Arene and Heteroarene Functionalization Enabled by Organic Photoredox Catalysis
Zhengbo Zhu1,2, Xuedan Wu1, Zibo Li1
1Department of Radiology, Biomedical Research Imaging Center, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Accounts of Chemical Research
|March 12, 2025
Summary
New methods for aromatic functionalization use photoredox catalysts to generate arene cation radicals, enabling C-H functionalization or nucleophilic aromatic substitution (SNAr) for diverse applications.
Area of Science:
- Organic Chemistry
- Synthetic Methodology
- Photoredox Catalysis
Background:
- Traditional aromatic functionalization methods like electrophilic aromatic substitution (EAS) and nucleophilic aromatic substitution (SNAr) have limitations based on substrate electronics.
- Developing alternative strategies is crucial for expanding the scope of accessible chemical space in arene elaboration.
- Electron-rich arenes are typically unreactive towards nucleophiles, presenting a challenge for synthetic chemists.
Purpose of the Study:
- To develop novel methods for the functionalization of electron-neutral and electron-rich arenes, particularly for late-stage applications.
- To explore the reactivity of arene cation radicals generated via photoredox catalysis.
- To investigate the application of these novel methods in developing radiotracers for positron emission tomography (PET).
Main Methods:
- Single electron oxidation of electron-rich arenes using photoredox catalysts under irradiation to form arene cation radicals.
- Investigating the dichotomy of reactivity: C-H functionalization under aerobic conditions and cation radical accelerated nucleophilic aromatic substitution (CRA-SNAr) under anaerobic conditions.
- Utilizing experimental and computational studies to understand reaction mechanisms and regioselectivity.
Main Results:
- Arene cation radicals exhibit high reactivity towards nucleophiles, enabling functionalization of typically unreactive arenes.
- Aerobic conditions favor C-H functionalization via *para*- or *ortho*-addition to the arene cation radical, followed by oxidation.
- Anaerobic conditions promote *ipso*-addition, leading to SNAr products with alcohol or HF nucleofuges.
Conclusions:
- Photoredox-generated arene cation radicals provide a versatile platform for both C-H functionalization and SNAr reactions.
- These methods offer expanded chemical space for arene functionalization, overcoming limitations of traditional approaches.
- Successful application in radiofluorination and radiocyanation for PET radiotracer development demonstrates the practical utility of these transformations.
![Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F60786.jpg&w=3840&q=50)
Related Concept Videos
02:17Reduction of Alkenes: Asymmetric Catalytic Hydrogenation
3.2K
Catalytic hydrogenation of alkenes is a transition-metal catalyzed reduction of the double bond using molecular hydrogen to give alkanes. The mode of hydrogen addition follows syn stereochemistry.
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an...
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an...
3.2K
01:26Photochemical Electrocyclic Reactions: Stereochemistry
1.8K
The absorption of UV–visible light by conjugated systems causes the promotion of an electron from the ground state to the excited state. Consequently, photochemical electrocyclic reactions proceed via the excited-state HOMO rather than the ground-state HOMO. Since the ground- and excited-state HOMOs have different symmetries, the stereochemical outcome of electrocyclic reactions depends on the mode of activation; i.e., thermal or photochemical.
Selection Rules: Photochemical Activation
Selection Rules: Photochemical Activation
1.8K
01:12Cycloaddition Reactions: MO Requirements for Photochemical Activation
2.0K
Some cycloaddition reactions are activated by heat, while others are initiated by light. For example, a [2 + 2] cycloaddition between two ethylene molecules occurs only in the presence of light. It is photochemically allowed but thermally forbidden.
2.0K
02:13Reduction of Alkenes: Catalytic Hydrogenation
11.8K
Alkenes undergo reduction by the addition of molecular hydrogen to give alkanes. Because the process generally occurs in the presence of a transition-metal catalyst, the reaction is called catalytic hydrogenation.
Metals like palladium, platinum, and nickel are commonly used in their solid forms — fine powder on an inert surface. As these catalysts remain insoluble in the reaction mixture, they are referred to as heterogeneous catalysts.
The hydrogenation process takes place on the...
Metals like palladium, platinum, and nickel are commonly used in their solid forms — fine powder on an inert surface. As these catalysts remain insoluble in the reaction mixture, they are referred to as heterogeneous catalysts.
The hydrogenation process takes place on the...
11.8K
02:36Regioselectivity and Stereochemistry of Hydroboration
8.0K
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn...
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn...
8.0K
01:25Radical Anti-Markovnikov Addition to Alkenes: Overview
3.2K
The addition of hydrogen bromide to alkenes in the presence of hydroperoxides or peroxides proceeds via an anti-Markovnikov pathway and yields alkyl bromides.
3.2K