Q2(c). Reduction of a carboxylic acid by LiAlH₄; chemoselectivity of NaBH₄

Introduction. LiAlH₄ is a source of nucleophilic hydride (H⁻). A carboxylic acid is reduced to the primary alcohol in four stages: acid–base reaction, hydride addition to the carboxylate, collapse to an aldehyde and a fast second reduction; water then liberates the alcohol.

Mechanism

1. Acid–base step: the acidic O–H destroys one hydride: RCOOH + LiAlH₄ → RCOO⁻ Li⁺ + AlH₃ + H₂ ↑. (Hydrogen gas is evolved; this is why excess reagent is used.)
2. Activation: aluminium (a Lewis acid) binds the carboxylate oxygens, making the carbon more electrophilic.
3. First hydride transfer (slow, rate-determining): H⁻ adds to the carboxylate carbon: a tetrahedral intermediate RCH(O-Al)₂ (an aluminium acetal).
4. Collapse: one O–Al leaves as O-Al (aluminate), giving an aldehyde RCHO (still complexed).
5. Second hydride transfer: the aldehyde is far more reactive than the carboxylate, so it is reduced at once to the alkoxide RCH₂O-Al: the aldehyde cannot be isolated.
6. Work-up: H₂O (or dilute acid) hydrolyses the Al–O bonds: RCH₂OH.

Scheme: Overall three hydrides are used per acid: one in the acid–base step and two in the reductions.

Net stoichiometry: 4 RCOOH + 3 LiAlH₄ → 4 RCH₂OH after work-up (with 4 H₂ evolved). Dry ether or THF is required: LiAlH₄ reacts violently with water.

Chemoselectivity: NaBH₄ versus LiAlH₄

4pt4ptxltabular@>X cc@ Functional group & NaBH₄ & LiAlH₄ Functional group (continued) & NaBH₄ & LiAlH₄ aldehyde, ketone → alcohol & reduced & reduced* acid chloride & reduced & reduced ester, lactone → alcohol(s) & not (or very slowly) & reduced carboxylic acid → RCH₂OH & not & reduced amide, nitrile → amine & not & reduced epoxide, alkyl halide, nitro (aliphatic) & usually not & reduced* isolated C=C, C≡C & not & not xltabular

• The Al–H bond is more polar than B–H (Al is more electropositive), so AlH₄⁻ is a much stronger, less selective hydride donor than BH₄⁻.
• Li⁺ is a stronger Lewis acid than Na⁺ and activates C=O further; NaBH₄ can even be used in water or ethanol.

Example: methyl 4-oxopentanoate, CH₃COCH₂CH₂CO₂CH₃. NaBH₄ in methanol reduces only the ketone (methyl 4-hydroxypentanoate, which cyclises to γ-valerolactone); LiAlH₄ reduces both groups (pentane-1,4-diol). So NaBH₄ is chemoselective: it distinguishes aldehydes and ketones from esters, acids, amides and nitriles; LiAlH₄ reduces almost every polar multiple bond.

Conclusion. LiAlH₄ first deprotonates the acid (H₂ evolved), then adds hydride to the carboxylate; the tetrahedral intermediate collapses to an aldehyde, which is reduced at once; hydrolysis gives RCH₂OH. NaBH₄ is milder and chemoselective: it reduces aldehydes and ketones but leaves acids, esters, amides and nitriles untouched.

Application. NaBH₄ is used in the manufacture of drugs (reduction of ketone intermediates in the presence of esters) and in bleaching wood pulp; LiAlH₄ is the laboratory reagent for making primary alcohols and amines from acids, esters and amides.