Anilines halogen substituents

Kamikawa et al. chose the first option to generate the benthocyanin skeleton [91]. To begin with, 100 and aniline 126 are transformed into o-nitrodi-phenylamine 127 by intermolecular N-arylation. Reduction of the nitro group and selective bromination produces 128, and this time an intramolecular Buch-wald-Hartwig reaction is used to derive a mixture of the desired phenazine 129 and the elimination product 130. The fundamental problem with this approach relates to the selective introduction of the halogen substituent that is required for the intramolecular N-arylation. 

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)...

TABLE 6. Enthalpies of formation of anilines with halogen substituents (kJ mol 1)... 

Ammonolysis of aromatic halides, however, may lead to unexpected products. For example, Gilman and Martin report that aryl ethers, thio ethers, and sulfones with ortho-halogen substituents rearrange to metarsubstituted anilines when treated with sodamide in liquid NH3. 

Several subgroups of chemicals that fall into the general class of polar, nonspecific toxicants were found to be more toxic than calculated from the respective QSARs (Table 5.4) because they exerted additional specific effects. These outliers from the polar non-specific QSARs comprise, for example, phenols and anilines with < 6.3, > two NO2 substituents and/or > three halogen substituents (Bradbury et al, 1989 Nendza and Seydel, 1990 OECD 1992a). They may act as uncouplers of the oxidative phosphorylation with diverging physiological syndromes and hence their QSARs must use different structural descriptors because their toxicity is caused by different chemical properties. 

Conformational equilibria of amines and aminoacids have been studied in low-temperature matrix under UV or IR irradiation." Amine-imine tautomerism and formation of a radical was observed from adenine. New studies on the aniline excited states has evidenced the role of Rydberg states. A re-examination of the Oilman reaction has demonstrated that this is an electron transfer process. The photo-cyclization of halogenated (iodine is by far to be preferred) N-ben lani-lines to phenanthridine has been studied with particular attention at the preparative value and the tolerance of alko)q, dio)q methylene and halogen substituents, to which it was found to be quite tolerant. ... 

He classified dyes into three groups the primary amino dyes, the sulfonic acid derivatives of aniline blue, and the acidic dyes containing nitro and halogen substituents... 

Weak acid respiratory uncouples Phenols and anilines with four or more halogen substituent or more than one nitro group, or single nitro group and more than one halogen group... 

Category Ic cyclizations involve formation of the C3-C3a bond and require aniline derivatives with a nitrogen substituent appropriate for such reaction. Some, but not all, such cyclizations also require an o-substituent, frequently halogen. The rctrosynthetic transformations corresponding to the most important of this group of syntheses are shown in Scheme 4.1... 

There are two sequences in which the reaction can be carried out. For most anilines the first step is /V-chlorination which can be done with t-butyl hypochlorite[9]. However, for anilines with ER substituents it may be preferable to halogenate the thioester. The halogenation can be done with Cl2[lbl or SOjCljCU]. For some anilines simply adding f-butyl hypochlorite to a mixture of the aniline and thioester is satisfactory (Entries 1, 4, Table 7.6). 

Nucleophilic Reagents. In contrast to electrophilic reactions, nucleophiles attack positively charged, even carbons ia the chain. The reactions lead to the exchanging of substituents or terminal residues. Thus, SR and OR groups, or halogen atoms can be exchanged by other suitable nucleophiles (4,69,70), for example, by aniline ... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

This compound is also described as diethanol-p-toluidine in the older literature. Anilines bearing hydroxyl groups are preferred because they are less volatile than anilines without polar substituents. Tertiary aromatic amines with para-halogen substitution have also been reported for use in adhesives [42]. 

Nearly every substitution of the aromatic ring has been tolerated for the cyclization step using thermal conditions, while acid-promoted conditions limited the functionality utilized. Substituents included halogens, esters, nitriles, nitro, thio-ethers, tertiary amines, alkyl, ethers, acetates, ketals, and amides. Primary and secondary amines are not well tolerated and poor yield resulted in the cyclization containing a free phenol. The Gould-Jacobs reaction has been applied to heterocycles attached and fused to the aniline. 

In spite of their efficiency, in most cases hydrogen fluoride/pyridine mixtures are not suitable for the thermal fluorodediazoniation of ort/io-substituted anilines, especially those in which the substituent bears a heteroatom with unshared electron pairs (halogen, methoxy, etc.). 

Experimental studies of the reactivity of other aniline derivatives in substitution reactions are far more limited, de la Mare and Hassan (1958) and Bradfield and Jones (1928) examined the influence of acyl substituents on the amino function on the rate of halogenation at the para position. These interesting data are too limited to be useful for the evaluation of a linear free-energy relationship and are not included in Table 4. 

When Cl, Br, or I is the substituent, there is a size mismatch, and therefore a poor overlap, between the 2p orbitals from the carbon atoms and the p orbitals from the halogen (3p for chlorine, 4p for bromine, and 5p for iodine). This size mismatch is clearly illustrated by comparing the reactivities of aniline and chlorobenzene chlorine and nitrogen have approximately the same electronegativity, but aniline is much more reactive than chlorobenzene because of the better overlap between the carbon and nitrogen 2p orbitals. 

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