Haloform reactions

In the previous section, we learned how to make enolates. Now, we will begin to see what an enolate can attack. In this section, we will explore the reaction between an enolate and a halogen (such as Br, Cl, or I). In the following sections, we will explore the reactions between an enolate and other electrophiles. 

Consider what might happen under the following conditions  

We have a ketone and hydroxide, which means that the equilibrium will involve a small amount of enolate  

This enolate is formed in the presence of Br2, which can function as an electrophile. The initial product is not surprising  

The enolate attacks Br2 and expels Br as a leaving group. The result is that we have installed Br at the alpha position  

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. 

The methyl group of a methyl ketone is converted into an a ,a ,a -trihalomethyl group by three subsequent analogous halogenation steps, that involve formation of an intermediate enolate anion (4-6) by deprotonation in alkaline solution, and introduction of one halogen atom in each step by reaction with the halogen. A 

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

o -trihaloketone 7 can further react with the hydroxide present in the reaction mixture. The hydroxide anion adds as a nucleophile to the carbonyl carbon the tetravalent intermediate suffers a carbon-carbon bond cleavage  

The reaction also works with primary and secondary methyl carbinols 8. Those starting materials are first oxidized under the reaction conditions to the corresponding carbonyl compound 1  

aryl X2 = CI2, Br2, I2 halogen source NaOCI, NaOBr, NaOl, ION X3C = F3C, CIsC.BrsC, I3C MOH = NaOH, KOH  

The mechanism of the haloform reaction has been extensively studied, and it can be concluded that it is a very complex process. The exact mechanistic pathway is dependent on the structure of the substrate and the specific reaction conditions. The scheme depicts the oxidation of a methyl carbinol to the corresponding methyl ketone via an organic hypohalite. The methyl ketone then undergoes deprotonation, and three sequential a-halogenations take place to afford the trihalomethyl ketone. This compound undergoes rapid hydrolysis to afford the haloform and a carboxylate. 

A novel synthetic route for the preparation of unsymmetrically substituted benzophenones was developed in the laboratory of C.-M. Andersson utilizing an iron-mediated aromatic substitution as one of the key steps. The power of this method was demonstrated by the formal synthesis of the benzophenone moiety of the protein kinase C inhibitor balanol. In the late stages of the synthesis, it became necessary to convert the aromatic methyl ketone functionality of the highly substituted benzophenone substrate to the corresponding carboxylic acid. Bromine was added to sodium hydroxide solution, and the resulting sodium hypobromite solution was slowly added to the substrate at low temperature. Upon acidification the desired carboxylic acid was obtained in fair yield. 

The biomimetic total synthesis of (+)-20-epiervatamine was accomplished by J. Bosch et al. The authors used the addition of 2-acetylindole enolate to a 3-acylpyridinium salt as akey step to connect the two main fragments. The in situ formed 1,4-dihydropyridine was trapped with trichloroacetic anhydride to afford the corresponding trichloroacetyl-substituted 1,4-dihydropyridine derivative. The conversion of the trichloroacetyl group to a methyl ester was achieved by treatment with sodium methoxide. This transformation can be regarded as the second step of the haloform reaction. 

During the total synthesis of (+)-anthoplalone by K. Fukumoto et al. one of the intermediates was a cyclopropyl methyl ketone, and the synthetic sequence required the conversion of this functionality to the corresponding cyclopropane carboxylic acid methyl ester. This transformation was accomplished via the haloform reaction using bleach in methanol. The methyl ester and some carboxylic acid was obtained after this step, so the product mixture was treated with diazomethane to convert the acid side product to the methyl ester. 

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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... 

Haloform reaction (Section 18 7) The formation of CHX3 (X = Br Cl or I) brought about by cleavage of a methyl ketone on treatment with Br2 CI2 or I2 in aqueous base... 

Efaloform Reaetion. Ethyl alcohol reacts with sodium hypochlorite to give chloroform [67-66-3] (haloform reaction). 

One of these reactions is the well-known haloform reaction Another leads to some unusual trifluoromethylamines... 

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. 

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 ... 

Haloform reaction (Section 22.6) The reaction of a methyl ketone with halogen and base to yield a haloform (CHX3) and a carboxylic acid. 

Haloalkane,. see Alkyl halide Haloform reaction, 854-855 Halogen, inductive effect of, 562 resonance effect of, 563 Halogenation, aldehydes and, 846-848... 

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

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