18.7 The Haloform Reaction CH3 CHa H← The three most stable resonance forms of this anion are →C Enolate ions of B-dicarbonyl compounds are useful intermediates in organic syn thesis. We shall see some examples of how they are employed in this way later in the 18.7 THE HALOFORM REACTION Rapid halogenation of the a-carbon atom takes place when an enolate ion is generate in the presence of chlorine, bromine, or iodine RoCHCR RC=CR′—RCCR′ Aldehyde Enolate a-Halo aldehyde As in the acid-catalyzed halogenation of aldehydes and ketones, the reaction rate is inde- pendent 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 genation and cleavage on treatment with a halogen in aqueous base a novel polyhalo limited to monohalogenation. Methyl ketones, for example, undergo RCCH3 3X2 4HO 2 RCo+ CHX X3+3X-+3H2O Methyl logen Hydroxide Carboxylate Trihalomethane Halide Water This is called the haloform reaction because the trihalomethane produced is chloroform, bromoform, or iodoform, depending, of course, 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 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The three most stable resonance forms of this anion are Enolate ions of -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. 18.7 THE HALOFORM REACTION Rapid halogenation of the -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, halogenation in base cannot normally be limited to monohalogenation. Methyl ketones, for example, undergo a novel polyhalogenation and cleavage on treatment with a halogen in aqueous base. This is called the haloform reaction because the trihalomethane produced is chloroform, bromoform, or iodoform, depending, of course, on the halogen used. The mechanism of the haloform reaction begins with halogenation via the enolate. The electron-attracting effect of an halogen increases the acidity of the protons on the carbon to which it is bonded, making each subsequent halogenation at that carbon faster than the preceding one. Methyl ketone RCCH3 O Carboxylate ion RCO O Halogen 3X2 Trihalomethane CHX3 Water 3H2O Halide ion 3X Hydroxide ion 4HO Aldehyde or ketone R2CHCR O -Halo aldehyde or ketone R2CCR O X Enolate R2C CR O HO, slow X2, fast O O O CH3 O CH3 O CH3 O H OH O O CH3 OH O CH3 H O 18.7 The Haloform Reaction 711 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTEr EIGHTEEN Enols and enolates RCH2xXRC<、x2,.0 RCCX3 (slowest ( fastest step) The trihalomethyl ketone(RCCX3)so formed then undergoes nucleophilic addition of hydroxide ion to its carbonyl group, triggering its dissociation. CCX CX2-RC-OH OH HO Carboxylate Trihalomethane The three electron-withdrawing halogen substituents stabilize the negative charge of the trihalomethide ion(: CX3), permitting it to act as a leaving group in the carbon-carbon bond cleavage step The haloform reaction is sometimes used for the preparation of carboxylic acids from methyl ketones (CH3)32C( 1. Br,, NaOH, H (CH3)3CCOH CHBr3 3, 3-Dimethyl-2-butanone 2, 2-Dimethylpropanoic Tribromomethane acid(71-74%) bromoform) The methyl ketone shown in the example can enolize 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- gens, as in CH3 CH2 CCH3, the first halogenation step is not very regioselective and the isolated yield of CHi CH2CO2H is only about 50% 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 was a methyl ketone. This application has been superseded by spectroscopic methods of structure determination interest in the haloform reaction has returned with the realiza- tion that chloroform and bromoform occur naturally and are biosynthesized by an anal- ogous process. (See the boxed essay"The Haloform Reaction and the Biosynthesis of Trihalomethanes Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The trihalomethyl ketone so formed then undergoes nucleophilic addition of hydroxide ion to its carbonyl group, triggering its dissociation. The three electron-withdrawing halogen substituents stabilize the negative charge of the trihalomethide ion (:CX3), permitting it to act as a leaving group in the carbon–carbon bond cleavage step. The haloform reaction is sometimes used for the preparation of carboxylic acids from methyl ketones. The methyl ketone shown in the example can enolize in only one direction and typifies the kind of reactant that can be converted to a carboxylic acid in synthetically acceptable yield by the haloform reaction. When C-3 of a methyl ketone bears enolizable hydrogens, as in , the first halogenation step is not very regioselective and the isolated yield of CH3CH2CO2H is only about 50%. 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 was a methyl ketone. This application has been superseded by spectroscopic methods of structure determination. Interest in the haloform reaction has returned with the realization that chloroform and bromoform occur naturally and are biosynthesized by an analogous process. (See the boxed essay “The Haloform Reaction and the Biosynthesis of Trihalomethanes.”) CH3CH2CCH3 O X 3,3-Dimethyl-2-butanone (CH3)3CCCH3 O 2,2-Dimethylpropanoic acid (71–74%) (CH3)3CCOH O Tribromomethane (bromoform) CHBr 3 1. Br2, NaOH, H2O 2. H O RCCX3 Trihalomethyl ketone HO O RC CX3 OH O RC OH HO O RC O Carboxylate ion H2O CX3 Trihalomethane HCX3 (RCCX3) O X RCCH3 O RCCH2X O RCCHX2 O RCCX3 O (slowest halogenation step) X2, HO X2, HO X2, HO (fastest halogenation step) 712 CHAPTER EIGHTEEN Enols and Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website