Fluoroarenes—chemical building blocks used in many medicines and agrochemicals—could be made directly from calcium fluoride, a common mineral, bypassing the need to manufacture and transport toxic hydrogen fluoride gas. The chemical industry relies on fluoroarenes for drugs that improve patient care and for pesticides that support food security. But making them today requires hydrogen fluoride, a highly hazardous substance that must be shipped under strict safety controls. Supply chain disruptions and the risks of handling this material create real costs and vulnerabilities. The researchers have already invented a solid-state reagent, Fluoromix™, that works with calcium fluoride, but it only works on a narrow range of starting materials and gives modest yields. This project aims to develop a new method that activates calcium fluoride in solution, allowing it to be used with a much wider variety of chemical precursors. If successful, the approach could enable kilogram-scale production of fluoroarene building blocks from either natural or waste calcium fluoride. That would reduce dependence on hydrogen fluoride, simplify supply chains, and lower the environmental and safety burden of manufacturing essential fluorochemicals. The work is applied chemistry with a clear industrial target, not fundamental science.
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The chemical sector including its fluorochemical segment is facing pressing challenges including the management of raw materials, transportation disruptions, complex and unreliable supply chains, and climate change. This new urgency encouraged us to revisit fluorine chemistry with global challenges in mind. One class of essential fluorochemicals are fluoroarenes because of their pivotal role in medicinal and agrochemical chemistry; indeed, fluorine substitution generally improves the bioavailability, lipophilicity, and metabolic stability of target molecules. In the past decades, numerous elegant synthetic strategies to forge fluoroarenes have been developed with new reactivities featuring diverse arene precursors, fluorinating reagents and catalysts. These spectacular advances have supported countless research and development programs in the pharmaceutical and agrochemical industry as well as in materials science. Innovation for beneficial impact on the manufacturing of fluoroarenes has received less attention. We propose to revisit the synthesis of fluoroarenes with global challenges in mind. Specifically, we aim to prepare fluoroarenes and fluoroheteroarenes building blocks directly from calcium fluoride (CaF2) applying a strategy bypassing the necessity to manufacture, transport and supply toxic and highly hazardous hydrogen fluoride (HF). In previous work, we formulated a solution with the invention of the new reagent FluoromixTM that was prepared by ball milling calcium fluoride with a phosphate salt. This reagent was applied to access fluoro(hetero)arenes derived from highly activated precursors amenable to SNAr, albeit in modest yields. We now propose to invent a novel strategy to activate calcium fluoride in solution to enable its use for the synthesis of fluoroarenes with diverse electronic properties and substitution patterns. Both natural and waste calcium fluoride will be considered as fluoride source for the kilogram scale production of fluoroarenes building blocks that are essentials for the synthesis of critically needed fluorochemicals used as medicines for patient care, or as agrochemicals for food security.
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