# Catalysts Bearing Traceless Tethers for Single Step Meta and Para C-H Functionalization

> **NIH NIH R21** · UNIVERSITY OF MEMPHIS · 2020 · $204,990

## Abstract

Project Summary/Abstract
Rapid development of new target drugs, essential to the improvement of public health, is reliant
on the ability to efficiently synthesize a wide range of organic molecules, commonly substituted
arenes. Regioselective derivatization of aromatic substrates is most commonly accomplished
using cross-coupling reactions. Unfortunately, regioselectivity is attained at the expense of
stoichiometric quantities of various, often toxic, waste products. To decrease the need for costly
separation associated with current synthetic practices, direct functionalization of C-H bonds
provides a promising, atom-economical alternative. However, controlling reaction selectivity
becomes challenging due to the large number of energetically similar C-H bonds in any given
arene substrate. While “directed activation” strategies are now well-known to provide selective
ortho-functionalization of substituted arenes, analogous one-step directed functionalization of
arenes at meta- and para- C-H bonds has remained elusive. In this project, catalysts will be
developed which allow for direct, one-step, meta- and para- C-H functionalization of
benzaldehydes and benzylamines. Developed systems will rely on ligand “tethers” which will
dock and orient the substrate molecule in such a way that kinetically favors reaction at the
desired C-H bond. In principle, the methodology developed could be used to selectively
functionalize ANY C-H bond in ANY molecule that contains an aldehyde or amine functional
group. This extremely powerful contribution to the field of synthetic organic chemistry
has the potential to revolutionize pharmaceutical synthesis.
Three specific aims have been developed to further guide the proposed work. (1) Design and
synthesis of tether ligands. Designed ligands must serve to both dock and orient the
substrate in the proper manner for regioselective functionalization. Ligands will be designed
computationally to ensure that the geometrical parameters for proper orientation are met. (2)
Synthesis and stability of organometallic complexes bearing ligand tethers. With ligands
in hand, the synthesis of palladium complexes will be undertaken. Eventual catalytic conditions
will require the presence of both acid and water. The stability of our prospective catalysts under
these conditions will be evaluated. (3) Catalyst testing and substrate scope. Complexes will
be evaluated for their ability to facilitate C-H functionalization based on reaction rate and
regioselectivity. Functional group tolerance will also be explored. In the long term we will work
to extend our “tether” methodology to additional pharmaceutically relevant substrate classes.

## Key facts

- **NIH application ID:** 9989872
- **Project number:** 5R21GM134339-02
- **Recipient organization:** UNIVERSITY OF MEMPHIS
- **Principal Investigator:** Timothy Brewster
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $204,990
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989872

## Citation

> US National Institutes of Health, RePORTER application 9989872, Catalysts Bearing Traceless Tethers for Single Step Meta and Para C-H Functionalization (5R21GM134339-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989872. Licensed CC0.

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