Halogenation_&_Haloform_reactions

8/7/2019 Halogenation_&_Haloform_reactions

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742 17 Carbonyl C ompoun ds II. Enols; Enolate Anions. Unsaturated and Polycarbonyl Com pounds

Figure 17-1 Proton nmr spectrum of 2,4-pentanedione at 60 MHz. Cali-brations are relative to tetramethylsilane.

17-2 HALOGENATION OF ALDEHYDES AND KETONES17-2A Synthesis of a-Halo KetonesHalogenation of saturated aldehydes and ketones usually occurs exclusivelyby replacement of hydrogens alpha to the carbonyl group:

0 0II I/CH3-C-CH3 + C I2 --+ CH3-C-CH2CI + H CII-chloro-2-propanone(chloroacetone)

The reagents that commonly are used to halogenate carbonyl com-pounds ar e thos e tha t a re used to halogenate alkanes (e.g., Cl,, Br,, SO,Cl,,and N -bromoamides; see Sections 4-4 and 14-3). How ever, the characteris-tics of the two types of halogenation normally are very different. 2-Propanonehas been particularly well studied, an d the important features of the halogena-tion of this compoun d ar e sum ma rized as follows:

1. 2-P ropanone reac ts easily w ith chlorine, bromine, and iodine.


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17-2A Synthesis of @-HaloKetones 7432. 2-Propanone reacts at the same rate with each halogen. Indeed, the

rate of formation of the 1-halo-2-propanone is independent of the concentra-tion of the halogen, even at very low halogen concentrations.

3. The halogenation of 2-propanone is catalyzed by both acids andbases. The rate expressions for formation of 1-halo-2-propanone in watersolution are:v = /c[CH3COCH3][OHG] at moderate OHGconcentrationsv = k t [CH3COCH3][Ha] at moderate Ha concentrationsThe ratio of k to k t is 12,000, which means that hydroxide ion is a much moreeffective catalyst than is hydrogen ion.

To account for the role of the catalysts and the independence of the ratefrom the halogen concentration, the ketone necessarily must be slowly con-verted by the catalysts to something that can react rapidly with halogen togive the products. This something is either the en01 or the enolate anion of2-propanone:

/ or @OH), CH3-CCH3-C /\ slow \\

fastCH3COCH,Br + HBr

enolate anion

As long as the first step is slow compared with the steps of Equations 17-2and 17-3, the overall rate of reaction will be independent of both the con-centration of halogen and whether it is chlorine, bromine, or iodine (cf. Sec-tion 4-4C).

The reaction of either the en01 or the enolate anion (Equations 17-2 or17-3) with Br, resembles the first step in the electrophilic addition of halogensto carbon-carbon multiple bonds (Section 10-3A). However, the second step,


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744 17 Carbon yl Compo unds II. Enols; Enolate Anions. Unsaturated and Polycarbon yl Comp oundsaddition of the nucleophilic halide, if it occurs at all, does not produce anystable product:

Exercise 17-5 a. Would you expect the enol or the enolate anion of 2-propanoneto be more react ive towa rd brom ine if each were present at the same conc entrat ion?Why?b. W ould you expe ct the enolate an ion to react with brom ine at the oxygen? Ex plain.(Consider the b ond e nergies involved!)

Exercise 17-6 Would you anticipate any signif icant dif ference in the rate of halo-genat ion between CH3CO CH3 and CD3CO CD3 under (a) basic condi t ions and (b)acidic condit ions? Explain. (Review Section 15-6B.)Exercise 17-7 A detailed study of the rate of bromination of 2-propanone in water,in the presence of ethanoic acid and ethanoate ions, has shown that v = (6 x l o F 9+ 5.6 x 10 -4 [ H 3 0 0 ] + 1.3 x 10 -6 [ CH3C02H]+ 7[OHe] + 3.3 x 10 -6 [ CH3C02@]+ 3.5 x 10 -6 [ CH3C02H ] [ CH3C02@ ] )[CH3CO CH3 ] in which the rate v is expressedin moles liter-' secF1 when the con centrations are in moles liter-'.a. Calcu late the rate of the react ion for a 1 M solution of 2-propanone in water at pH= 7 in the absence of CH,C02H and CH 3C02@ .b. Calcu late the rate of the react ion for 1 M 2-propanone in a solut ion ma de b y neu-tral izing 1M ethanoic acid wi th suf f ic ient sodium hydroxide to give pH = 5.0 (K , ofethanoic acid = 1.75 x 1O-5).c. Exp lain how the num erical value s of the co eff icients for the rate equa tion may beobtained from observat ions of the react ion at various pH values and e thanoate ionconcentrations.d. The equil ibrium concentrat ion of enol in 2-propanone is est imated to be - 1.5x l o F 4 % .If the rate of conversion of 1M 2-propanone to enol at pH 7 (no CH3C0,H orCH3C02@present) is as c alc ula ted in Part a, calc ulate the rate of the reverse reactionfrom en ol to ketone at p H 7 i f the en ol were present in 1 M concentrat ion.e. Suggest a m echa nist ic ex planation for the term 3.5 x 10 -6 [ CH3C02H ] [ CH3C02@ ]in the rate expression.Exercise 17-8 In wh ich of the ketones studied in Section 17-1 wou ld you expe ct therate-l imit ing step in halogenation to be the react ion of the enol with halogen ratherthan formation of the enol?


