# New Synthetic Methods Enabled by Excited-State Redox Chemistry

> **NIH NIH R35** · PRINCETON UNIVERSITY · 2021 · $542,114

## Abstract

Project Summary
The work described in this proposal aims to develop novel synthetic methods enabled by excited-state redox
events to address longstanding challenges in catalysis and synthetic organic chemistry. A primary focus of this
proposal is the continued development of proton-coupled electron transfer (PCET) technologies in organic
synthesis. In particular we focus on developing PCET-based methods for the catalytic functionalization of
aliphatic C-C bonds, including redox-neutral isomerization reactions of cyclic alcohols to form linear carbonyl
compounds, and novel methods for the catalytic ring-expansion and ring-contraction of carbocyclic alcohols.
We also discuss efforts to develop a new class of chiral amide-based catalysts that can be activated by PCET
to generate transient amidyls, which can then mediate enantioselective and site-selective functionalization of
aliphatic C-H bonds. A second goal of this work is the development of out-of-equilibrium synthetic methods
enabled by excited-state redox events. These technologies provide opportunities to use photon absorption
events to drive reaction against a thermochemical gradient, but without requiring generation of excited state
substrates. Importantly, these methods provide novel approaches to achieve non-Boltzmann product
distributions and reaction outcomes that are not, by definition, possible to obtain using conventional ground-
state methods. Applications to the development of light-driven deracemization reactions are presented. A third
goal is to advance our efforts in developing photocatalytic methods for olefin hydroamination and
hydroetherification. We propose to develop the first general catalytic protocol for intermolecular anti-
Markovnikov hydroamination reactions between unactivated olefins with primary alkyl amines to yield
secondary amine products, selectively, based on the chemistry of aminium radical cations. PCET-based
methods for enantioselective hydroaminations with sulfonamides are also proposed, wherein the asymmetric
induction is proposed to arise from direct non-covalent interactions between a chiral H-bond donor and a
neutral N-centered radical intermediate. We also present plans to develop analogous intermolecular
hydroetherification methods and their enantioselective variants. If successful, these efforts will provide valuable
new reactions and concepts for the chemistry communities engaged in the discovery, synthesis, and
manufacture of pharmaceuticals and other small-molecule probes of biological function, and thus create a
significant benefit to human health.

## Key facts

- **NIH application ID:** 10077567
- **Project number:** 5R35GM134893-02
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Robert R Knowles
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $542,114
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077567

## Citation

> US National Institutes of Health, RePORTER application 10077567, New Synthetic Methods Enabled by Excited-State Redox Chemistry (5R35GM134893-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10077567. Licensed CC0.

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