Reactivity of para-benzynes in solution and in the gas phase

To rationally design less cytotoxic synthetic drugs based on biologically active para-benzyne intermediates, it is essential to obtain a better understanding on the reactivity of para-benzynes. However, little is still known about their fundamental chemical properties, which requires examination of pure species in simple solvents instead of biological matrices. While fundamental solution studies are limited, the solvent-free reactivity of protonated para-benzynes has been examined previously in the gas phase by using mass spectrometry. In order to facilitate the comparison of results obtained in the gas phase and in solution, we attempted to compare the reactivity of a neutral para-benzyne analog toward dimethyldisulfide in solution to that of its protonated form in the gas phase. The neutral para-benzyne analog, 5,8-didehydroquinoline, was successfully generated via photolysis of an enediyne precursor in dimethyldisulfide/methanol solution and the reaction products were analyzed using a dual linear quadrupole ion trap tandem mass spectrometrometer. However, examination of of the reactions of the same para-benzyne in its protonated form in the gas phase in the mass spectrometer proved to be challenging. Therefore, an analogous, isomeric para-benzyne cation, the 5,8-didehydroisoquinolinium cation, was instead generated in the gas phase from the 5-iodo-8-nitroisoquinoline precursor and its reactions with dimethyldisulfide were examined. This protonated para-benzyne reacted with dimethyl disulfide in the gas phase in the same manner as its neutral isomer in solution; both predominantly abstracted a thiomethyl group by each of the two radical sites. The structures of these products were verified by tandem mass spectrometry experiments based on collision-activated dissociation and using an authentic model compound. These findings suggest that the reactivity of the studied para-benzynes toward dimethyldisulfide is similar in spite of their different protonation states and the different phases in which the reactions were carried out.