Synthesis Of Halomethylated And Trihalomethylate Aromatic Compounds

Halomethylated and trihalomethylated aromatics are of major importance and have found a large number of uses from dyes and polymers to pharmaceuticals and agrochemicals. Among them, benzotrifluoride derivatives constitute a particular class with specific properties, such as polarity, thermal and metabolic stabilities as well as the high lipophilicity brought by the trifluoromethyl moiety that enhances their bioavailability. These molecules are very useful in the biochemical fields as well as in the material design and synthesis. Consequently, a sustained interest has been focused on the halomethylated and trihalomethylated aromatics preparation. Traditionally, the former compounds can be obtained through either a direct halogenation of the benzylic methyl, or a deoxybromination of benzylic alcohol. Methods for the preparation of latter aromatic compounds include trihalomethylation of aromatics as well as the halogen exchange reactions. However, most protocols often give poor selectivity and require either toxic reagents or harsh conditions typically involving high temperature and long reaction time. In addition, some substituents on the aromatic ring may have adverse effects on these preparations. In order to overcome these barriers, this thesis research is aimed at developing novel and effective synthesis strategies for these halomethylated and trihalomethylated aromatic compounds.(1) Chloromethylation of aromatics. Popular approach for the chloromethylation of aromatics is Blanc reaction, which is normally performed in the presence of insoluble Lewis acid. The use of Lewis acids is important to activate formaldehyde. In the present study, a novel catalytic system consisting of soluble Lewis acid, sulfuric acid and acetic acid has been developed and employed for the Blanc reaction of aryl compounds in the presence of formaldehyde and hydrogen chloride. Regioselective mono- and di-chloromethylation of aryl compounds with different reactivities have been successfully performed with this catalytic system in good yields. It is found that catalyst activity can be optimized and catalyst selectivity can be manipulated by adjusted the catalytic system compositions as well as the concentration of sulfuric acid. In addition, such catalysts can be reused multiple times, thus saving costs and energy and reducing environmental impact from disposal of spent catalysts. (2) Synthesis of trichloromethylated aromatic compounds. Trichloromethylation reaction of aromatic carboxylic acids or aroylchlorides has been accomplished by using tetrachlorophenylphosphine or dichlorophenylphosphine/phosphoric chloride as the transforming agent. The trichloromethylation reaction can be well controlled and the phenylphosphonic dichloride produced in the process can be reclaimed for reuse. A series of trichloromethylated aromatics including two new compounds, such as 3-trichloromethylbromobenzene and 2-trichloromethylmethbenzenetoluene, have been synthesized. The influences and the mechanism of the reaction have also been studied. It was found that the reaction was accelerated obviously with the electron-pushing groups attached to dichlorophenylphosphine and was decreased with the electron-withdrawing groups attached. On the other hand, the effects of substituents of the aromatic acids (or aroylchloride) on the reaction were opposed.(3) Preparation of benzyl bromide derivatives. A facile method for the benzylic monobromination of toluene derivatives has been developed using boron tribromide as bromine source at ambient temperature. The best conditions for boron tribromide mediated benzylic bromination were defined using toluene as model substrate. It is found that increasing temperature resulted in decreasing in the yield of benzyl bromide, but slightly increased the yield of benzal bromide. Similarly, increasing the equivalence of boron tribromide caused an increase in the yield of benzal bromide. In addition, the solvent has shown a dramatic influence on the bromination yields. Increasing the solvating power of solvent decreased the benzyl bromide yield. Alkylbenzenes with electron-pushing group on the aromatic ring were found to convert into their corresponding benzyl bromides in high yields. Under identical conditions, deactivated toluene derivatives afforded lower quantities amount of benzyl bromides. This bromiantion approach seems to have an ionic transition state with a positive charge on methyl carbon and ionic stabilization from nearby BBr₄^- anion, which is quite different from the traditional radical ones and appears attractive. Furthermore, this procedure allows the easy isolation of products since the by-product of the reaction, dibromoborane, is hydrolyzed to boric acid and hydrogen bromide upon treatment with water during the work-up procedure.(4) Preparation of tribromomethylarenes. A novel approach for the synthesis of tribromomethylarenes by halogen exchange of trichloromethyl or trifluoromethyl arenes with boron tribromide has reported. A series of tribromomethylarenes were prepared efficiently from trifluoro(chloro)methylarenes at room temperature with boron tribromide as the brominating reagent. It is found that the reaction was accelerated for the substrates with electron-pushing groups on the aromatic ring and decreased by the presence of electron-withdrawing groups. In addition, the reaction was inhibited greatly when the substrate had a substituted group at the ortho-position. A likely mechanism for this reaction is presented. Electrophilic attack of boron tribromide on the trichloromethylated aromatic ring gives an ionic complex which results in the displacement of one of the chlorides by bromine. The displacement reaction can then take place between the aromatic CBrCl₂ group and BBr₂Cl until benzotribromide derivatives are formed. The high yield of the conversion of benzotrichloride into benzotribromide can be explained by assuming that the equilibria are shifted toward the formation of benzotribromide due to an escape of BCl₃ gas from the reaction system.(5) Preparation of trifluoromethylarenes. Electrophilic chloro-fluorine exchange reaction between trichloromethylarenes and HF was catalyzed By various catalysts such as phosphorus pentachloride, arsenic pentachloride, antimony pentachloride tetrachlorophenylphosphine, and tetrachloro(n-butylphosphine), respectively. It was found that tetrachlorophenylphosphine had the highest catalytic activity for this chloro-fluorine exchange reaction. However, the real catalyst was PhPF₄, which was formed in-situ through the reaction of tetrachlorophenylphosphine and HF, providing the fluorinating reagent, PhPF₄-HF. Based on these study, an efficient one-pot approach was developed and used to transform aromatic carboxylic acids to their corresponding trifluoromethylarenes. The synthesis strategy included the treatment of aromatic carboxylic acids with excess tetrachlorophenylphosphine to afford their corresponding trichloromethylarenes, followed by HF to complete the halogen exchange reaction. A plausible mechanism for this reaction was proposed.