Halogenation a to Carbonyl Groups

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

The reaction can also be effected with hypochlorite ion, and this constitutes a useful method for converting methyl ketones to carboxylic acids. 

The most common preparative procedures involve use of the halogen, usually bromine, in acetic acid. Other suitable halogenating agents include IV-bromosuccinimide, tetrabromocyclohexadienone, and sulfuryl chloride. 

Chakabartty, in Oxidations in Organic Chemistry, Part C, W. Trahanovsky, ed., Academic Press, New York, 1978, Chap. V. 

Electrophilic Additions to Carbon-Carbon Multiple Bonds 

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Halogens a to carbonyl groups can be successfully coupled using organocopper reagents. For example, 3,9-dibromocamphor is selectively arylated a to the carbonyl. 

Don t forget that halogenation of the a-position of many carbonyl compounds can be accomplished via their enolates (Section 17.4, Figure 20.12). Halogens a to carbonyl groups are also particularly easy to displace (Section 9.6.2). 

Halogenation of a- to Carbonyl Groups. Regioselective a-bromination or chlorination of unsymmetrical ketones at the more substituted -position has been demonstrated with trimethylsilyl halides in DMSO the halogenating species is presumed to be the... 

The facilitation of the C-halogen bond reduction by a neighboring carbonyl group is due to the imposed donor character of the a-carbon, and by extension, the heightened acceptor character of the halogen atom. 

In a general sense, the Reformatsky reaction can be taken as subsuming all enolate formations by oxidative addition of a metal or a low-valent metal salt into a carbon-halogen bond activated by a vicinal carbonyl group, followed by reaction of the enolates thus formed with an appropriate electrophile (Scheme 14.1).1-3 The insertion of metallic zinc into a-haloesters is the historically first and still most widely used form of this process,4 to which this chapter is confined. It is the mode of enolate formation that distinguishes the Reformatsky reaction from other fields of metal enolate chemistry. 

On principle, both the hydroxamic acid and the hemiacetal are partially oxidised structures. Thus, the hydroxamic acid should be accessible both from a nitro precursor by reductive cyclisation and from a lactam by N-oxidation (Fig. (7)). Similarly, access to the hemiacetal should e.g. be possible by oxidation of a 2-methylene group as well as by reduction of a 2-carbonyl group, and also by hydrolysis of a 2-halogen function. The influence of substituents at the aromatic ring on the synthesis of the 1,4-benzoxazinone ring is hardly foreseeable. However, another circumstance has a very rational basis. Due to the fact that the structural instability arises from the cyclohemiacetal (see Fig. (4)) this unit is prepared at the very end of most syntheses. 

Essentially all nucleophilic reagents add to carbonyl groups, often in a reversible fashion. In this case, the addition reaction is strongly favored by the halogen substitution (p. 780) So, the addition of hydroxide to the carbonyl looks like a reaction that is almost certain to occur. Once the addition reaction has taken place, there is an opportunity to generate the acid and the haloform in an elimination step if the triiodomethyl anion can be lost as the carbonyl group re-forms. Protonation of the carbanion completes the reaction. 

Chelate systems can also occur in certain cases. Rasmussen and Brattain [6] have observed this in a-acetyl-7-butyrolactone, which has the j3-keto ester structure. The non-enolised form gives rise to bands at 1773 cm (five-membered ring lactone) and 1718 cm (ketone), but there is also a band at 1656 cm , which the authors attribute to a chelated carbonyl group similar to those observed in open-chain products. Halogen substitution in the a-position also raises the carbonyl frequencies. In the extreme case, perflouro-butyrolactone absorbs at 1873 cm due to the influence of the fluorine atoms [29], 2-bromobutyrolactone [12] absorbs at 1797 cm . Anomalous frequencies also occur when electronegative substituents are present on the carbon atom of 7-lactones. Brugel et al. [60] have cited a number of such cases, of which 7-acetoxy-7-valerolactone which absorbs at 1797 cm is a typical example... 

Other than nucleophilic addition to the carbonyl group the most important reac tions of aldehydes and ketones involve replacing an a hydrogen A particularly well stud led example is halogenation of aldehydes and ketones... 

Esterification of carboxylic acids involves nucleophilic addition to the carbonyl group as a key step In this respect the carbonyl group of a carboxylic acid resembles that of an aldehyde or a ketone Do carboxylic acids resemble aldehydes and ketones m other ways Do they for example form enols and can they be halogenated at their a carbon atom via an enol m the way that aldehydes and ketones can ... 

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