1.
2 Aldehydes and Ketones
1.2.6 Reactions: Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation
Addition of Hydride Reagents: Reduction
The most common method for preparing alcohols, both in the laboratory and in living organisms, is by the reduction of carbonyl
compounds. Aldehydes are reduced with sodium borohydride (NaBH4) to give primary alcohols, and ketones are similarly
reduced to give secondary alcohols.
Carbonyl reduction occurs by a typical nucleophilic addition mechanism under basic conditions.
The nucleophile is a negatively charged hydride ion (:H-) supplied by NaBH4, and the initially formed alkoxide ion intermediate is
protonated by ethanol solvent. The reaction is irreversible because the reverse process would require expulsion of a very poor
leaving group.
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1.2 Aldehydes and Ketones
1.2.6 Reactions: Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation
Addition of Grignard Reagents
Just as aldehydes and ketones undergo nucleophilic addition with hydride ion to give alcohols, they undergo a similar addition
with Grignard reagents, R:- +MgX. Aldehydes give secondary alcohols on reaction with Grignard reagents in ether solution, and
ketones give tertiary alcohols.
Like the reaction with hydride ion, a Grignard reaction takes place by a typical nucleophilic addition mechanism under basic
conditions. The nucleophile is a carbanion (R:-) from the Grignard reagent, which adds to the CO bond and produces a
tetrahedrally hybridized magnesium alkoxide intermediate. Protonation by addition of aqueous acid in a separate step then
gives the neutral alcohol. Like reduction, the Grignard reaction is irreversible.
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1.2 Aldehydes and Ketones
1.2.7 Reactions: Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation
Although widely applicable, the Grignard reaction also has limitations.
For example, a Grignard reagent can’t be prepared from an organohalide that has other reactive functional groups in the same
molecule. Some functional groups—carbonyls, for instance—cause the Grignard reagent to add to itself. Other groups—
alcohols, for instance—destroy the Grignard reagent by protonation. In general, Grignard reagents can’t be prepared
from compounds that contain the following functional groups:
Question: How can you use the addition of a Grignard reagent to a ketone to synthesize 2-phenylpropan-2-ol?
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1.2 Aldehydes and Ketones
1.2.7 Reactions: Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation
Strategy: Look at the product, and identify the groups bonded to the alcohol carbon atom. In this instance, there are two
methyl groups (-CH3) and one phenyl (-C6H5). One of the three must come from a Grignard reagent, and the remaining two
must come from a ketone. Thus, the possibilities are addition of CH3MgBr to acetophenone and addition of C6H5MgBr to
acetone.
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1.2 Aldehydes and Ketones
1.2.8 Other reactions
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1.2 Aldehydes and Ketones
1.2.9 Reactions : Oxidation
Carbonyl Group Reactions
Carbonyl groups in aldehydes and ketones may be oxidized to form compounds at the next “oxidation level”,
that of carboxylic acids.
Alcohols are oxidized to aldehydes and ketones (example: biological oxidation of ethanol to acetaldehyde)
The carbonyl group may be further oxidized to carboxylic acids
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1.2 Aldehydes and Ketones
1.2.9 Reactions : Oxidation
Aldehydes are readily oxidized to carboxylic acids by a number of reagents, including those based on Cr(VI) in aqueous
media.
Mechanistically, these reactions probably proceed through the hydrate of the aldehyde and follow a course similar to that of
alcohol oxidation.
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1.2 Aldehydes and Ketones
1.2.9 Reactions : Oxidation
Oxidation of Ketones: Baeyer–Villiger oxidation
The reaction of ketones with peroxy acids is both novel and synthetically useful. An oxygen from the peroxy acid is inserted
between the carbonyl group and one of the attached carbons of the ketone to give an ester. Reactions of this type were first
described by Adolf von Baeyer and Victor Villiger in 1899 and are known as Baeyer–Villiger oxidations.
Methyl ketones give esters of acetic acid; that is, oxygen insertion occurs between the carbonyl carbon and the
larger of the two groups attached to it.
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1.2 Aldehydes and Ketones
1.2.9 Reactions : Oxidation
The overall reaction:
Step 1: The peroxy acid adds to the carbonyl group of the ketone. This step is a nucleophilic addition analogous to gem-diol
and hemiacetal formation.
Step 2: The intermediate from step 1 undergoes rearrangement. Cleavage of the weak O—O bond of the peroxy ester is
assisted by migration of one of the substituents from the carbonyl group to oxygen. The group R migrates with its pair of
electrons in much the same way as alkyl groups migrate in carbocation rearrangements.
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1.2 Aldehydes and Ketones
1.2.9 Reactions : Oxidation
Oxidation of Ketones: Baeyer–Villiger oxidation
In general, it is the more substituted group that migrates. The migratory aptitude of the various alkyl groups is:
The reaction is stereospecific; the alkyl group migrates with retention of configuration.
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1.2 Aldehydes and Ketones
1.2.9 Reactions : Oxidation
Oxidation of Ketones: Baeyer–Villiger oxidation
As unusual as the Baeyer–Villiger reaction may seem, what is even more remarkable is that an analogous reaction occurs in
living systems. Certain bacteria, including those of the Pseudomonas and Acinetobacter type, can use a variety of organic
compounds, even hydrocarbons, as a carbon source. With cyclohexane, for example, the early stages proceed by oxidation to
cyclohexanone, which then undergoes the “biological Baeyer–Villiger reaction.”
The product (6-hexanolide) is a cyclic ester or lactone. Like the Baeyer–Villiger oxidation, an oxygen atom is inserted
between the carbonyl group and the carbon attached to it. But peroxy acids are not involved in any way; the oxidation of
cyclohexanone is catalyzed by an enzyme called cyclohexanone monooxygenase with the aid of certain coenzymes.
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