Nitrogen-Centered Radicals in Visible-Light-Promoted Reactions

Abstract

Nitrogen-centered radicals (NCRs) have been known in the literature since the beginning of the 1900s, but only with the spread of photoredox catalysis, and in particular visible-light-mediated radical processes, has nitrogen-radical chemistry become more accessible via the in situ generation of such radicals under mild conditions. Historically, unlike their carbon counterparts, nitrogen radicals were not utilized widely in academia or industry due to a lack of efficient strategies for their production. Nowadays, NCRs are more established, and this graphical review highlights key publications from the literature, categorizing them by both the type of NCR and the type of reaction. Such nitrogen radicals can be divided into four different categories according to their electronic configuration, orbital structure and chemical behavior. Additionally, the reactivity of these radicals is mostly exploited via four main types of process: (i) intramolecular cyclization, (ii) intramolecular hydrogen atom abstraction, (iii) Norrish type I fragmentation, and (iv) intermolecular addition to π systems.

Key words

nitrogen radicals - photoredox catalysis - visible-light-driven reactions - amidyl radicals - cyclizations - addition to π systems - hydrogen atom transfer

Biosketches

Monica F. Boselli earned her master’s degree in chemical science in 2019 at the University of Milan, Italy. She then worked as an Erasmus+ fellow for five months in Prof. Markus Kalesse’s group at the University of Hannover, Germany, as part of the yearly Master Internship Program focused on total synthesis. Following graduation, she worked as a fellowship student in the group of Prof. Maurizio Benaglia at the University of Milan, where she developed continuous-flow processes. In June 2024, she completed her Ph.D. in chemistry under the guidance of Prof. Alessandra Puglisi, with a thesis on amidyl radicals in light-promoted reactions. During her Ph.D., she worked for six months in Prof. Burkhard Koenig’s group at the University of Regensburg, Germany. Currently she is a postdoctoral fellow researching the fields of stereoselective photocatalysis and organocatalysis under the direction of Prof. Sergio Rossi and Prof. Maurizio Benaglia at the University of Milan.

Fabrizio Medici earned his master’s degree in chemical science (organometallic chemistry) in 2014 under the supervision of Prof. Angelo Maspero at the University of Insubria, Como, Italy. He subsequently moved to UPMC, Sorbonne University, Paris, where he received his Ph.D. in 2017 in molecular science under the supervision of Prof. Louis Fensterbank and Dr. Gilles Lemiere with a thesis entitled: Interactions Between the Martin’s Spirosilane and Lewis Bases: Coordination, Frustration and New Anionic Ligands. He then joined the group of Dr. Angela Marinetti and Dr. Arnaud Voituriez at the ICSN-CNRS, Gif-sur-Yvette, France, to undertake postdoctoral studies focused on Au(I) catalysis. He returned to Italy in 2020 to commence postdoctoral studies at the University of Milan under the supervision of Prof. Alessandra Puglisi and then Prof. Maurizio Benaglia, studying organic photochemistry, organic electrochemistry and flow synthesis. Currently, he is an RTDA (Tenure Track Professor) at the University of Milan as part of the MUSA project under the PNRR plan.

Francesca Franco earned her master’s degree in chemical science in 2018 in organometallic chemistry under the supervision of Prof. Mina Mazzeo and Prof. Chiara Costabile at the University of Salerno, Italy. She subsequently switched to organic chemistry and completed her Ph.D. in 2022 under the guidance of Prof. Alessandra Lattanzi with a thesis entitled: Exploring Batch and Flow Catalytic Reactions as Valuable Tools for Safer and Greener Synthesis of APIs and Their Fluorine Intermediates. During her Ph.D. studies she spent three months at Laboratori Alchemia and six months at the University of Milan. After completing her Ph.D., she moved to the University of Pavia to work as a postdoctoral researcher in Prof. Giuseppe Zanoni’s group, focusing on the application of biomimetic reactions in the synthesis of natural compounds. Currently, she is employed on a postdoctoral fellowship studying the fields of electrochemistry and stereoselective organocatalysis under the direction of Prof. Maurizio Benaglia at the University of Milan.

Organic compounds bearing nitrogen atoms are widely found in pharmaceutical and agrochemical products. In fact, the use of C–N cross-coupling methods in medicinal chemistry accounts for approximately 23% of reported reactions in recent publications, highlighting the ubiquitous nature of this transformation. Furthermore, functionalized amine and amide products are important building blocks in active pharmaceutical ingredients (APIs). For this reason, new and green synthetic strategies to construct C–N bonds under mild conditions are a central goal for chemists. In traditional chemistry, sp² C–N bonds are typically formed by Pd-catalyzed Buchwald–Hartwig reactions or Cu-catalyzed Ullman–Goldberg reactions, while sp³ C–N bonds are usually installed through reductive amination and alkylation, Gabriel synthesis and Hoffman degradation. However, these approaches have the same drawbacks: the requirement for prefunctionalization of the substrates and the use of high temperatures.

In recent decades, with the increased use of photocatalysis and, in particular, visible-light-mediated radical processes, nitrogen-radical chemistry has become more accessible. This revolutionary technique has made it possible to develop novel and previously unattainable synthetic approaches. Photocatalysis describes transformations that require light as an energy input to proceed, and they typically use catalytic amounts of light-absorbing photocatalysts such as metal complexes or organic dyes. Moreover, photocatalysis is characterized by the use of low-energy photons as reagents, opening the door to environmentally safe, more sustainable, and non-hazardous visible-light-based chemical synthesis.

