Bromination of acetophenone

Bromination of acetophenone ketazine followed by reaction with benzylamine gives (491) (710PP289). Halogenation of the product leads to ring contraction probably via an intermediate of type (482) <75H(7)547). 

Fig. 12.5. Electrophilic side chain bromination of acetophenone (A). With catalytic amounts of AlCL, the acetophenone is transferred into the enol iso-A, while stoichiometric amounts of AlClj lead to the formation of acetophenone in the form of the Lewis acid/Lewis base complex D. So in the presence of catalytic amounts of AlCl the enol iso-A is brominated (- F, "phenacyl bromide") in the presence of stoichiometric amounts of AlCl3, however, bromination of the aromatic moiety of D takes place (-> meto-bromoaceto-phenone, cf. Section 5.2.1).

Pearson - found that if the bromination of acetophenone is done without solvent and with aluminum chloride taken not in catalytic amount but in large excess (2.5 COCH, COCH,... 

Pearson27 was to manipulate orientation in various ways to obtain any isomer desired. An example cited on 1, 32-33 is the meru-bromination of acetophenone, described by Pearson as a swamping catalyst effect. In the bromination of a phenol, para substitution ordinarily predominates over ortho substitution, but considerable increase in the proportion of ortho isomer can be achieved by operating at — 70° in the presence of a strongly basic aliphatic amine.28 The best procedure was to add bromine to a cold solution of f-butylamine in toluene, cool to about — 7(P, and add a phenol dropwise over a short period of time. By this procedure, phenol was converted by 1 equivalent of bromine into 2-bromophenol in 60% yield and by 2 equivalents of bromine into 2,6-dibromophenol in 87% yield. Tertiary amines such as DABCO and triethylamine serve also for enhanced o-bromination of phenols. Chlorination under the same conditions gave a mixture of o- and p-chlorophenols in the ratio 2 1. 

Bromination of acetophenone ketazine (5) yielded the dibromo derivative (6), which was treated with benzylamine in the presence of triethylamine to produce the 4,6-dihydro-5//-l,2,5-triazepine (7). The triazepine (7) upon treatment with bromine gave the imidazole derivative (10). This reaction may involve the 5//-l,2,5-triazepine (9) formed from the triazanorcaradiene (8), as shown in Scheme... 

Aldehydes and ketones with at least one a-hydrogen react at the a-carbon with bromine and chlorine to form a-haloaldehydes and a-haloketones as illustrated by bromination of acetophenone. 

Bromine is an ortho, para director, acetyl a meta director. Reasoning backward from the target, disconnection a makes electrophilic bromination of acetophenone the last synthetic step disconnection b makes Friedel-Crafts acylation of bromobenzene the last step. Of the two approaches, only bromination of acetophenone delivers the desired meta relationship of the two substituents and suggests the following synthesis. 

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. 

Not every excess acidity mechanistic analysis has been an outstanding success. For instance, several enolization studies have used this technique. The enolization of acetophenone was one of the reactions originally studied by Zucker and Hammett 146 their sulfuric acid rate constant data, obtained by iodine scavenging (the reaction is zero-order in halogen), was used in an excess acidity analysis,242 together with additional results obtained for some substituted acetophenones (using bromine scavenging).243... 

The very small p- and m-values observed for the fast bromination of a-methoxystyrenes deserve comment since they are the smallest found for this electrophilic addition. The rates, almost but not quite diffusion-controlled, are amongst the highest. The sensitivity to polar effects of ring substituents is very attenuated but still significant that to resonance is nil. These unusually low p-values for a reaction leading to a benzylic carbocation are accompanied by a very small sensitivity to the solvent. All these data support a very early transition state for this olefin series. Accordingly, for the still more reactive acetophenone enols, the bromination of which is diffusion-controlled, the usual sensitivity to substituents is annulled. 

Under carefully controlled conditions the selective mono bromination of an electronically diverse range of acetophenone derivatives can be realized using the polymer-supported pyridinium perbromide reagent. The resultant a-bromoketone... 

We used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

On the other hand, if only catalytic amounts of A1C13 are added, the acetyl group of the acetophenone is brominated. Under these conditions the carhonyl oxygen of a fraction of acetophenone can be complexed. The bulk of the substrate still contains uncomplexed carhonyl oxygen. It allows acetophenone to equilibrate with its tautomeric enol (for details see Figure 12.5). The enol is a better nucleophile than the aromatic ring because it is brominated elec-trophilically without intermediate loss of aromaticity. HBr is the stoichiometric by-product of this substitution. Just like the HC1 that is formed initially, it catalyzes the enolization of unreacted acetophenone and thus keeps the reaction going. 

Experiments on the bromination of equilibrated ketone-acetal systems in methanol were also recently performed for substituted acetophenones (El-Alaoui, 1979 Toullec and El-Alaoui, 1979). Lyonium catalytic constants fit (57), but for most of the substituents the (fcA)m term is negligible and cannot be obtained with accuracy. However, the relative partial rates for the bromination of equilibrated ketone-acetal systems can be estimated. For a given water concentration, it was observed that the enol path is more important for 3-nitroacetophenone than for 4-methoxyacetophenone. In fact, the smaller the proportion of free ketone at equilibrium, the more the enol path is followed. From these results, it can be seen that the enol-ether path is predominant even if the acetal form is of minor importance. The proportions of the two competing routes must only depend on (i) the relative stabilities of the hydroxy-and alkyoxycarbenium ions, (ii) the relative reactivities of these two ions yielding enol and enol ether, respectively, and (iii) the ratio of alcohol and water concentrations which determines the relative concentrations of the ions at equilibrium. Since acetal formation is a dead-end in the mechanism, the amount of acetal has no bearing on the relative rates. Bromination, isotope exchange or another reaction can occur via the enol ether even in secondary and tertiary alcohols, i.e. when the acetal is not stable at all because of steric hindrance. 

Bromophenacyl bromide has been prepared by the interaction of bromobenzene and bromoacetyl chloride in the presence of aluminum chloride2 and by the bromination of -bromo-acetophenone.1,3... 

Bromoacetophenone was obtained by Emmerling and Engler by the reaction of bromine on acetophenone. 

In the laboratory it is usually prepared by Mohlau s modification of Emmerling s original method, that is, by the action of bromine on acetophenone. 

Benzoylacrylic acid has been prepared by the condensation of acetophenone and chloral to l,l,l-trichloro-2-hydroxy-3-benz-oylpropane, followed by hydrolysis to the corresponding acid and dehydration by the action of iodine, potassium iodide, and sodium carbonate on 7-phenylisocrotonic acid by bromination of /3-benzoylpropionic acid and subsequent dehydrohalogena-tion 1 and by the action of phenylzinc chloride on maleic anhydride. The present method is based on the work of von Pech-mann and others. ... 

Bromination catalyst. Aluminum chloride in catalytic amount promotes bromina-tion of the methyl group of acetophenone to give phenacyl bromide. Ether and... 

A SOLUTION of 50 g. (49 cc., 0.42 mole) of acetophenone in 50 cc. of pure anhydrous ether (Note 1) is placed in a dry threenecked flask fitted with a separatory funnel, mechanical stirrer, and reflux condenser (Note 2). The solution is cooled in an ice bath, o-s g. of anhydrous aluminum chloride is introduced (Note 3), and 67 g. (21.5 cc., 0.42 mole) of bromine is added gradually from the separatory fuimel, with stirring, at the rate of about I cc. per minute. The bromine color disappears rapidly although very little hydrogen bromide is evolved towards the end of the reaction the solution becomes pink in color. 

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