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DOI: 10.1055/s-0043-1775497
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Dual-Functional Group Transfer Reagents for Dihalogenation Reactions

Egor Zhilin 
,
Rahul Giri
,
Dmitry Katayev  ∗

D.K. acknowledges the Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung (Swiss National Science Foundation) (PCEFP2_186964) for the financial support of this research.
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Abstract

Functional group transfer reagents (FGTRs) represent a powerful strategy for introducing diverse functionalities into organic molecules. Herein, we describe the development and application of novel dual-functional group transfer reagents designed to facilitate efficient and selective vicinal dihalogenation of unsaturated hydrocarbons under mild photoredox catalytic conditions. Experimental investigations, coupled with density functional theory calculations, provide detailed mechanistic insights into the reaction, highlighting a unique radical-polar crossover mechanism involving radical ‘halogen dance’ and ionic addition of molecular dihalogens. The developed dual-FGTR approach showcases superior scalability, functional group tolerance, and practical applicability in a synthetic chemistry context.

1 Introduction

2 Reagent Design

3 Transfer Dihalogenation Span

4 Mechanistic Insights

5 Conclusion


#

Key words

functional groups - FGTRs - hydrocarbons - dihalogenation - photocatalysis
1

Introduction

Zoom Image
Egor Zhilin (left) obtained his M.S. in chemistry from Lomonosov Moscow State University in 2019. He subsequently received his Ph.D. in 2022 from the Zelinsky Institute of Organic Chemistry under the supervision of Prof. Leonid Fershtat. He is currently conducting postdoctoral research at the University of Bern in the group of Prof. Dmitry Katayev. His current interests are light-driven transformations in organic chemistry. Rahul Giri (center) was born in Jharkhand, India. He completed his B.Sc. at the University of Delhi and studied for his M.S. at IISER Bhopal in the group of Prof. Alakesh Bisai. In 2021, he joined the group of Prof. Dmitry Katayev at the University of Bern, where he obtained his Ph.D. in 2025. His research is focused on the development and application of novel reagents using photo- and electrochemical methodologies. Dmitry Katayev (right) received Ph.D. from the University of Geneva. After two postdoctoral stays at TU Kaiserslautern and ETH Zürich, funded by the Swiss National Science Foundation (SNSF), he was awarded the Ambizione and Holcim Stiftung and launched his independent research at ETH Zürich in 2018. As a recipient of the Eccellenza Professorial Grant, he joined the University of Fribourg in early 2021. Shortly thereafter, in 2022, he was appointed as an Assistant Professor with Tenure Track in Organic Chemistry at the University of Bern.

Functional groups are at the core of organic chemistry as they define the physical and chemical properties of a molecule. They play a key role in determining how molecules interact in different reactions.[1] Achieving molecular diversity and modifying reactivity often rely on the addition, removal, or interconversion of functional groups.[2] In this context, halogens are important functional groups due to their versatility as synthetic tools. Halogen transfer reactions can occur through electrophilic, nucleophilic, or radical pathways, using a wide range of reagents. The use of simple approaches, such as halides under oxidative conditions and binary halogens, represent traditional methods that often possess low selectivity and handling challenges, especially in complex systems.[3] [4] [5] To overcome these limitations, organic chemists have developed efficient and selective functional group transfer reagents (FGTRs) as bench-stable alternatives to harsh reagents. A notable example are the N-halosuccinimides, which have found widespread use in halogenation chemistry.[6] For optimal efficiency and safety, these mono-FGTRs are designed to transfer a single functional group with precise modifications to the core organic framework and functional groups.[7] [8] [9] [10] [11] [12]

To access enhanced stability and a refined commercial profile, focus has shifted towards dual-FGTRs, where a single core can facilitate the successive transfer of two functional groups (Figure [1]A).[13] [14] The design principles for these reagents involve an organic structural core onto which two functional groups are installed.[15] By employing a mild activation methodology, such as photoredox catalysis[16] or electrochemistry,[17] [18] these reagents allow for precise and efficient modification of hydrocarbons through the transfer of both functional groups. The activation of these dual-transfer reagents is often enforced by an inherent thermodynamic or kinetic driving force such as unsaturation/extrusion of gas or rearomatization.[19] [20]

