Organic Synthesis Using Nitroxides

Abstract

Nitroxides, also known as nitroxyl radicals, are long-lived or stable radicals with the general structure R 1 R 2 N−O • . The spin distribution over the nitroxide N and O atoms contributes to the thermodynamic stability of these radicals. The presence of bulky N-substituents R 1 and R 2 prevents nitroxide radical dimerization, ensuring their kinetic stability. Despite their reactivity toward various transient C radicals, some nitroxides can be easily stored under air at room temperature. Furthermore, nitroxides can be oxidized to oxoammonium salts (R 1 R 2 N�O + ) or reduced to anions (R 1 R 2 N−O − ), enabling them to act as valuable oxidants or reductants depending on their oxidation state. Therefore, they exhibit interesting reactivity across all three oxidation states. Due to these fascinating properties, nitroxides find extensive applications in diverse fields such as biochemistry, medicinal chemistry, materials science, and organic synthesis. This review focuses on the versatile applications of nitroxides in organic synthesis. For their use in other important fields, we will refer to several review articles. The introductory part provides a brief overview of the history of nitroxide chemistry. Subsequently, the key methods for preparing nitroxides are discussed, followed by an examination of their structural diversity and physical properties. The main portion of this review is dedicated to oxidation reactions, wherein parent nitroxides or their corresponding oxoammonium salts serve as active species. It will be demonstrated that various functional groups (such as alcohols, amines, enolates, and alkanes among others) can be efficiently oxidized. These oxidations can be carried out using nitroxides as catalysts in combination with various stoichiometric terminal oxidants. By reducing nitroxides to their corresponding anions, they become effective reducing reagents with intriguing applications in organic synthesis. Nitroxides possess the ability to selectively react with transient radicals, making them useful for terminating radical cascade reactions by forming alkoxyamines. Depending on their structure, alkoxyamines exhibit weak C−O bonds, allowing for the thermal generation of C radicals through reversible C−O bond cleavage. Such thermally generated C radicals can participate in various radical transformations, as discussed toward the end of this review. Furthermore, the application of this strategy in natural product synthesis will be presented.

Recent advancements in the use of Bobbitt's salt and 4-acetamidoTEMPO

“…1 Nitroxyl radicals serve as excellent electrochemical mediators as they readily oxidize to an oxoammonium species under a variety of electrochemical conditions. 98–100 To date, there are various electrochemical methods that can be employed to oxidize alcohols and aldehydes with nitroxyl radicals. 101 The employment of ACT ( 2 ) in electrochemistry was pioneered by Bobbitt in 1991, for the efforts of oxidizing alcohols with a TEMPO-modified electrode.…”

Sequential C−F Bond Transformation of the Difluoromethylene Unit in Perfluoroalkyl Groups: A Combination of Fine‐Tuned Phenothiazine Photoredox Catalyst and Lewis Acid

“…Herein we propose a reaction design based on a sequential process via radical and ionic paths (Figure 1C). The primary substitution of F with RO groups involves C−F bond activation by photocatalysis [4g] and capture of the perfluoroalkyl radical by an oxyl radical [10] . Then the second transformation employs a Lewis acid and nucleophiles.…”

TEMPO-Grafted Polystyrene/Polymethacrylate Organosiloxane Janus Nanohybrids as Efficient Pickering Interfacial Catalyst for Selective Aerobic Oxidation of Cinnamyl Alcohol

“…To eliminate the above obstacles, several strategies have been applied, particularly the functionalization of TEMPO on solid materials, which makes the system heterogeneous and simplifies the recovery process. Therefore, effective separation and recovery of TEMPO for practical applications is highly desirable to make the Anelli–Montanari alcohol oxidation process more sustainable in industries. − …”