PROJECT SUMMARY/ABSTRACT Considering 20-25% of pharmaceuticals on the market today contain one or more fluorine atoms in their active ingredient (several of which appear on the WHO’s List of Essential Medicines), it is evident that fluorine chemistry continues to have a profound impact on drug development. Yet, despite the indisputable significance of fluorine atoms and fluorinated groups in modern medicinal chemistry, there has been a historical lag in their implementation in pharmaceuticals over the last century. The reason for this lag can most often be attributed to synthetic accessibility, as methods to install fluorine on molecules have been notoriously reliant on hazardous reagents, e.g., F2 and HF. While methods to incorporate, for instance, CF3, OCF3, and SCF3 groups on complex molecules have become far safer and more accessible in the last few decades (and these groups have since become commonplace in drug design), there remain a number of fluorinated groups with untapped potential that cannot be easily synthesized yet. This proposal specifically identifies the SF5, N(CF3)2, and N(CF3)(CF2H) groups as desirable motifs that have demonstrated promise yet continue to be underemployed due to the fact that there are virtually no user-friendly methods to make them. Accordingly, the proposed work is centered on addressing the synthetic chemistry bottlenecks that are preventing the realization of applications of these fluorinated groups. For one, the SF5 group has been studied as a bioisosteric replacement for a CF3 or t-Bu group, but only aryl-SF5 compounds have been made available commercially. Given the recent increase in accessibility of SF5Cl, we can now envision ways to expand the realm of possibility in C(sp3)–SF5 bond formation. Specifically, SF5 radical chemistry can be merged with strain- release functionalization to form novel “hybrid bioisosteres” that add another dimension of flexibility in molecular design. Methods are also envisioned to synthesize and examine some of the first benzylic-SF5 compounds, as well as other potential building blocks for the medicinal chemistry toolkit. The N(CF3)2 group (notably distinct from N–CF3) is arguably even less accessible/explored than the SF5 group, but it has demonstrated promise as a lipophilic NO2 group alternative. While all known methods make this group to date strictly require F2 or aHF, our approaches seek reasonable ways to circumvent these reagents altogether. This will make the N(CF3)2 group available to a significantly broader community of scientists. Lastly, the N(CF3)(CF2H) group is evidently the least accessible of them all, but it is liable to be an interesting alternative to the N(CF3)2 group with its added ability to serve as a lipophilic hydrogen-bond donor. We have envisioned ways to make this that avoid the current reliance on toxic SF4 gas. In all, safer methods to make the SF5, N(CF3)2, and N(CF3)(CF2H) groups will enable the study of their physical properties and how ...