Preparation of Bromobenzene

Note The macro method is not recommended for beginners, due to the danger involved in handling bromine in a separatory funnel over a reaction vessel. The macro experiment is suitable for advanced work and for demonstration by the instructor. The semimicro method involves the use of 3 ml of bromine, and with suitable precautions the experiment can be assigned to beginners. 

Introduction. The action of halogens on saturated open chain hydrocarbons, as for example, pentane or hexane, gives several monohaJogen derivatives. Since the separation of the isomeric monohalides is difficult in the laboratory, they are usually prepared from alcohols. Direct halogenation is used industrially. The cyclic hydrocarbons, such as cyclohexane and benzene, jdeld only one monohalide. The present experiment illustrates direct bromination of a hydrocarbon. Chlorination is more difficult it is described in the latter part of the text (page 229). The catalyst used for bromination is iron other substances which can be used for the same purpose are anhydrous aluminum chloride and pyridine. 

Caution Bromine quickly produces severe bums if it comes in contact with the skin. Wear goggles, and become familiar with method of treating bromine bums (page 348). 

Place in the tube 4 g (5 ml) of benzene and 0.3 g of iron filings. Measure out 3 ml of bromine (with caution) into a small beaker 

140-165°. Allow the residue in the distilling tube to cool to about 50° and then add 5 ml of methanol to dissolve it. Pour the contents of the tube through a small filter paper into a 50 ml beakeri From the filtrate, on cooling, crystals of p-dibromobenzene separate. 

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An example of bromination of an aromatic hydrocarbon by Water s method is provided by the preparation of bromobenzene 374a... 

Ullman reaction The synthesis of diaryls by the condensation of aromatic halides with themselves or other aromatic halides, with the concomitant removal of halogens by a metal, e.g. copper powder thus bromobenzene gives diphenyl. The reaction may be extended to the preparation of diaryl ethers and diaryl thio-ethers by coupling a metal phenolate with an aryl halide. 

Propiophenone. Prepare a solution of diphenyl-cadmium in 110 ml. of dry benzene using 4 9 g. of magnesium, 32 4 g. of bromobenzene and 19 5 g. of anhydrous cadmium chloride. Cool the solution to 10°, and add during 3 minutes a solution of 14 -8 g. of propionyl chloride (b.p. 78-79°) in 30 ml. of dry benzene use external coohng with an ice bath to prevent the temperature from rising above 40°. Stir the mixture for 2 hours at 25-35°. Work up the product as detailed above except that 6 per cent, sodium carbonate solution should replace the saturated sodium bicarbonate solution. The yield of propiophenone, b.p. 100-102°/16 mm., is 17 6 g. 

The preparation of the bromobenzodioxole or bromobenzene is going to be the same no matter which one is used and no matter which precursor the chemist wishes to make. This means that this first part needs to be done correctly. This first part of preparation that Strike is talking about is the creation of a Grignard reagent out of the bromo compound starting material [125,131-134]. Mr. Grignard earned a Nobel prize for this in 1912 so you can bet that it s a pretty good procedure. 

To a mixture of 100 ml of THF and 0.10 mol of the epoxide (note 1) was added 0.5 g Of copper(I) bromide. A solution of phenylmagnesium bromide (prepared from 0.18 mol of bromobenzene, see Chapter II, Exp. 5) in 130 ml of THF was added drop-wise in 20 min at 20-30°C. After an additional 30 min the black reaction mixture was hydrolysed with a solution of 2 g of NaCN or KCN and 20 g of ammonium chloride in 150 ml of water. The aqueous layer was extracted three times with diethyl ether. The combined organic solutions were washed with water and dried over magnesium sulfate. The residue obtained after concentration of the solution in a water-pump vacuum was distilled through a short column, giving the allenic alcohol, b.p. 100°C/0.2 mmHg, n. 1.5705, in 75% yield. 

Salicyl-u-toluide has been prepared only by the action of phosphorus oxychloride upon a mixture of salicylic acid and o-toluidine. The useful methods of preparation of salicylanilide are by the interaction of salicylic acid and aniline in the presence of phosphorus trichloride, by heating phenyl salicylate and aniline, and from o-hydroxybenzamide and bromobenzene in the presence of small amounts of sodium acetate and metallic copper. A number of these and other anilides have been described. ... 

