The Haloform Reaction

The three most stable resonance forms of this anion are 

Enolate ions of 3-dicarbonyl compounds are useful intermediates in organic synthesis. We shall see some examples of how they are employed in this way later in the chapter. 

Rapid halogenation of the a-carbon atom takes place when an enolate ion is generated in the presence of chlorine, bromine, or iodine. 

As in the acid-catalyzed halogenation of aldehydes and ketones, the reaction rate is independent of the concentration of the halogen chlorination, bromination, and iodination all occur at the same rate. Formation of the enolate is rate-determining, and, once formed, the enolate ion reacts rapidly with the halogen. 

Unlike its acid-catalyzed counterpart, a halogenation in base cannot normally be limited to monohalogenation. Methyl ketones, for example, undergo a novel polyhalo-genation and cleavage on treatment with a halogen in aqueous base. 

11 For a review of the haloform reaction, see Fuson and Bull, Chem. Revs., 16, 276 (1934). 

18 Hammett, Physical Organic Chemistry, Chapter VIII, pp. 96-98, McGraw-Hill Book Co., New York, 1940. 

Presumably the slow step in the sequence is the formation of the carbanion, since rate studies have shown that in basic solution iodine and bromine react with acetone at the same rate.14 Similarly, at a pH less than 9, acetophenone is brominated or chlorinated in the a-position at the same rate.16 With each ketone the rate of reaction is independent of the concentration of halogen present but directly proportional to the concentration of base. 

This same study 15 showed further that in the reaction of hypobromite or hypoiodite with acetone, carbanion formation is so slow that it controls completely the overall rate of polyhalogenation. Consequently monobromoacetone and dibromoacetone must form carbanions much more readily than acetone itself. This is in agreement with the point of view that Sn2 reactions (in this instance at a hydrogen atom) should be favored by electron withdrawal from the seat of reaction (p. 89). 

The cleavage stage of the haloform reaction may be regarded as a hydroxide ion displacement reaction at the keto group, although again w e cannot be sure that preliminary addition at the carbonyl group does not take place (p. 90)  

We saw earlier in this chapter that aldehydes and ketones undergo a-halogenation in neutral and acidic media via an enol intermediate. A similar reaction occurs in basic solution except, in this case, the reactive intermediate is an enolate ion. 

Unlike its acid-catalyzed coimterpart, this reaction is difficult to limit to monohalogenation. 

Interestingly, the trihalomethanes chloroform (CHCI3), bro-moform (CHBr3), and iodoform (CHI3) are biosynthesized by an entirely different process, one that is equivalent to the haloform 

Further chlorination of the chloromethyl ketone gives the corresponding trichloromethyl ketone, which then undergoes hydrolysis to form chloroform. 

Purification of drinking water, by adding CI2 to kill bacteria, is a source of electrophilic chlorine and contributes a non-enzymatic pathway for a chlorination and subsequent chloroform formation. Although some of the odor associated with tap water may be due to chloroform, more of it probably results from chlorination of algae-produced organic compounds. 

When water is chlorinated to purify it for public consump)-tion, chloroform is produced from organic impurities in the water via the haloform reaction. (Many of these organic impurities are naturally occurring, such as humic substances.) The presence of chloroform in public water is of concern for water treatment plants and environmental officers, because 

3D a-Halo Carboxylic Acids The Hell-Volhard-Zelinski Reaction 

Carboxylic acids bearing a hydrogen atoms react with bromine or chlorine in the presence of phosphorus (or a phosphorus hahde) to give a-halo carboxylic acids through a reaction known as the HeU-Volhard-Zelinski (or HVZ) reaction. 

Chapter 18 Reactions at the a Carbon of Carbonyl Compounds General Reaction 

If more than one molar equivalent of bromine or chlorine is used in the reaction, the products obtained are a.a-dihalo acids or a.a.a-trihalo acids. 

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This IS called the haloform reaction because the trihalomethane produced is chloroform (CHCI3) bromoform (CHBrj) or iodoform (CHI3) depending on the halogen used... 

The mechanism of the haloform reaction begins with a halogenation via the eno late The electron attracting effect of an a halogen increases the acidity of the protons on the carbon to which it is bonded making each subsequent halogenation at that car bon faster than the preceding one... 

The haloform reaction is sometimes used for the preparation of carboxylic acids from methyl ketones... 

The methyl ketone shown in the example can enohze in only one direction and typifies the kind of reactant that can be converted to a carboxylic acid in synthetically accept able yield by the haloform reaction When C 3 of a methyl ketone bears enolizable hydro O... 

The haloform reaction using iodine was once used as an analytical test in which the formation of a yellow precipitate of iodoform was taken as evidence that a substance... 

The haloform reaction of unsymmetrical perfluoroalkyl and co-hydroper-fluoroalkyl trifluororaethyl ketones gives the alkane corresponding to the longer alkyl chain [54] (equation 53) If the methyl group contains chlorine, the reaction can take different pathways, leading to loss of chlorine (equation 54), because of the variable stability of the chlorine-substituted methyl carbanions in alkali. 

The applicability of the Cannizzaro reaction may be limited, if the substrate aldehyde can undergo other reactions in the strongly basic medium. For instance an a ,a ,a -trihalo acetaldehyde reacts according to the haloform reaction. 

Methyl ketones 1, as well as acetaldehyde, are cleaved into a carboxylate anion 2 and a trihalomethane 3 (a haloform) by the Haloform reaction The respective halogen can be chlorine, bromine or iodine. 

Fluorine cannot be used, although trifluoroketones can be cleaved into carboxylate and trifluoromethane. The haloform reaction can be conducted under mild conditions—at temperatures ranging from 0-10 °C—in good yields even a sensitive starting material like methylvinylketone can be converted into acrylic acid in good yield. 

Besides its synthetic importance, the haloform reaction is also used to test for the presence of a methylketone function or a methylcarbinol function in a molecule. Such compounds will upon treatment with iodine and an alkali... 

Which of the following substances would undergo the haloform reaction ... 

The oxidation of aldehydes to carboxylic acids can proceed by a nucleophilic mechanism, but more often it does not. The reaction is considered in Chapter 14 (14-6). Basic cleavage of (3-keto esters and the haloform reaction could be considered at this point, but they are also electrophilic substitutions and are treated in Chapter 12 (12-41 and 12-42). 

In the haloform reaction, methyl ketones (and the only methyl aldehyde, acetaldehyde) are cleaved with halogen and a base. The halogen can be bromine, chlorine, or iodine. What takes place is actually a combination of two reactions. The first is an example of 12-4, in which, under the basic conditions employed, the methyl group is trihalogenated. Then the resulting trihalo ketone is attacked by hydroxide ion ... 

It is exactly the same with the haloform reaction. If chloroform is poured onto the acetone/sodium hydroxide mixture, there can be an explosion whereas incorporating hydroxide in the other two substances would not be dangerous. In this case the risk factor is the high hydroxide concentration. 

There is also the haloform reaction (effect of a haloform on a ketone in a basic medium), already described with halogen derivatives on p.272 (the danger is more related to the interaction of the polyhalogen derivative with the base, according to the author). A large number of accidents involved the ketone as much as butanone. The accident below illustrates the danger of this reaction ... 

While the haloform reaction normally only cleaves methyl ketones because of the structural requirements for the a,a,a-tribromomethyl ketone to induce fragmentation, the strain release that accompanies cleavage of a cyclobutanone permits extension... 

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