Halogen anilines

The direct chlorination or bromination of aniline takes place more easily than that of benzene, the result being the symmetrical tri-chlor or tri-brom aniline, viz., i-amino 2-4-6-tri-chlor benzene, C6H2CI3-(NH2) and I-amino 2-4-6-tri-brom benzene, CeH2Br3(NH2). The mono-halogen anilines are prepared by reducing mono-chlor nitro benzenes, or by halogenating acetanilide and then hydrolyzing. 

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Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

The selectivity of the cyclization using enamino-esters 18-20 derived from m-halogenated anilines 14-16, provided mixtures of 5- and 7-substituted quinolines. In all of these cases, the cyclization gave either equal amounts of the 5- and 7- isomers or in the case of m-iodoaniline, about a 1 2 ratio was observed. During the time of these publications, it was the desire of the authors to obtain the 7-substituted quinolines, which were potential drugs for the treatment of malaria. 

Available information on the thermal instability of halogenated anilines during vacuum distillation is presented and analysed, and the roles of dehyrohalogenation, polymerisation, salt formastion and dissociation, aerobic oxidation, corrosion and metal-catalysed decomposition are discussed. Experimental work on these topics is presented, and preventive measures proposed. 

Gute Ausbeuten liefert die Oxidation der 4-Halogen-aniline mit Peressigsaure in Eisessig. Auf diese Weise laBt sich z. B. 4,4 -Dijod-azobenzol in 62% Ausbeute herstellen3. 

The lower the peak potential for oxidation of a compound, the more specifically it can be determined (since a lower detector voltage can be used). Therefore compounds such as MMPDA, MDA, DCB, MBOCA, and benzidine (i.e. aromatic diamines) can be more readily determined by HPLC/EC than are the aniline derivatives. This does not imply that HPLC/EC is not useful for the determination of anilines. In fact, a recent paper illustrates the usefulness of HPLC/EC for the determination of halogenated anilines in urine. 

In summary, the data given in this section show that HPLC/EC technique should be useful for the determination of aromatic diamines and halogenated anilines but is of little value for determining nitro-substituted anilines. 

Amidine derivatives are effective dehalogenation inhibitors for the chemoselective hydrogenation of aromatic halonitro compounds with Raney nickel catalysts. The best modifiers are unsubstituted or N-alkyl substituted formamidine acetates and dicyandiamide which are able to prevent dehalogenation even of very sensitive substrates. Our results indicate that the dehalogenation occurs after the nitro group has been completely reduced i.e. as a consecutive reaction from the halogenated aniline. A possible explanation for these observations is the competitive adsorption between haloaniline, nitro compound, reaction intermediates and/or modifier. The measurement of the catalyst potential can be used to determine the endpoint of the desired nitro reduction very accurately. 

Carbonyl compounds, -halogenated anilines, benzidines, nitro compounds, phenols, polychlorinated compounds, alkylbenzene, sulphonates, alkyl sulphonates, alkylbenzene sulphonates, carbamates [155]... 

Substituted urea herbicides are a widely used group of compounds. Urinary metabolites of these compounds are halogenated anilines. Recent research has lead to the development of analytical methodology for trace levels of these compounds in the urine of experimental animals (17). The next logical step in this sequence is application to human exposure assessment. 

Peroxidase transformation of mono- and dichlorinated anilines have been extensively studied, but there is scarce information about highly halogenated anilines. From several peroxidases tested, only chloroperoxidase from C.fumago was able to transform highly chlorinated anilines [69]. This first report on peroxidase transformation of pentachloroaniline showed that the main product is a polymeric material, and pentachlorophenol and tetrachloro-l,4-benzoquinone are also produced (Fig. 8.3). The mechanism of pentachlorophenol production from pentachloroaniline is still unknown. However, the tetrachloro-l,4-benzoquinone seems to be a product of the pentachlorophenol intermediate and not produced directly from the pentachloroaniline as found in pentachlorophenol peroxidase transformation [69]. The identified products from the chloroperoxidase-mediated transformation of tetrachloroaniline are the polymer, which represented 87-95% of the total mass, pentachloroaniline, and three different dimers, which have been identified as minor products [69]. 

Fig. 8.3 Detected products from the peroxidase oxidation of highiy halogenated anilines [69]...

Righettini, R. R. and Dawdy, T. H., Free Radical Polymerizable Compositions Including Para-Halogenated Aniline Derivatives, U.S. Patent 5,932,638 (1999). 

Baumeister et al. studied the hydrogenation of various halonitrobenzenes using Raney Ni modified with amidine derivatives.115 Formamidine acetate (19b) has been found to be the most effective inhibitor for dehalogenation. It has been shown that the dehalogenation occurs as a consecutive reaction after the halogenated aniline has been formed. A typical example with use of this inhibitor is shown in eq. 9.51 for the hydrogenation of l-chloro-2,4-dinitrobenzene in comparison with dicyandiamide. It is noted that the reaction time could be shortened with 19b compared to that with 19a. 

The photochemistry of the halogenated anilines had received little attention until about 10 years ago, when the elucidation of the mechanisms of the photolysis of the halophenols, as described above, raised the question of the more general applicability of the obtained results. As will be detailed below, there are indeed close similarities between the halogenated phenols and anilines, but characteristic differences also exist. 

Fig. 10-2. Assumed geometry of the triplet exciplex between p-substituted halogen aniline with thionine. Here, only p-orbitals of halogen substituent are indicated. (Reproduced from Ref. [4a] by permission from The Royal Society of Chemistry)...

Triplet exciplexes ( (AD ) fromed in the reaction of thionine triplet ( A ) with halogen anilines (D) undergo ISC to the singlet ground state ( (A D)) mainly due to the influence of the haligen substituent in the aniline part. The rate constant of ISC (kj) can be expressed by... 

Cnubben, N.H., Peelen, S., Borst, J.W., Vervoort, J., Veeger, C. and Rietjens, I.M. (1994). Molecular Orbital Based Quantitative Structure-Activity Relationship for the Cytochrome P450 Catalyzed 4 Hydroxylation of Halogenated Anilines. Chem.Res.Toxicol., 7, 590-598. 

TABLE 6. Calculated proton affinities (PA, kJ mol-1 at 0 K) of halogenated anilines... 

FIGURE 5. 70 eV El mass spectra of para-halogenated anilines (a) para-fluoroaniline,... 

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