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17-2A Synthesis of a-Halo Ketones 745Unsymmetrical ketones, such as 2-butanone, can form two different

enols that will react with halogens to give isomeric halo ketones:

The composition of the product mixture will depend on the relative rates offormation of the isomeric enols, provided that the halogenation step is not areversible reaction. Barring any serious steric effects that influence the rate ofreaction, the more rapidly formed en01 generally is the more thermodynam-ically stable enol.

Exercise 17-9 a. Explain why 2-butanone is halogenated preferential ly on the ethylside with an acidic catalyst. (Review of Section 11-3 should be helpful.)b. What product would predominate in the acid-catalyzed bromination of 1-phenyl-2-propanone? Give your reasoning.Exercise 17-10 When a sm all amount of brom ine is ad de d to a solution of cyclo-hexanone in carbon tetrachloride, the brown-red bromine color persists for quite sometime. Subsequent addit ions of bromine result in more rapid reaction and f inal ly thebromine is decolorized almost as rapidly as i t can b e poured in (unti l al l of the ketonehas reacted ). Explain this se quence of events.Exercise 17-11 The direct halogenation of aldehydes under ei ther acidic or basiccondit ions is comp licated by side reactions involving either oxidation of the aldehyde-CHO grou p or add itions to the -CH=O do ub le bo nd . Therefore the synthesis ofa-halo aldehydes by the procedure described for ketones is not of much practicalvalue. a-Halo aldehydes can be prepared indirectly from the enol ethanoate of thealdehyde. The en01 ethanoate is made by treating the aldehyde with ethanoicanhydride an d potassium ethanoate. The overal l sequenc e fol lows:

II(CH3C0)20 > CH,CH=CHOCCH, (A ) ---+CH3CH2CH0 CH,CO,%@

Br, C H OH HC I- BA C-CH3CHCH0CCI, H2O I


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746 17 Carbonyl Com pou nds 11. Enols; Enolate Anions. Unsaturated an d Po lycarb ony l Comp oundsWrite the structures of the intermediate products,B and 6,and the steps involved ineach of the react ions to pro duce A, B, C, and 2-bromopropanal. What is the functionof potassium e thanoate in the formation of A ? (You may wish to review Sections 15-4Dand 15-4E.)

17-2B The Haloform ReactionThe previous discussion of the halogenation of ketones is incomplete in oneimportant respect concerning base-induced halogenation. That is, once ana-halo ketone is formed, the other hydrogens on the same carbon are renderedmore acidic by the electron-attracting effect of the halogen and are replacedmuch more rapidly than the first hydrogen:

/I slow I1 fast lICH,-C-CH, --+ CH3-C-CH2Br -CH,-C-CHBr2Br2 Br2fast I1-CH3-C-CBr,Br2

The result is that, if the monobromoketone is desired, the reaction is carriedout best with an acidic catalyst rather than a basic catalyst. A further complica-tion in the base-catalyzed halogenation of a methyl ketone is that the trihalo-ketone formed is attacked readily by base, thereby resulting in cleavage of acarbon-carbon bond:

hi A, slowBr,-

tr i bromomethane(bromoform)

This sequence is called the haloform reaction because it results in the produc-tion of chloroform, bromoform, or iodoform, depending upon the halogen used.The haloform reaction is a useful method for identification of methyl ketones,particularly when iodine is used, because iodoform is a highly insoluble, bright-yellow solid. The reaction also is very effective for the synthesis of carboxylic


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17-2B The Haloform R eaction 747acids when the methyl ketone is more available than the corresponding acid:

Because the haloform reaction is fast, in some cases it can be used toprepare unsaturated acids from unsaturated ketones without serious complica-tions caused by addition of halogen to the double bond:c\"3 0I/ 1. Cl,, OH@,H 2 0 C H ,C=CHCCH, 2. H@ \C=CHCO,H + CHCl,/ 50%CH3 CH3

A reaction somewhat similar to the cleavage of haloforms with hy-droxide occurs with ketones that do not have a-hydrogens through the actionof sodium amide:

0 0I I benzene, 80"R-C-R' + NaNH, II: > R-C-NH, + R'HThis reaction, called the Haller-Bauer reaction, has utility for the preparationof amides of the types ArCONH, and tert-RCONH,, and, through hydrolysis,the corresponding carboxylic acids.

Exercise 17-12 Trichloromethane (chloroform) at one t ime was synthesized com-me rcially by the ac tion of sodium hypoc hlorite on ethanol. Formulate the reactionsthat m ay reasonably be involved. What other types of alcohols m ay be expec ted togive haloforms with halogens and base?Exercise 17-13 The AH0 values calculated from bond energies for the followingreactions in the vapor phase are equal (-9 kcal mole-'):

Explain why the f irst, but not the second, reaction proceeds rapidly with the aid ofsodium hydrox ide. Would you expec t ethanoic a ci d to unde rgo the haloform reaction?Explain.Exercise 17-14* The Haller-Bauer cleavag e of 2,2-dimethyl-1 -phenyl-1 -propano newith sodium am ide forms benzenecarboxam ide and 2-methylpropane. Write a mech-anism for the Haller-Bauer reaction analogous to the haloform clea vage reaction. .

Halogenation_&_Haloform_reactions

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