alcohols), LiAlH(OtBu)3 (aldehydes), Grignard reagents (tertiary alcohols), and organocuprates (ketones). Anhydrides undergo the same nucleophilic substitutions but always release a carboxylic acid as the second product. Esters are hydrolysed under basic (saponification) or acidic conditions, reduced to alcohols (LiAlH4) or aldehydes (DIBAH), and react with Grignard reagents to give tertiary alcohols. Lactones behave like esters but the leaving group stays tethered to the molecule.
Saponification
Base-promoted hydrolysis of an ester, producing a carboxylate salt and an alcohol. The equilibrium is driven to completion because the carboxylate anion is very stable and does not re-react. In simple terms, this is why soap is made from fats and lye.
Lactone
A cyclic ester. It undergoes the same reactions as an acyclic ester, but the alkoxide leaving group remains attached to the same carbon chain as the carboxylate, so the product is a hydroxy acid rather than two separate molecules.
DIBAH (diisobutylaluminium hydride)
A bulky, mild hydride source (R2Al–H) that delivers only one equivalent of H⁻ to esters or nitriles, stopping at the aldehyde stage. LiAlH4, by contrast, pushes all the way to the alcohol. Think of DIBAH as the "gentle" reducing agent you reach for when you want to stop at the aldehyde.
LiAlH(OtBu)3 (lithium tri-tert-butoxyaluminium hydride)
A sterically hindered, less nucleophilic hydride. It reacts only with very electrophilic carbonyls such as acid chlorides (not aldehydes), so it converts acid chlorides selectively to aldehydes.
Organocuprate (Gilman reagent, R'2CuLi)
A copper-based organometallic that transfers one R' group to an acid chloride, yielding a ketone and stopping there (unlike Grignard reagents, which add twice).
Acetic anhydride (Ac2O)
The anhydride of acetic acid. Commonly used as a protecting-group reagent: it converts –OH groups into acetyl esters (–OAc) and –NH2 groups into acetamides (–NHAc), shielding them from unwanted reactions.
Acid chlorides are the most reactive carboxylic acid derivatives. Every reaction below proceeds through the standard nucleophilic acyl substitution mechanism (nucleophile attacks carbonyl carbon → tetrahedral intermediate → Cl⁻ leaves). Pyridine is often added as a base to absorb the HCl generated.
1. Hydrolysis to carboxylic acids
RC(=O)Cl + H2O → RCO2H + HCl
Water acts as the nucleophile. NaOH or pyridine is typically added to neutralise the HCl produced.
2. Conversion to esters
RC(=O)Cl + R'OH → RCO2R' + HCl (pyridine as base)
The least sterically hindered alcohol reacts fastest. A base (pyridine) is added to scavenge HCl.
3. Conversion to amides
RC(=O)Cl + NH3 → RC(=O)NH2 + HCl
Primary and secondary amines work too (giving substituted amides). Tertiary amines (R3N) cannot form amides because they have no N–H proton to lose. Two equivalents of amine are needed unless pyridine is added as a separate base: one equivalent acts as nucleophile, the other neutralises HCl.
4. Reduction to alcohols (LiAlH4)
RC(=O)Cl + LiAlH4, then H2O workup → RCH2OH
LiAlH4 delivers H⁻ to the acid chloride, generating an aldehyde intermediate. Because LiAlH4 is powerful, it immediately reduces the aldehyde further to the primary alcohol. You cannot stop at the aldehyde with LiAlH4.
5. Reduction to aldehydes (LiAlH(OtBu)3)
RC(=O)Cl + LiAlH(OtBu)3, then H2O → RCHO
The bulky tert-butoxy groups make this hydride less nucleophilic, so it reacts only with the very electrophilic acid chloride and does not touch the less electrophilic aldehyde product. Solvent: Et2O or THF, low temperature.
6. Grignard addition (R'MgBr)
RC(=O)Cl + 2 eq. R'MgBr, then H2O → RC(OH)(R')2 (tertiary alcohol)
The first equivalent of Grignard converts the acid chloride to a ketone (via substitution). The ketone is still reactive toward Grignard reagents, so the second equivalent adds again, giving a tertiary alcohol with two identical R' groups. If only one equivalent is added carefully, a ketone can be isolated, but the organocuprate route below is more reliable for that purpose.
7. Organocuprate reaction (R'2CuLi)
RC(=O)Cl + R'2CuLi, –78 °C, then H2O → RC(=O)R' (ketone)
Organocuprates are less reactive than Grignard reagents, so the reaction stops cleanly at the ketone without a second addition. This is the preferred method for making ketones from acid chlorides.