Diverse platforms have been created to develop dual-FGTRs, with dihalogenation being a key focus (Figure [1]B). Waldvogel, Morandi, and co-workers advanced shuttle catalysis by electrochemically activating dihaloalkanes for traceless alkene dihalogenation, driven by ethylene extrusion and release of halonium ions.[21] A similar shuttle halogenation concept was employed by the Xie group, utilizing quantum dot photocatalysis for radical dihalogenation of alkenes.[22] Recently, Oestrich and co-workers reported a dihalogen surrogate with an oxime ester core, where the activation of these reagents occurs through a radical-polar crossover mechanism under photoredox catalysis.[23]

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Figure 1 (A) Concept of functional group transfer reagents. (B) Introduction to dual-FGTRs for the dihalogenation of olefins. Y = Ph or OH.

Given our experience with FGTR development and utilization,[24] [25] [26] [27] we envisioned a rationally designed carbon-based dual-FGTR system derived from chalcone or cinnamic acid cores. The compounds are either commercially accessible or synthesized in a single step, and they serve as efficient platforms for dual-FGTRs in the dihalogenation protocol. These reagents are activated through photoredox catalysis, and their conjugative unsaturation facilitates the controlled release of molecular halogens, enabling diverse functionalization of unsaturated hydrocarbons.[28]


# 2

Reagent Design

We initiated our investigation by identifying an appropriate reagent capable of promoting efficient dihalogenation through photocatalytic activation (Scheme [1]). Considering reaction inputs, we selected an olefinic substrate as the acceptor, given its fundamental role in unsaturated hydrocarbon functionalization; styrene derivative 1 was thus employed for this purpose. Chlorine transfer emerged as the key transformation of interest. Well-established fac-Ir(ppy)3 was chosen as an optimal photocatalyst due to its potent reductive capabilities and energy transfer properties, making it particularly versatile for mediating halogen-related reactions.

Zoom Image
Scheme 1 Key FGTRs for transfer dihalogenation. FGTR screening conditions: substrate (0.5 mmol, 1.0 equiv), fac-Ir(ppy)3 (1 mol%), reagent (2.0 equiv), DMF (1.0 mL), blue LEDs, rt, 24 h.

Initially, we evaluated simple halogenated compounds, such as carbon tetrachloride and dichloroethane, and observed their inability to deliver the desired vicinal dihalide derivative 2a. This observation underscored the critical role played by the α-carbonyl motif adjacent to halogenated carbons in facilitating single-electron transfer processes. To substantiate our hypothesis regarding the necessity of activated C–Cl bond fragmentation, we synthesized a series of symmetrical and unsymmetrical α-carbonyl and α-carboxyl dihalogen derivatives and subsequently tested their effectiveness in the targeted reaction. Gratifyingly, chalcone-derived reagent I successfully provided the desired dichlorinated product 2a with a yield of 66%, exhibiting the highest yield among the investigated substrates.

Encouraged by this result, we proceeded to explore the heterodihalogen transfer reaction, particularly targeting the challenging bromochlorination of styrene. The structurally analogous FGTR reagent II yielded the target bromochlorinated compound 2b in a moderate yield of 51%. Notably, 2b was obtained exclusively as a single regioisomer, suggesting a regioselective mechanism inherent to the reaction conditions. We further extended the applicability of our photocatalytic strategy to dibromination reactions. Consistent with the dichlorination results, conventional dibromo reagents, including tetrabromoethane and dibromoethane, failed to produce the desired dibrominated products. Conversely, the chalcone-based FGTR demonstrated remarkable effectiveness. Noteworthy, α,β-dibromohydrocinnamic acid derivative III was selected as a viable alternative to chalcone-based reagents, showing comparable bromination efficiency and furnishing product 2c with 95% yield. After comprehensive optimization, reagents I , II , and III were established as essential dihalogen transfer reagents, effectively achieving dihalogenation under stoichiometric conditions.

Zoom Image
Scheme 2 Substrate scope of transfer the dichlorination, bromochlorination, and dibromination reactions. Y = Ph or OH. Standard conditions: substrate (0.5 mmol, 1.0 equiv), fac-Ir(ppy)3 (1 mol%), reagent I , II or III (1.1 equiv), DMF (1.0 mL), blue LEDs, rt, 24 h.

