# Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks

> **NIH NIH R35** · CORNELL UNIVERSITY · 2021 · $380,718

## Abstract

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 kno...

## Key facts

- **NIH application ID:** 10225599
- **Project number:** 5R35GM138165-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Phillip John Milner
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,718
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225599

## Citation

> US National Institutes of Health, RePORTER application 10225599, Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks (5R35GM138165-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225599. Licensed CC0.

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