# Mechanistically guided improvement in radical alkene coupling by base metal catalysts

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $286,954

## Abstract

Project Summary/Abstract
HAT (hydrogen atom transfer) alkene reactions offer the opportunity to functionalize unactivated
alkenes under mild conditions, creating highly substituted carbon sites that are prevalent in
biologically active molecules. However, the rational design of catalysts for HAT alkene reactions
with higher yield, faster rates, and less waste is currently held back by a lack of mechanistic
information. A particular challenge is the discovery of structure and reactivity trends for the
hydride complexes that perform the key HAT step. The proposed project aims to improve the
HAT alkene reactions through study of metal-hydrides and radical intermediates in the catalytic
cycle of HAT alkene reactions, starting with alkene cross-coupling and continuing to other
alkene hydrofunctionalization reactions. The expected outcome of these studies is that the HAT
alkene reactions will become possible at or below room temperature, with high chemoselectivity,
regioselectivity, and stereoselectivity. This will include the first examples of enantioselective
HAT alkene reactions. The PI, Patrick Holland, is an expert in mechanistic studies with
paramagnetic iron-alkyl and iron-hydride compounds, and the project will provide rigorous
identification of the structures, spectroscopy, reactions and mechanisms that are relevant to the
catalytic cycle. A special focus in the first funding period will be the iron-catalyzed reductive
cross-coupling of alkenes, where we will leverage our discovery of important but unrealized
aspects of the mechanism such as the presence of proton-coupled electron transfer from metal-
alcohol species. The lessons learned will be applied to a broad family of radical C-C and C-N
bond coupling reactions catalyzed by Mn, Co, and Fe. These advances will make the HAT
alkene reactions milder and higher-yielding, will minimize byproducts/waste, and will
accommodate a broader range of substrates for preparation of biologically relevant products.
The enantioselective versions of the alkene cross-coupling reactions will provide a new route to
heavily substituted, stereodefined carbon sites that are useful in natural products and bioactive
molecules.

## Key facts

- **NIH application ID:** 9906258
- **Project number:** 5R01GM129081-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PATRICK L HOLLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $286,954
- **Award type:** 5
- **Project period:** 2019-04-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906258

## Citation

> US National Institutes of Health, RePORTER application 9906258, Mechanistically guided improvement in radical alkene coupling by base metal catalysts (5R01GM129081-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906258. Licensed CC0.

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