Abstract: Heme enzymes mediate a plethora of paramount reaction pathways in a wide variety of organisms, including humans, wherein dioxygen activating heme enzymes are prevalent.[1, 2] Interestingly, a number of pivotal geometric and electronic parameters in concert fine-tune such heme centers for their specialized reactivities, which strongly modulate the reactivity properties of their relevant reaction intermediates. Dioxygen activating heme enzymes shuttle through a distinct panel of heme-dioxygen intermediates, wherein the exact active oxidant can vary according to the specific heme enzyme in question.[2] Mid-valent (i.e., heme Fe(III) containing) heme-oxygen adducts are the first members of this series of intermediates, which are followed by the formation of high-valent (i.e., heme Fe(IV) containing) heme-oxygen species after the cleavage of the dioxygen derived O–O bond. These high-valent heme intermediates typically are strong oxidants, which competently facilitate the selective, high-yielding cleavage of strong substrate bonds.[3] Accordingly, the chemistries of high-valent intermediates have been rigorously evaluated over the past several decades, and a majority of their principal reactivity properties are well documented in the contemporary literature. Attributes of mid-valent heme-oxygen intermediates, on the other hand, are only faintly understood, and in-depth studies into their reactivity properties are severely lacking.[4, 5] Nonetheless, heme enzymes where mid-valent intermediates are active oxidants/key species are rapidly emerging as potent drug targets (e.g., tryptophan/indoleamine 2,3-dioxygenases, aromatase, heme oxygenase, nitric oxide synthase, etc.),[6] warranting a clear comprehension into their precise chemical properties. Moreover, unlike their high-valent counterparts, mid-valent heme-oxygen adducts exhibit significantly versatile chemical properties, making the unequivocal description of their bio-relevant chemistries quite challenging. Synthetic model systems can be powerful probes in this endeavor, where important geometric and electronic properties of the heme center can be modified more feasibly and straightforwardly, and readily investigated in detail by various spectroscopic and computational methods.[7, 8] This work utilizes small molecule synthetic analogs of mid-valent heme-oxygen intermediates in evaluating their key bio-relevant reaction properties, and factors that govern the mechanistic subtleties of corresponding reaction landscapes. Characterization of important reaction intermediates, and salient structure-function relationships will also be discussed in detail.