Thus, to avoid the hydroxylated product which could serve as a thermodynamic trap, enzymes must have chemical or structural strategies to favor halogenation over hydroxylation. For larger halides chloride and bromide, the OH-rebound intermediates are much more favorable than the halide-rebound intermediates by almost 35 kcal/mol, despite the fact that it is known that several enzymes do selectively brominate or chlorinate (Figure ). Surprisingly, we observe that the OHrebound intermediate is more stable than fluoride-rebound intermediate by a much smaller amount, ca. 18 kcal/mol (Figure ). Despite the smaller energetic difference between OH-rebound and halide-rebound intermediates for fluoride relative to chloride/bromide, the higher barrier for rebound to fluoride could make C-H fluorination challenging compared to C-H chlorination or bromination (Figure and Supporting Information Table ).