10.6
Alcohols from Carbonyl Compounds: Reduction
Reduction is a simple strategy to convert a carbonyl group to a hydroxyl group. The three major pathways to reduce carbonyls to alcohols are catalytic…
Alcohols can be prepared from carbonyl compounds by adding two hydrogen atoms across the double bond.
This reduction is important in the synthesis of essential molecules like the perfume ingredient muscone and the antidepressant drug Prozac.
While aldehydes, carboxylic acids, and esters are reduced to primary alcohols, ketones are reduced to secondary alcohols.
The classical method involves catalytic hydrogenation using hydrogen and transition-metal catalysts. However, this requires high temperature and pressure and also reduces any carbon–carbon multiple bonds present in the molecule.
The laboratory method involves the stepwise addition of nucleophilic hydride ions from sodium borohydride, lithium aluminum hydride, and their derivatives, in an irreversible reaction, followed by protonation with solvent or acid. This method selectively reduces the carbonyl group in comparison to hydrogenation.
In unsymmetrical ketones, the planar carbonyl group can undergo a nucleophilic hydride attack from either face with equal probability. This generates a chiral tetrahedral intermediate, giving a pair of enantiomeric products.
Reduction by sodium borohydride is carried out in polar protic solvents. Lithium aluminum hydride, on the other hand, needs dry, aprotic solvents to avoid its violent reaction with proton donors.
Lithium aluminum hydride is a stronger reducing agent—and hence, more reactive—than sodium borohydride due to the greater polarity of the aluminum–hydrogen bond compared to the boron–hydrogen bond.
This reactivity difference is reflected in the ease with which different carbonyl groups undergo selective reduction by the two hydride reagents.
To illustrate, sodium borohydride can selectively reduce a ketone in the presence of an ester, unlike lithium aluminum hydride that does not allow for selective reduction of the ketone group.
Lithium borohydride and borane are useful reagents with opposite chemoselectivity in reducing esters and acids, respectively.
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Q1: What are the main methods for reducing carbonyl compounds to alcohols?
Three major pathways exist: catalytic hydrogenation using transition metal catalysts like Raney Ni or Pd–C under mild to moderate heat and pressure; hydride reduction using sodium borohydride or lithium aluminum hydride as nucleophilic reagents; and borane reduction using borane solutions to selectively reduce electron-rich carbonyl groups. Each method offers different selectivity and reactivity profiles for various functional groups.
Q2: How does sodium borohydride differ from lithium aluminum hydride in carbonyl reduction?
Lithium aluminum hydride is a stronger reducing agent due to greater polarity of the aluminum–hydrogen bond, making it more reactive and capable of reducing aldehydes, ketones, esters, acids, and acyl chlorides. Sodium borohydride is milder and selectively reduces aldehydes and ketones in the presence of esters, alkyl halides, and nitro groups. LAH requires dry aprotic solvents and reacts violently with water, while NaBH4 works in protic solvents like ethanol.
Q3: What products form when aldehydes and ketones undergo reduction?
Aldehydes are reduced to primary alcohols, while ketones are reduced to secondary alcohols. In unsymmetrical ketones, the planar carbonyl group can undergo nucleophilic hydride attack from either face with equal probability, generating a chiral tetrahedral intermediate and producing a pair of enantiomeric products as a racemic mixture.
Q4: Why is catalytic hydrogenation less selective than hydride reduction?
Catalytic hydrogenation adds hydrogen across the carbonyl double bond but also reduces any carbon–carbon multiple bonds present in the molecule, making it non-selective. Hydride reduction from sodium borohydride or lithium aluminum hydride selectively targets the carbonyl group through nucleophilic attack, leaving other functional groups intact depending on the reagent's reactivity profile.
Q5: How does the hydride reduction mechanism proceed after nucleophilic attack?
Nucleophilic hydride attack forms alkoxide ions as the first step. The byproduct alkoxyborohydride or alkoxyaluminate then reduces three additional carbonyl molecules by successively transferring all hydrogen atoms. Since hydride is a poor leaving group, these hydride transfer steps are irreversible, driving the reaction to completion. The reaction mixture is then worked up with solvent or acid to protonate the alkoxide.
Q6: What is the advantage of borane reduction for selective carbonyl reduction?
Borane reduction selectively reduces electron-rich carbonyl groups like carboxylic acids in the presence of other reducible functional groups such as esters and even ketones. The formation of a reactive triacylborate intermediate with a more electrophilic carbonyl group than the starting ester molecule drives the reduction reaction forward, enabling chemoselectivity unavailable with other hydride reagents.
Q7: Why must lithium aluminum hydride be used in aprotic solvents?
Lithium aluminum hydride reacts violently with water and other protic solvents, liberating hydrogen gas and forming metal hydroxides or alkoxides. To prevent this dangerous decomposition and maintain the reagent's reducing power, LAH reductions are carried out in dry aprotic solvents like anhydrous diethyl ether or THF, ensuring safe and effective carbonyl reduction.