# Mild Strategies in the Direct Generation of Carbocation Intermediates from C(sp3)–H Bonds

> **NIH NIH R35** · WORCESTER POLYTECHNIC INSTITUTE · 2022 · $341,864

## Abstract

Project Summary/Abstract
 The broad goal of the proposed research is to develop highly enabling and rapid
chemical technologies for the synthesis of life-altering drug compounds. Our focus is in
the area of C–H functionalization, a synthetic strategy that is well-established to expedite
the discovery of bioactive small molecules. Since its conception, the majority of Csp3–H
functionalization methods rely on open-shell mechanistic pathways via alkyl radicals or
metal alkyl intermediates. To continue the advancement of C–H modification technologies,
there is a critical need for new mechanistic designs. We hypothesize that polar (two-
electron) mechanisms can be accessed in a C–H functionalization context to offer
orthogonal reactivity to the current state-of-the-art methods. To this end, our central
hypothesis is to design reaction platforms that can access carbocation intermediates
directly from a Csp3–H bond. The design will bypass the need for pre-installed functional
groups that are usually required to generate carbocations, thus streamlining the direct
modification of late-stage drug leads and resulting in the rapid synthesis of compound
libraries for high-throughput drug development. The innovative approach to convert
Csp3–H bonds into highly reactive carbocations is via a stepwise dismantling process: first
hydrogen atom abstraction at the desired bond followed by a radical-polar crossover, or
oxidation of a carbon radical to its cationic equivalent. With the design of the mechanism
executed with a photocatalytic platform, we envision the reaction to be mild and capable
of engaging a broad scope. The five-year goal is to utilize the proposed strategy to target
benzylic, aliphatic and a-halo C–H bonds and utilize the resulting carbocations to facilitate
high value bond formations with abundant nucleophilic partners. The proposal is
significant in that we will be investigating an underexplored reaction space that is ripe
with new synthetic opportunities that have the potential to offer modularity in approach,
simplicity of reagents, and complexity of products.

## Key facts

- **NIH application ID:** 10499683
- **Project number:** 1R35GM147021-01
- **Recipient organization:** WORCESTER POLYTECHNIC INSTITUTE
- **Principal Investigator:** Patricia Zhang Musacchio
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $341,864
- **Award type:** 1
- **Project period:** 2022-07-05 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499683

## Citation

> US National Institutes of Health, RePORTER application 10499683, Mild Strategies in the Direct Generation of Carbocation Intermediates from C(sp3)–H Bonds (1R35GM147021-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10499683. Licensed CC0.

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