Ketones

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Chapter: Organic Chemistry : Functional Group Synthesis

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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