Anhydrides react with the same nucleophiles as acid chlorides, but one half of the anhydride always leaves as a carboxylic acid. All examples below use acetic anhydride (Ac2O) for clarity.
With water: Ac2O + H2O → 2 CH3CO2H (two equivalents of acetic acid)
With alcohols: Ac2O + CH3OH → CH3CO2CH3 + CH3CO2H (methyl acetate + acetic acid)
With amines: Ac2O + NH3 → CH3CO(NH2) + CH3CO2H (acetamide + acetic acid)
With LiAlH4: Ac2O + LiAlH4, then H2O → CH3CH2OH (ethanol, full reduction)
Protecting-group use: Ac2O with pyridine converts a hydroxyl group (–OH) into an acetyl ester (–OAc), protecting it from further reaction. It also converts aromatic amines (–NH2) into acetamides (–NHAc). Acetylation of aniline, for example, deactivates the nitrogen before electrophilic aromatic substitution, directing substitution to the para position.
Esters are less reactive than acid chlorides and anhydrides. They generally require either acid/base catalysis for hydrolysis or strong nucleophiles (LiAlH4, Grignard) for reduction and addition.
1. Hydrolysis to carboxylic acids
(a) Basic hydrolysis (saponification):
RCO2R' + NaOH, H2O → RCO2⁻ Na⁺, then H3O⁺ workup → RCO2H + R'OH
Hydroxide attacks the carbonyl carbon, forming a tetrahedral intermediate. The alkoxide (R'O⁻) departs, giving the carboxylic acid. Under basic conditions the acid is immediately deprotonated to the carboxylate anion, pulling the equilibrium to completion. Acidic workup (H3O⁺) then regenerates the free acid.
¹⁸O-labelling evidence confirms acyl bond cleavage: when the ester oxygen between C and OR' is labelled with ¹⁸O, the label ends up in the alcohol (R'–¹⁸OH), proving the acyl C–O bond breaks.
(b) Acidic hydrolysis:
RCO2R' + H2O, H⁺ → RCO2H + R'OH
The mechanism is the reverse of Fischer esterification (same steps, opposite direction). This is an equilibrium, so excess water is needed to drive it toward hydrolysis.
2. Conversion to amides
RCO2R' + NH3, Et2O → RC(=O)NH2 + R'OH
This works but gives lower yields than the acid chloride route, so it is not commonly used in practice.
3. Reduction (LiAlH4)
RCO2R' + LiAlH4, THF, then H2O → RCH2OH + R'OH
LiAlH4 delivers H⁻, forming an aldehyde intermediate that is immediately reduced again to the primary alcohol. The alkoxide leaving group (R'O⁻) is protonated during aqueous workup to give R'OH. Two alcohols are produced.
4. Selective reduction to aldehyde (DIBAH)
RCO2R' + DIBAH, toluene, –78 °C, then H3O⁺ → RCHO
DIBAH's bulky isobutyl groups and single available hydride mean it delivers only one H⁻. At low temperature, the reaction stops at the aldehyde stage because DIBAH is not reactive enough to reduce the aldehyde further.
5. Grignard addition
RCO2R' + 2 eq. R''MgBr, Et2O, then H2O → RC(OH)(R'')2
The Grignard first converts the ester to a ketone (substitution), then the ketone reacts with a second equivalent of Grignard (addition), giving a tertiary alcohol with two identical R'' groups. Same logic as the acid chloride case.
Lactones undergo the same reactions as acyclic esters, with one key difference: the leaving group (the alkoxide fragment) remains attached to the same carbon chain as the acid portion. So hydrolysis of a lactone gives a single hydroxy acid rather than two separate molecules.
