Phenazine, chlorination

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

In the case of substituted phenazine fV-oxides some activation of substituents towards nucleophilic substitution is observed. 1-Chlorophenazine is usually very resistant to nucleophilic displacements, but the 2-isomer is more reactive and the halogen may be displaced with a number of nucleophiles. 1-Chlorophenazine 5-oxide (56), however, is comparable in its reactivity with 2-chlorophenazine and the chlorine atom is readily displaced in nucleophilic substitution reactions. 2-Chlorophenazine 5,10-dioxide (57) and 2-chlorophenazine 5-oxide both show enhanced reactivity relative to 2-chlorophenazine itself. On the basis of these observations, similar activation of 5- or 6-haloquinoxaline fV-oxides should be observed but little information is available at the present time. 

Direct halogenation of quinoxaline appears to be of limited value but pyrazine may be chlorinated in the vapor phase to give monochloropyrazine at 400 °C or at lower temperatures under catalytic conditions 72AHC(14)99, and at higher temperatures tetra-chloropyrazine formation occurs in high yields. Mention has already been made of direct chlorination (see Section 2.14.2.1) of phenazine. 

With phenazine (97) there is considerable resistance to any electrophilic halogenation, but in aqueous solution chlorine converted it into a mixture of 1-chloro, 1,4-dichloro-, 1,4,6-trichloro-, and 1,4,6,9-tetrachloro-phenazines (53G327). 

Chlorination of phenazine in refluxing carbon tetrachloride in the presence of sodium acetate yields a mixture of 1-chloro- (32%) and 1,4-dichlorophenazine (25%) chlorination of phenazine in hydrochloric acid gives a mixture of mono- and polychlorinated compounds. Bromination of phenazine with bromine in acetic acid affords 1,4,6,9-tetrabromophenazine (see Houben-Weyl, Vol. 5/4, p 330). 

Chlorinating agents convert phenazine mono- and di-(V-oxides into 2-chloro- and 2,6-dichlorophenazine, respectively. " When phenazine W-oxide is refluxed in thionyl chloride, phenazine (33%), 1-chlorophenazine (23%), and 2-chlorophenazine (10%) are formed. When phenazine Woxide reacts with tosyl chloride, 1-tosyloxyphenazine and, in addition 1-chloro- and 2-chlorophenazines are formed. 

Tryptophan, phenylalanine, tyrosine Aniline, chloroanlines, methylanilines, chloromethylanilines Nitrophenols, chlorinated phenols, phenolic acids (benzoic, p-hydroxybenzoic, vanillic, caffeic, p-coumaric, ferulic, salicylic, phenazine-1-carboxylic), aromatic anionic surfactants (alkylbenzenesulfonates)... 

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