Aj Preparation of (2-Amino-5-ChlorophenyljPhenylmethaneimine (4356 CB) A solution of 228.7 g (1.5 mols) of 2-amino-5-chlorobenzonitrile in 1,800 ml of dry ether is added slowly in the course of about 3.5 hours to a solution of phenyl magnesium bromide prepared from 109 g (4.5 g-atoms) of magnesium turnings and 848 g (5.4 mols) of bromobenzene In 3,600 ml of anhydrous ether, and the mixture then heated under reflux for 15 hours. 

The manufacture of the cyclohexyl analog is as follows. Phenyl magnesium bromide was prepared from 48.5 g (0.308 mol) of bromobenzene, 7 g (0,29 mol) of magnesium, and 125 ml of dry ether. To it was added at 5°C over a period of A hour 40 g (0.18 mol) of cyclohexyl (3-(N-piperidyl)-ethyl ketone (BP 115° to 117°C/1 mm) in 125 ml of dry ether. The mixture was allowed slowly to come to room temperature, refluxed for one hour, and then poured into ice containing 80 ml of concentrated hydrochloric acid. Ammonium chloride (100 g) and 200 ml of concentrated ammonium hydroxide were added and the organic layer was separated. After drying and removing the solvent, the residue was distilled under reduced pressure. The base distilled at 158° to 170°C (1 mm) and solidified. Upon recrystallization from methanol it melted at 112° to 113°C. 

The residue was dissolved in 75 ml of tetrahydrofuran, treated with charcoal, and sodium sulfate and filtered. This solution was added to a solution in 250 ml of tetrahydrofuran of phenyl magnesium bromide prepared from 17.7 ml (0.17 mol) of bromobenzene. This mixture was stirred and heated under reflux for 1 hour. It was then cooled and diluted with 400 ml of ether and sufficient 3N hydrochloric acid to make it acidic. The aqueous phase was separated, adjusted to pH 8 with 3N sodium hydroxide and extracted 3 times with 200 ml of ether. The ether extracts were combined, washed with water and dried over sodium sulfate. The residue left on removal of the ether in vacuo was crystallized from petroleum ether to give 3.3 g of 7-chloro-2,3-dihvdro-1-methyl-5-phenvl-1 H-1,4-benzodiazepine, according to U.S. Patent 3,624,703. 

To the Grignard reagent prepared from 0.59 part of magnesium, 3.95 parts of bromobenzene... 

The present method of preparation of 4,4 -dimethyl-l,l -biphenyl is that described by McKillop, Elsom, and Taylor 15 It has the particular advantages of high yield and manipulative simplicity and is, moreover, applicable to the synthesis of a variety of symmetrically substituted biaryls 3,3 - and 4,4 -Disubstituted and 3,3, 4,4 -tetrasubstituted 1,1 -biphenyls are readily piepared, but the reaction fails when applied to the synthesis of 2,2 -disubstituted-l,T biphenyls The submitters have effected the following conversions by the above procedure (starting aromatic bromide, product biphenyl, % yield) bromobenzene, biphenyl, 85,1 -bromo-4-methoxybenzene, 4,4 -dimethoxy-l, 1 -biphenyl, 99, 1 bromo 3 methylbenzene, 3,3 dimethyl-1,l -biphenyl, 85 4-bromo-l,2-dimethylbenzene, 3,3, 4,4 -tetramethyl-l,l -biphenyl, 76, l-bromo-4-chlorobenzene, 4,4 -dichloro-l,l -biphenyl, 73, l-bromo-4-fluorobenzene, 4,4 -difluoro-l,l -biphenyl, 73... 

The fact that n-butyl benzene can be prepared in reasonable yield by the action of sodium upon a mixture of bromobenzene and re-butyl bromide can be partly explained on the assumption that re-butyl bromide reacts with phenjd-sodium more rapidly than does bromobenzene. It is interesting to note that re-butylbenzene can be prepared either from benz.vlsodium and re-propyl bromide or from phenylsodium and re-butyl bromide (Section VI,29). 

In a modified preparation of phenyllithium, bromobenzene was added to finely powdered lithium (rather than coarse particles) in ether. The reaction appeared to be proceeding normally, but after about 30 min it became very vigorous and accelerated to explosion. It was thought that the powdered metal may have been partially coated with oxide or nitride which abraded during stirring, exposing a lot of fresh metal surface on the powdered metal. 

