Halogen-substituted anilines

When HCI or HF is used, one gets ortho and para halogen-substituted anilines. 

Susarla, S., Masunaga, S. and Yonezawa, Y. (1996). Kinetics of Halogen Substituted Aniline Transformation in Anaerobic Estuarine Sediment. Water ScLTechnoL, 34,37-43. 

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]. 

Rappoport and Topol investigated the displacement of the halogen of bromo- and chloromethylenemalonates (287 X= Br, Cl) by several substituted anilines and that of the brosyloxy group of (4-nitrophenyl)(4-bromo-phenylsulfonyloxy)methylenemalonate (289) by morpholine and piperidine, in acetonitrile. A rate-determining nucleophilic addition of the amines was suggested as the mechanism for these reactions. Activation parameters (AH, AS ) were determined [72JCS(P2)1823]. 

The data in Table I shows that addition of a nitro group to aniline increases the peak potential 200-250 mV whereas addition of a halogen has very little affect. Therefore HPLC/EC should be more useful for determining aniline and its halogen substituted derivatives, than for nitro substituted anilines. 

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. 

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.). 

The following reactions show halogenation of aniline derivatives, which occurs readily without a catalyst. If an excess of the reagent is used, all the unsubstituted positions ortho and para to the amino group become substituted. 

Displacement of this halogen by the amino group of the substituted aniline (149) then affords intermediate 150. The labile fluoride on the quinazoline... 

Prior structure-activity studies with diclofenac analogs indicate that methyl or chlorine substituents on the lower aniline ring of the inhibitor in the ortho position are required for potent inhibition of COX (44). Analogs with halogen substitutions (fluorine or chlorine) at the 5 position of the phenylacetic acid ring demonstrate an even higher potency for COX inhibition (44). 

In summary, it is confirmed that while the nitrogen protonation in the unsubstituted ANI is favored marginally, by about 4 kJ mol-1, over the para-C4-protonation, the protonation sites in substituted anilines are essentially determined by the nature and position of the substituents. The halogen atoms consistently reduce the basicity whereas the alkyl groups enhance it. Substitution at meta positions induces a larger increment than that at ortho positions. The overall effects of substituents on PAs are essentially additive. 

In conclusion, special attention is called to the fact that not only aniline and its homologues can be diazotised, but all the derivatives of these, as the nitro-amines, halogen-substituted amines, amido-alde-hydes, amido-carbonic adds, etc. 

The photochemistry of the para-substituted phenyl sulphamates (308)-(312) has been found to be substituent dependent. Photolysis of (308) and (309) in methanol gave photo-Fries products (i.e. the expected aniline sulphonic acids) as well as aniline, while the nitro derivative (311) was photochemically inert, and the halogen substituted sulphamates (310) all gave the photosolvolysis product (312)... 

Aniline is converted into a sulphonic acid when heated with concentrated sulphuric acid, into halogen substitution-products by the halogens, and into nitro derivatives by nitric acid. These compounds will be considered in some detail later. 

The analogs were prepared from readily available anilines. Halogen substitution as well as substitution with other electron withdrawing groups did not substantially improve potency in the PCA assay. Simple alkyls also had only minor impact on potency. More significant improvements were made with hydroxyl functions and their derivatives, as shown in Table II. The phenol esters were prepared by conventional methods from the phenoxide and a suitable acid halide or anhydride. The PCA activity of the various esters reached a maximum with the valerate (19) but even this was not significantly more potent than the parent 4-hydroxy derivative, 15, which was our early lead candidate. 

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