Gas-Phase Experimental and Computational Studies of 5-Halouracils: Intrinsic Properties and Biological Implications

The gas-phase acidity and proton affinity (PA) of 5-halouracils (5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil) have been examined using both theoretical and experimental methods. This work represents a comprehensive study of the thermochemical properties of these nucleobases. Other than 5-fluorouracil acidity, the intrinsic acidity and PA of these halouracils have not been heretofore measured; these new experimental data provide a benchmark for the computational values. Furthermore, we examine these 5-halouracils in the context of the enzyme thymine DNA glycosylase (TDG), which is an enzyme that protects the genome by cleaving these substrates from DNA. Our gas-phase results are compared and contrasted to TDG excision rates to afford insights into the TDG mechanism.