# Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis

> **NIH NIH F32** · HARVARD UNIVERSITY · 2022 · $67,582

## Abstract

Project Summary/Abstract: Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding
Catalysis
Nucleophilic aromatic substitution (SNAr) is one of the most broadly utilized reactions in pharmaceutical and
medicinal chemistry, allowing access to aromatic and heterocyclic molecules. Despite its enormous importance, the
scope of this reaction class remains constrained by its intrinsic mechanistic features. As a result, the diversity of
structures that can be explored in medicinal chemistry research using SNAr is relatively limited. Existing methods
suffer from several limitations: 1) reliance on harsh reaction conditions and powerful stoichiometric reagents, which
limits functional group compatibility, 2) required use of aryl substrates with strongly electron withdrawing groups,
which inherently restricts the scope of accessible products, 3) reliance on aryl electrophiles with halide leaving
groups, precluding the use of inexpensive phenol, anisole, and aniline feedstock chemicals and producing large
quantities of halogenated waste. Alternative cross coupling approaches often rely on expensive transition metal
catalysts that must be removed assiduously before biological testing. The use of SNAr to generate medicinally
valuable enantioenriched structures is largely unexplored.
 An attractive new approach would be to use an organocatalyst to promote an asymmetric SNAr reaction in which
tertiary or even quaternary enantioenriched stereocenters might be generated by coupling unactivated aryl
electrophiles and prochiral nucleophiles such as enolates. This approach would address each of the previously
mentioned key limitations.
 Hydrogen-bond donor (HBD) organocatalysts are known to activate neutral organic molecules via leaving group
binding while also controlling the stereochemical outcome of nucleophilic trapping of these species. By leveraging
the powerful transition state stabilization and synergistic dual nucleophilic and electrophilic activation capabilities
unique to HBD catalysts, this approach should enable previously unfeasible SNAr reactions to be accomplished with
exquisite site- and enantioselectivity.
 The goal of this proposal is to design a leaving group binding organocatalyst that will catalyze the first general and
synthetically useful asymmetric SNAr reaction capable of merging unactivated aryl electrophiles and prochiral
nucleophiles. The research plan outlines a strategy to develop such a catalyst system guided by hypothesis-driven
experimentation, computational modeling, and structure-activity studies. To add to the information gained in the
reaction development, a detailed mechanistic study of HBD organocatalyst activation of simple aryl electrophiles
such as anisole, analine, and phenol derivatives, as well as more traditional aryl halides will be undertaken using
data-intensive multi-dimensional correlation. This study will enable simple and inexpensive bench-stable feedstock
aryl electrophiles to be utilized to pr...

## Key facts

- **NIH application ID:** 10311063
- **Project number:** 5F32GM136042-03
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Gabriel J Lovinger
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 5
- **Project period:** 2020-01-10 → 2023-07-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311063

## Citation

> US National Institutes of Health, RePORTER application 10311063, Asymmetric Nucleophilic Aromatic Substitution Enabled by Hydrogen-Bonding Catalysis (5F32GM136042-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10311063. Licensed CC0.

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