Halobenzenes, amination

Pure samples are best prepd by the methylation of acetanilide or benzanilide to the N-methyl compds followed by acid hyd. It has been prepd commercially by the action of methyl ale on aniline in an autoclave under press and by the action of methyl amine on halobenzenes. For a summary of prepns see Refs 6 9. It may be separated from aniline and dime thy laniline by treatment of the mixt with benzenesulfonyl chloride. Dimethylamline fails to react and is extd out with dil acid. Aniline forms benzenesulfonanilide which is acidic and is removed by washing with dil base, leaving the N-methylbenzenesulfonanilide. Purified N-methylaniline is obtd by acid hyd (Ref 8). N-Methylaniline is used as an additive to raise the octane no of motor fuels (Ref 6), as a dyestuff intermediate (Ref 3), in the prepn of Tetryl (see below), and in the prepn of Methylcentralite (Encycl, Vol 2, C137-R)... 

Cu-exchanged zeolites have been examined in the nucleophilic substitution of halobenzenes towards aminated and oxygenated systems. Selectivities are dependent on the zeolite s pore sizes. 

Figure 10. Reactions in Cu-zeolite catalyzed amination of halobenzenes.

Anilines, aliphatic amines, and ammonia react with electron-deficient halobenzenes and haloheteroarenes to produce the expected amino derivatives in good yield (Table 2.7) [37,64-67]. 

Activation Energies for Nucleophiuc Astatination of Halobenzenes The Influence of Aliphatic Amines... 

Exercise 14-19 The intervention of benzyne in the amination of chlorobenzene, bromobenzene, and iodobenzene with sodium amide in liquid ammonia originally was demonstrated by J. D. Roberts using 14C-labeled halobenzenes. Show explicitly how the use of a chlorobenzene-14C label could differentiate between amination by addition-elimination (Section 14-6B) versus amination by elimination-addition (benzyne mechanism). 

The benefits of initial product studies, followed by a more detailed examination using isotopic labelling, are well illustrated by the amination of halobenzenes, Scheme 2.7. The reaction of p-bromomethoxybenzene (15) with lithium diethylamide in ether gives a 1 1 mixture of m- and p-diethylamino-substituted products (16 and 17), with no trace of the o-isomer. One possible mechanism for these and many related reactions was that a normal direct displacement reaction to give 17 was in competition with an abnormal displacement,... 

Scheme 2.8 Benzyne mechanism to account for rearrangement during amination of halobenzenes.

Nucleophilic halogen substitution in solutions of halobenzenes containing aliphatic amines has been used by Norseyev and coworkers24-27 to produce astatobenzene and its substituted derivatives. 

Intermolecular Nucleophilic Substitution with Heteroatom Nucleophiles. A patent issued in 1965 claims substitution for fluoride on fluorobenzene-Cr(CO)3 in dimethyl sulfoxide (DMSO) by a long list of nucleophiles including alkoxides (from simple alcohols, cholesterol, ethylene glycol, pinacol, and dihydroxyacetone), carboxylates, amines, and carbanions (from triphenyhnethane, indene, cyclohexanone, acetone, cyclopentadiene, phenylacetylene, acetic acid, and propiolic acid). In the reaction of methoxide with halobenzene-Cr(CO)3, the fluorobenzene complex is ca. 2000 times more reactive than the chlorobenzene complex. The difference is taken as evidence for a rate-limiting attack on the arene ligand followed by fast loss of halide the concentration of the cyclohexadienyl anion complex does not build up. In the reaction of fluorobenzene-Cr(CO)3 with amine nucleophiles, the coordinated aniline product appears rapidly at 25 °C, and a carefiil mechanistic study suggests that the loss of halide is now rate limiting. 

This reagent also reduces nitro, nitrile, and amide derivatives to amines, and carboxylic acids and anhydrides to alcohols. The yields of these reductions arc nearly quantitative. Esters and halobenzene derivatives are not reduced. 

Recently, several selective bromination reagents for reactive aromatic amines have been developed, for example, 2,4,4,6-tetrabromocyclohexa-2,5-dienone (35), iV-bromosuccinimide-dimethylformamide (36), and hexabro-mocyclopentadiene (37). Although molecular bromine is too reactive to perform selective bromination (mono- versus polybromination), the combined used of bromine and zeolites X and Y has been reported to be applicable to the selective bromination of halobenzenes and alkylbenzenes (38). This zeolite method, however, was not successful in the selective bromination of highly active aromatic compounds. Bromine preadsorbed on zeolite 5A (Ca type) was found to monobrominate aniline in carbon tetrachloride with excellent regioselectivity (91-93% para selectivity) in the presence of organic base, pyridine or 2,6-lutidine (Table XII) (39). The preadsorption of bromine on zeolite 5A is necessary for selective bromination, because the inverse procedure of adding bromine to aniline that had been adsorbed on zeolite beforehand caused a nonselective reaction. 

The degree of rearrangement in the amination of substituted halobenzenes with alkali amides is influenced by the position of the substituent, relative to the halogen. Whereas... 

Uses. Tetramethylene sulfone has high solvent power for aromatics and has been used extensively by Olah and co-workers for Friedel-Crafts type nitrations and for studies of the mechanism of nitronium tetrafluoroborate nitration of alkyl-benzenes and halobenzenes in homogeneous solution. It is a superior solvent for quaternization of tertiary amines with alkyl halides, since it has a high dielectric constant and does not enter into side reactions observed with nitrobenzene and dimethylformamide. For example in the synthesis of the acridizinium salt (3), Bradsher and Parham effected quaternization of (1) with benzyl bromide in tetramethylene sulfone at room temperature in excellent yield. Several other salts analagous to (2) were obtained in good yield and in crystalline form with use of tetramethylene sulfone, whereas with other solvents the products were colored... 

Reactions of this type have been used in the synthesis of indoles on a solid phase [143, 144]. Yamazaki et al. described a combination of palladium-catalyzed amination and Heck reaction in a synthesis of indole [145]. One indole synthesis is performed by a Heck reaction of N-acyl dehydroalanine immobilized on REM resin (24) -with 1-2 halobenzenes (26). In the case of 2-N-acyl-aminocinnamoyl esters, the N-acetyl groups gave higher yields than CBz-groups and 1,2-dibromo-benzene (78%) was more efficient than l-bromo-2-triflyloxybenzene (41%) (Scheme 3). 

Treated with NaNH2, aromatic halides lead to the elimination of a hydrogen halide and the formation of benzyne (refs. 74-77). This reaction can be followed by the addition of the amide ion, resulting in the obtention of anilines. The reaction occurs on the two reactional centres of the benzyne. Using 14C labelled chlorobenzene leads almost to a 1 1 ratio of aniline 1-I4C and 2-14C (Fig. 13). Fluorides are less reactive than chlorides which are less reactive than bromides. When the halobenzene bears a substituent there are several possibilities (Fig. 13). With a halogen in the meta position, two benzynes are possible, the direction of the elimination is predictable on the basis of which hydrogen is more acidic. With an ortho or a para substituent only one benzyne is produced but the amination takes place according to the nature of the substituent (refs. 74-79). 

Table 5. Orientation in the homolytic amination of halobenzenes 2 ) and methyl cinamate 2D by N-chlorodimethylamine...

In his classic paper on the mechanism of amination of halobenzenes Roberts expended considerable effort and ingenuity to eliminate alternatives to the aryne mechanism. In particular he convincingly demonstrated that no rearrangement of the starting aryl halide took place. Such rearrangements do occur under aryne forming conditions, however, with polyhalobenzenes and a variety of monohaloheterocycles. This reaction has been labeled the... 

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