Project Summary Despite decades of reaction development, medicinal chemists still frequently face synthetic barriers when preparing molecules with potential therapeutic value. For example, the substitution of C–H bonds for C–F bonds in a target molecule can improve its metabolic stability, membrane permeability, and biological activity, but this substitution is often impossible to realize in the laboratory. This obstacle arises because the fluorination of otherwise simple building blocks or reagents generally renders them gaseous, toxic, corrosive, or unstable. While this “reagent problem” is not limited to organofluorine chemistry, it has prevented significant advances in this area. Therefore, the overall objective of the proposed research is to “tame” the reactivity of fluorinated building blocks and enable their use for the construction of complex fluorinated molecules. Specifically, the proposed multidisciplinary program aims to employ insoluble porous nanomaterials, which commonly serve as “hosts” for “guest” molecules in materials science, to control the reactivity of fluorinating agents. The resulting heterogeneous species will function as “nanovessels” capable of controllably releasing the stored reagents or as “nanoreactors” that facilitate new transformations within their pores. The central hypothesis of this proposal is that metal–organic frameworks, a relatively new class of porous, crystalline materials constructed from organic “linkers” and inorganic “secondary building units,” are the ideal platform to achieve this objective due to their unparalleled structural tunability. This research aim is part of the PI’s broader research program to unlock the potential of metal–organic frameworks for applications in organic synthesis, medicine, and structural biology. The proposed research is composed of three comprehensive projects that target specific challenges of working with fluorinated reagents, all of which can be translated to applications involving non-fluorinated building blocks as well. First, fluorination depresses the boiling point of molecules, rendering most simple building blocks (such as trifluoromethyl iodide, CF3I) gases at room temperature. By using metal–organic frameworks to reversibly sequester these gases into the solid state, medicinal chemists will be able to safely handle them as powders. Second, fluorinated anions such as trifluoromethoxide (CF3O–) are typically unstable, and one of the most promising avenues to utilize them in organic synthesis – stabilization in stoichiometric late transition metal complexes – is hindered by purification, cost, and reliability concerns. This proposal aims to overcome these challenges by moving these complexes to the solid state as recyclable metal–organic framework ”nanoreactors.” Last, radical and electrophilic fluorinated building blocks can be tricky to prepare and often have undesirable reactivity patterns. This proposal aims to overcome these limitations by building on known reactivity in molecular complexes and metal–organic frameworks to generate these species in controlled fashion at high-valent metal centers. Overall, the proposed research program is significant because over the next five years it will enable the preparation of previously inaccessible fluorinated compounds and their evaluation as next-generation medicines.

Project Narrative Fluorine is a ubiquitous element in active pharmaceuticals, but its controlled installation presents a significant challenge due to the volatile reactivity of many fluorinating agents. This proposal aims to tackle this challenge by a completely new, multidisciplinary approach that borrows from materials science, namely, to stabilize reactive fluorinated species in porous, sponge-like materials and deliver them on demand. The success of the proposed research will open up new avenues in the synthesis of biologically active molecules and, more broadly, demonstrate the unrealized potential of porous materials in medicine and human health.