Chlorobromobenzene has been prepared by the diazotiza-tion of o-bromoaniline followed by replacement of the diazonium group by chlorine 1 by the elimination of the amino group from 3-chloro-4-bromoaniline 2 by the chlorination of bromobenzene in the presence of thallous chloride,3 aluminum chloride,4 or ferric chloride 4 by the bromination of chlorobenzene without a catalyst6 or in the presence of aluminum,4 iron,4 or ferric bromide 6 by the diazotization of o-chloroaniline followed by replacement of the diazonium group with bromine 4,6 and from o-chlorophenylmercurie chloride by the action of bromine.7... 

A 500-ml. three-necked round-bottomed flask is fitted with an efficient reflux condenser, a glycerol-sealed mechanical stirrer,1 a dropping funnel, and a gas inlet tube extending nearly to the blades of the stirrer (Note 1). An absorption train,2 with the addition in / of a safety tube which extends nearly to the bottom, is connected to the upper end of the reflux condenser (Note 2). A 2-cm. layer of water in J allows it to serve as a bubble counter K is one-third filled with a 50% potassium hydroxide solution. The entire apparatus is set up in subdued light in a hood and swept with dry hydrogen (Notes 3 and 4). Phenyl-magnesium bromide is prepared in the flask by the usual procedure 3 from 78.5 g. (0.5 mole) of bromobenzene, 12 g. (0.5 gram... 

Bio-oxidation of bromobenzene 11 catalyzed by Pseudomonas putidae leads to diol 12. Protection of diol 12, followed by the addition of an acyl nitroso dienophile and subsequent reduction gives compound 14. This compound can be used as the key intermediate in the preparation of (+)-l-deoxy-galacto-nojirimycin (16) and related indolizidine compounds (15) (Scheme 8-5).12... 

Ethyl benzoate (15 g.) mixed with 15 c.c. of absolute ether is dropped into a Grignard solution prepared as just described from 6-4 g. of magnesium and 40 g. of bromobenzene. The conditions are the same as those observed in the preceding preparation at the end the solution is boiled for half an hour and worked up as before. Colourless prisms of triphenylcarbinol, melting point 162°, are obtained by recrystallising the solid residue from hot alcohol. Yield over 20 g. For further information about this important alcohol see p. 355. 

Ethyl phenylacetate may be prepared by the treatment of benzyl cyanide with alcohol and hydrochloric acid gas.1 It is much more convenient in the laboratory, however, to use sulfuric acid in place of hydrochloric acid in fact, the yields obtained are better than those recorded in the literature. This ester may also be made by the esterification of phenylacetic acid with hydrochloric acid and alcohol 2 or with alcohol and sulfuric acid 3 the following less important methods of preparation may be mentioned the action of benzyl magnesium chloride upon ethyl chlorocarbonate,4 and the action of copper on a mixture of bromobenzene and ethyl chloroacetate at 1800.5... 

A. Preparation of an ether solution of phenylmagnesium bromide (Note 1). Ether (100 mL) is added to magnesium (Mg) turnings (74.6 g, 3.07 mol) in a dry, S-L flask equipped with an overhead stirrer, reflux condenser, and addition funnel. Iodine (several crystals) is added and the mixture is stirred for several minutes (the color dissipates). Bromobenzene (9.23 mL, 13.76 g, 87.64 mmol) is added and the mixture is heated with a heat gun to initiate the reaction. A solution of bromobenzene (322.8 mL, 481 g, 3.06 mol) in ether (600 mL) is added dropwise over 2.75 hr, maintaining a gentle reflux. The dark brown mixture is stirred an additional 3 hr at ambient temperature under nitrogen and then cooled in an ice/methanol bath to 0°C. 

Carbonylation of bromobenzene (Scheme 5.7) with [Pd(TPPTS)3] required still higher temperatures (150 T). The possible acyl intermediates of such reactions [PdBr(C6H5CO) Ph3)2] and [PdBr(C6H5CO)(TPPTS)2] were synthetized and characterized [26]. Bromobenzene was also carbonylated to benzoic acid in water/toluene using a catalyst prepared from [PdCl2(COD)j and 27 in the presence of NEt3 [21]. 

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