# Model Systems for C-H Bond Transformations through Multiple-Site Concerted Proton-Electron Transfer

> **NIH NIH F32** · YALE UNIVERSITY · 2020 · $64,926

## Abstract

Project Summary/Abstract
 C–H bond transformations lie at the heart of numerous metabolic pathways throughout the
biosphere. Oxidoreductase enzymes manipulate strong X–H bonds (X = C, N, O) with limited free
energy expenditure through a process known as multiple-site concerted proton-electron transfer
(MS-CPET) which underlies photosynthesis, respiration, and complex biomolecule synthesis. In
many of these reactions, the proton transfer coordinate is guided by pre-aligned hydrogen
bonding interactions, which are absent with C–H bonds. Consequently, the mechanisms of many
CH-CH oxidoreductase enzymatic reactions are not known despite the large number that rely on
distant electron transfer cofactors. Therefore, deriving principles behind MS-CPET involving C–H
bonds would be immensely informative to unveiling how a significant amount of enzymes function
in the biosphere.
 In this proposal, we seek to understand how the proton transfer coordinate governs C–H bond
reactivity through MS-CPET using molecular models. Specifically, we will probe how key aspects
such as proton transfer pre-alignment and proton tunneling distance affect C–H bond cleavage
through structural variation. We will also derive essential thermochemical principles for reductive
C–H bond formation in a stable radical system to develop kinetic free energy relationships. Finally,
we will build upon these kinetic and thermochemical models to assess the reductive
hydrogenation mechanism of aromatic substrates central to anaerobic microbe metabolism. Our
goal is to develop a mechanistic understanding of MS-CPET with C-H bonds in our model systems
to illuminate unknown CH-CH oxidoreductase reactivity. This research will help elucidate how
enzymes perform difficult C–H bond transformations and guide synthetic chemists towards new
approaches for manipulating strong bonds.
 My postdoctoral training in the Mayer group will expand my research skillset through learning
mechanistic and kinetic studies as well as allowing me to hone my mentorship, writing, and
presenting skills. Importantly, this training will teach me new ways to think and approach scientific
problems allowing me to expand the scope of research I can address in my future independent
career. Yale University fosters an ideal environment to train me with its exceptional facilities,
seminar and teaching opportunities, and prominent faculty who are experts in synthetic organic,
theoretical, and biological chemistry. I believe my training will sufficiently equip me to be a leading
independent researcher and teacher at an academic institution in the future.

## Key facts

- **NIH application ID:** 10067976
- **Project number:** 1F32GM139266-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Scott Christopher Coste
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067976

## Citation

> US National Institutes of Health, RePORTER application 10067976, Model Systems for C-H Bond Transformations through Multiple-Site Concerted Proton-Electron Transfer (1F32GM139266-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067976. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*