Synthesis of azobenzene-2,2’-dichloro-4,4’-dicarboxylic acid, a novel hypoxia-responsive linker for polymersome encapsulated drug delivery systems

Background: Polymersome encapsulated drug delivery systems based on hypoxia-responsive linkers may provide a targeted and highly efficient method for cancer treatment. The purpose of our project is to synthesize novel hypoxia-responsive linkers containing azo groups as hypoxia-sensitive moieties. The specific purpose is to synthesize a series of 2,2’-disubstituted azobenzene-4,4’-dicarboxylic acids with a variety of electron-donating and electron-withdrawing substituents. Initially, we reproduced and improved the synthesis of azobenzene-2,2’-dimethoxy-4,4’-dicarboxylic acid, the compound that was described in the literature earlier. We applied the improved procedure for the synthesis of azobenzene-2,2’-difluoro-4,4’-dicarboxylic acid and discovered that fluorine was lost in the course of the reaction. Hypothesis: We hypothesize that fluorine is uniquely sensitive to strong basic conditions of the reaction, and that the loss will not happen with other halogens. In this work, the hypothesis was tested in the synthesis of azobenzene-2,2’-dichloro-4,4’-dicarboxylic acid. Methods: The reaction was conducted on a 40 mmol scale at 50ºC - 60ºC. NMR-spectroscopy and elemental analysis were used to determine the structure of the product. Result: The reaction was completed in 30 minutes. The isolated yield of azobenzene-2,2’-dichloro-4,4’-dicarboxylic acid was 86%. Conclusion: The results of the reaction support the initial hypothesis that replacing fluorine with chlorine will lead to the successful synthesis of azobenzene-2,2’-dichloro-4,4’-dicarboxylic acid. Azobenzene-2,2’-dichloro-4,4’-dicarboxylic acid is a new compound. Support: Research presented in this presentation was supported by the National Science Foundation under NSF EPSCoR Track-1 Cooperative Agreement OIA #1946202