Basic hydrolysis: Lactone + NaOH, H2O, then H3O⁺ → hydroxy acid (–OH and –CO2H on the same chain)
LiAlH4 reduction: Lactone + LiAlH4, then H3O⁺ → diol (both oxygens become –OH)
DIBAH reduction: Lactone + DIBAH, –78 °C, then H2O → hydroxy aldehyde
Grignard: Lactone + 2 eq. CH3MgBr, then H2O → diol with a tertiary alcohol at the former carbonyl position
Acid chloride → acid: H2O
Acid chloride → ester: R'OH / pyridine
Acid chloride → amide: NH3 or RNH2 (need N–H)
Acid chloride → alcohol: LiAlH4, then H2O
Acid chloride → aldehyde: LiAlH(OtBu)3, then H2O
Acid chloride → tertiary alcohol: 2 eq. R'MgBr, then H2O
Acid chloride → ketone: R'2CuLi, –78 °C, then H2O
Ester → acid (basic): NaOH / H2O, then H3O⁺
Ester → acid (acidic): H3O⁺ / H2O, heat
Ester → alcohol: LiAlH4, then H2O
Ester → aldehyde: DIBAH, –78 °C, then H3O⁺
Ester → tertiary alcohol: 2 eq. R''MgBr, then H2O
Saponification is the chemistry behind soap-making: fats (which are esters of glycerol and fatty acids) are hydrolysed with NaOH to produce sodium carboxylate salts (soap) and glycerol. DIBAH reduction is widely used in the synthesis of complex natural products and pharmaceuticals whenever an aldehyde intermediate is needed without over-reduction.
Students often forget that Grignard reagents add twice to acid chlorides and esters, giving tertiary alcohols. If the question asks for a ketone, the answer is organocuprate, not Grignard.
Confusing LiAlH4 with DIBAH or LiAlH(OtBu)3 is common. LiAlH4 goes all the way to alcohol. DIBAH and LiAlH(OtBu)3 stop at the aldehyde, but each is used with a different starting material (DIBAH for esters/nitriles, LiAlH(OtBu)3 for acid chlorides).
Students sometimes think basic ester hydrolysis is an equilibrium like acidic hydrolysis. Under basic conditions, the carboxylate anion is so stable that the reaction is effectively irreversible.
With anhydrides, students forget that one half leaves as a carboxylic acid. The atom economy is poor compared to acid chlorides.
⚠️ "Give the reagent to convert an acid chloride to an aldehyde" is a classic exam question. Answer: LiAlH(OtBu)3, then H2O. Do not write LiAlH4 (that gives the alcohol).
⚠️ Know the difference between Grignard and organocuprate outcomes with acid chlorides: Grignard → tertiary alcohol, organocuprate → ketone.
⚠️ Be able to draw the full saponification mechanism, including the tetrahedral intermediate and the irreversible deprotonation step that drives the reaction to completion.
⚠️ Lactone problems test whether you recognise that the leaving group stays tethered. If you see a cyclic ester, the product is a single bifunctional molecule, not two separate fragments.
True or False: LiAlH4 reduction of an acid chloride can be stopped at the aldehyde stage.
Fill in the blank: R'2CuLi reacts with an acid chloride to give a ________.
True or False: Saponification of an ester is reversible.
Fill in the blank: DIBAH at –78 °C reduces an ester to a(n) ________.
True or False: Tertiary amines (R3N) can react with acid chlorides to form amides.
Answers: 1. False (LiAlH4 reduces through to the alcohol; use LiAlH(OtBu)3 for the aldehyde). 2. Ketone. 3. False (the carboxylate anion is too stable to re-react). 4. Aldehyde. 5. False (they have no N–H proton to lose).
Q: What product forms when benzoyl chloride is treated with (CH3)2CuLi at –78 °C, followed by aqueous workup?
A: Acetophenone (methyl phenyl ketone, C6H5COCH3). The cuprate delivers one methyl group and the reaction stops at the ketone.
Q: An ester RCO2CH2CH3 is treated with 1) NaOH, H2O, then 2) H3O⁺. Name both products.
A: The carboxylic acid RCO2H and ethanol (CH3CH2OH).
Q: Why does DIBAH reduce an ester to an aldehyde while LiAlH4 reduces it to an alcohol?
A: DIBAH is a bulky, mild hydride that delivers only one H⁻ equivalent and is not reactive enough to reduce the resulting aldehyde further. LiAlH4 is a powerful hydride with four available H⁻ equivalents, so it reduces the aldehyde intermediate immediately to the alcohol.
Q: Draw the product of treating a five-membered lactone with LiAlH4 followed by aqueous workup.
A: A 1,4-diol (a four-carbon chain with –OH at both ends). Both oxygens of the lactone are converted to hydroxyl groups.
Q: Why are two equivalents of amine needed when reacting an acid chloride with an amine without a separate base?
A: One equivalent acts as the nucleophile to form the amide; the second equivalent acts as a base to neutralise the HCl produced. Using pyridine as a separate base avoids wasting the amine.
Grignard and organocuprate chemistry here builds on the organometallic foundations from earlier chapters. DIBAH and LiAlH4 selectivity connects to the broader theme of controlling reduction levels in synthesis. Saponification links to biochemistry (lipid metabolism) and to industrial processes (soap production, biodiesel).
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