Ketones have the same oxidation level as aldehydes, but their preparation poses far fewer problems. Most importantly they are very resistant to oxidation so they can be prepared by any number of oxidative routes without difficulty.
KETONES
Ketones
have the same oxidation level as aldehydes, but their preparation poses far
fewer problems. Most importantly they are very resistant to oxidation so they
can be prepared by any number of oxidative routes without difficulty. Textbook
preparations of ketones are listed below and many of these traditional methods
remain the methods of choice for the preparation of ketones:
One
of the most common methods for the preparation of ketones is by the oxidation
of secondary alcohols. The use of chromic acid (Jones reagent) is easy, safe,
and effective for the oxidation of secondary alcohols to ketones. Furthermore
Jones reagent gives a nearly neutral solution and thus can be used with a
variety of acid-sensitive functional groups.
Sodium
hypochlorite (household bleach) and acetic acid offers a very cheap and
effective alternative to Jones reagent for the oxidation of secondary alcohols
to ketones and has been widely used for the synthesis of ketones.
If
very mild and/or basic conditions are required, PCC is the reagent of choice
and works very well.
There
are many other reported methods for
the oxidation of secondary alco-hols to ketones; in fact, over 140 different
methods are listed in Comprehensive Organic Transformations by Larock.
However, few are as versatile and useful as
those listed above.
Conversion
of carboxylic acid derivatives to ketones requires a net reduction of oxidation
level. Furthermore, since the two groups attached to the carbonyl group are
carbon-containing groups, it follows that a carbon nucleophile must be the
reductant, usually an organometallic reagent. Carboxylic acid derivatives such
as esters, acid chlorides, and acid anhydrides do not stop at the ketone
oxidation level upon reaction with most organometallic reagents but are further
reduced to tertiary alcohols. (This same problem of overreduction was seen for
aldehyde preparation.) However, carboxylic acids themselves react smoothly with
organolithium reagents to furnish ketones upon hydrolytic workup. This method
is an effective way to produce ketones. A key to the success of this reaction
is the fact that the tetrahedral intermediate is a dianion which is stable to
further addition. Only organolithium reagents are useful in this process for
only they are powerful enough nucleophiles to add to the very weakly
electrophilic carbonyl group of the carboxylate anion.
As
with aldehydes, production of ketones by nonredox processes is not a common
synthetic approach. Ketone derivatives having the same oxidation level are
usually produced from ketones themselves. Several examples of enol and acetal
ketone derivatives are shown below. All are prepared from ketones, all can be
readily hydrolyzed back to the ketone in the presence of acidic water, and,
with the exception of vinyl acetates, all are very stable to strong bases and
nucleophiles. Acetals are often used as ketone (and aldehyde) protecting groups
while enol derivatives are versatile synthetic intermediates.
One
hydrolytic method that is useful for the preparation of ketones is the
hydrol-ysis of dithianes. 1.3-Dithiane can be alkylated by treatment with butyl
lithium followed by an alkylating agent. The two sulfurs flanking the acetal
carbon acidify the protons on that carbon such that butyl lithium can remove
one giving a sulfur-stabilized anion. This anion reacts with alkyl halides or
sulfonates to give alkylated products. This sequence can be repeated to give a
bis-alkylated product. Hydroly-sis then yields a ketone. Dithioacetals are much
more resistant to hydrolysis than acetals and thus Hg2+ is often used to
promote efficient hydrolysis.
The acidifying effect of the sulfur atoms is an interesting phenomenon. It is not due to electronegativity since the corresponding 1,3-dioxane, which has even more electronegative oxygen atoms flanking the acetal carbon, cannot be converted to an anion by butyl lithium. The sulfur atoms have unfilled valence level d orbitals available that can accept electron density and thus stabilize an adjacent anion. One can consider the anion as being resonance stabilized with the negative charge being delocalized into the flanking sulfur atoms.
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