Nitrogen radicals can be divided into four different types according to their electronic configuration, orbital structure and chemical behavior. Iminyl radicals possess an sp²-hybridized nitrogen atom, a planar structure and a σ-configuration with amphiphilic behavior. Amidyl radicals have single electrons in a p orbital perpendicular to the nitrogen substituents, so they assume a π-configuration with electrophilic chemical behavior. Meanwhile, aminyl and aminium radicals both have a π-configuration but opposite reactivity. In fact, aminyl radicals are weak nucleophiles and are commonly utilized for their preference for H-atom abstraction, while aminium radicals are strong electrophiles. Although there are other types of nitrogen radicals, these four main classes can be used to illustrate their reactivity (e.g., carbamyl radicals and N-Ts radicals are consistent with the behavior of amidyl radicals). The philicity of radicals has been effectively defined by computational and experimental studies, and is a crucial parameter for developing new radical reactions.

The best way to generate nitrogen radicals is via cleavage promoted by light under mild conditions. In particular, the most suitable bonds to be broken are N–H, N–halogen, N–N, N–O and N–S. There are four main strategies to break these types of bond: homolytic cleavage, reduction, oxidation and oxidative proton-coupled electron transfer (PCET).

Homolytic cleavage can occur when an N–halogen, N–N, N–O or N–S bond is irradiated with UV light, generating two radical species that can lead to the desired transformation. The second and third methods involve a photoredox quenching cycle, which can be oxidative or reductive depending on the reaction counterparts. In detail, in the reductive quenching cycle, single-electron transfer (SET) occurs to generate a nitrogen-radical cation in two different ways: the electron can be abstracted either directly from the HOMO of the precursor or from an oxidizable group external to the key NCR moiety which can undergo a fragmentation (e.g., a decarboxylative cascade mechanism). Also, in the oxidative quenching cycle, the SET can occur via two different pathways: the electron can be donated either directly to the σ*-orbital of the nitrogen radical or to a π*-orbital of a suitable precursor (e.g., hydroxylamine and pyridinium ions). In oxidative PCET, the nitrogen-radical precursor undergoes concerted homolytic activation through the formation of a hydrogen bond complex between the N–H of the amide and a suitable base.

The reactivity of all these radicals can be classified into four main types: (i) intramolecular cyclization onto alkenes or alkynes via a classic exo-trig process, (ii) intramolecular hydrogen atom abstraction (e.g., 1,5-HAT), (iii) Norrish type I fragmentation (with limited examples), and (iv) intermolecular addition to π-systems such as olefins, alkynes and aromatic compounds. It is significant to highlight the fact that not all the classes of nitrogen radicals share these reaction modes, since it is their philicity that stabilizes (or destabilizes) the corresponding transition states.

In this graphical review, we have summarized the most well-known published examples of nitrogen-radical reactions, grouping them by their reactivity and the type of radical generated. Although there are numerous examples of reactions involving nitrogen-centered radicals in the literature, we will limit our report to reactions involving visible light.

Figure 1 Overview of nitrogen-centered radicals[1`] [b] [c] [d]

Figure 2 Intramolecular cyclizations for the synthesis of cyclic amines and substitutes indoles[2`] [b] [c] [d] [e] [f] [g]

Figure 3 Iminyl radical intramolecular cyclization for the synthesis of heteroarenes and functionalized pyrrolidines[3`] [b] [c]

Figure 4 Iminyl radical intramolecular cyclization for the synthesis of heteroarenes and functionalized pyrrolidines[4`] [b] [c]

Figure 5 Synthesis of γ-lactams and substituted pyrazoles via 5-exo-trig cyclization[5a] [b]

Figure 6 Bioactive heterocycle formation[6a] [b]

Figure 7 Heterocycle and sulfonamide formation[7`] [b] [c]

Figure 8 Heterocycle formation[8`] [b] [c]

Figure 9 Heterocycle formation via 5-exo-trig cyclization[9a] [b]

Figure 10 Addition of aminium radicals to ethyl vinyl ether and benzoxazoles[10a] [b]

Figure 11 Addition of aminium radicals to olefins and arenes[11`] [b] [c] [d]

Figure 12 Addition of pyridyl radicals to arenes for the synthesis of highly tunable pyridinium salts[12a] [b]

Figure 13 Addition of aminium radicals to arenes and olefins to synthesize pyridinium salts and diamines[13a] [b]

Figure 14 Amidyl radicals in enantioselective photoredox α-aminations of aldehydes[14`] [b] [c] [d] [e]

Figure 15 Amidyl radicals in imidations and amidations of arenes and heteroarenes and the halo-functionalization of alkenes[15`] [b] [c] [d]

Figure 16 Amidyl radicals in imidations and amidations of arenes and heteroarenes and double addition to alkenes[16`] [b] [c] [d] [e]

Figure 17 Amidyl radicals in amidations of arenes and α-aminations of 2-acylimidazoles[6b] [17a] [b]

Figure 18 Amidyl radicals in arene functionalization and double addition of olefins[18`] [b] [c]

Figure 19 Amidyl radicals in three-component reactions to aliphatic amines and the synthesis of sulfonamines[19`] [b] [c]

Figure 20 Remote C–H alkylation promoted by PCET[20`] [b] [c] [d]

Figure 21 Intramolecular C(sp³)–H imination for the synthesis of functionalized imidazoles[21`] [b] [c]

Figure 22 Aliphatic C–H functionalization through a 1,5-HAT cascade[22]

Figure 23 γ-C(sp³)–H functionalization of ketones[23a] [b]

Figure 24 Norrish fragmentations[23a] [24a] [b]

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 12 July 2024

Accepted after revision: 20 September 2024

Accepted Manuscript online:
14 October 2024

Article published online:
27 November 2024