Further consideration was given to the practical scalability and isolation of reagents I and II . The synthetic procedures were successfully scaled up to approximately 60 grams, utilizing recrystallization to circumvent the less desirable column chromatography step commonly criticized in process chemistry. The resulting reagents demonstrated excellent air and moisture stability and were manageable under ambient conditions, similar to the commercially available reagent FGTR III .


# 3

Transfer Dihalogenation Span

With optimized conditions established for reagent synthesis and reaction execution, we proceeded to investigate the substrate scope of the dichlorination reaction using reagent I (Scheme [2]). Initially, various styrene-based alkenes were evaluated, affording the corresponding vicinal dichlorides 2a and 3–8 in good to excellent yields. Interestingly, cyclic substrates such as indene and tetrahydronaphthalene delivered trans-dichlorinated products 9 and 10 with high selectivity. Subsequent examination of more structurally diverse substrates, including non-styrenic and non-biased alkenes, led to the formation of dichlorinated products 11–18 in good yields, demonstrating broad substrate compatibility. Remarkably, the reaction protocol demonstrated compatibility with non-alkene substrates, successfully providing 2,3-dichloropropenyl derivative 19 from the corresponding allene. The developed dichlorination method tolerated diverse functional groups, including halogens, esters, and azides, and was further validated through the preparation of functionalized steroid derivative 20.

Selective vicinal cross-halogen transfer reactions using a single reagent present considerable synthetic challenges due to common issues with selectivity and isolation. Previous reports often encountered difficulties with product separation and limited regioselectivity, or the need to employ two distinct reagents.[29] [30] Our approach addressed these limitations effectively, as demonstrated by reactions of FGTR II yielding bromochlorinated products 2b and 21–26 from styrenes featuring electronically varied substituents, such as alkyl groups, halogens, and trifluoromethyl groups. Notably, product 27, containing four distinct halogen atoms within a single molecule, highlights the utility of this method for precise molecular diversification. Activated benzylic styrenes provided products 28–30 with good yields. Bromochlorination of indene selectively produced the trans-configured product 31, exclusively. Additionally, successful outcomes were observed with non-styrene substrates, including vinyl esters 32–34 and vinyl imide 35, achieving precise regioselectivity and excellent trans-selectivity. Moreover, the applicability of the reaction to allenes and late-stage functionalization was also successfully demonstrated (36). Late-stage functionalization of an indomethacin derivative yielded bromochlorinated product 37.

We further explored the scope of bromine transfer utilizing reagent III , successfully applying dibromination to various unsaturated hydrocarbons, including styrenes, which smoothly yielded dibromides 2c, 38–41. Consequently, non-styrenic olefins were successfully dibrominated to afford products 42–44. The remarkable compatibility could be extended to seven- and eight-membered ring systems, providing dibrominated derivatives 45 and 46 with high diastereoselectivity. A vinyl imide was also a viable substrate, delivering product 47 in good yield. Additionally, alkynes were employed in this dibromination protocol to furnish dibromo alkenes 48–51. Dibromination of allenes was successfully performed, predominantly yielding Z-products 52–54 with moderate selectivity. This methodology enables the functionalization of two reactive olefinic sites, leading to the formation of the polybrominated product 55. A non-activated alkene exhibited selective functionalization over electron-deficient counterparts, illustrated by compound 56, preserving valuable enone functionality. Additionally, sulfonyl bicyclobutanes (BCBs) efficiently underwent dibromination, affording highly functionalized derivatives 57–59 suitable for subsequent diversification.

Zoom Image
Scheme 3 (A) Proposed mechanism for transfer dihalogenation. Y = Ph or OH. (B) Additional experimental observations revealing the radical-ionic nature of dihalogen addition. Standard conditions: substrate (0.5 mmol, 1.0 equiv), fac-Ir(ppy)3 (1 mol%), reagent I or III (1.1 equiv), DMF (1.0 mL), blue LEDs, rt, 24 h. (C) Custom reaction setup design for tracking Br2, Cl2 or BrCl to be released and captured. (D) Regioisomeric reagent testing. (E) Association enthalpies (ΔH) and free Gibbs energies (ΔG) in kcal·mol–1 of various dihalide-solvent complexes, referenced to the separated reactants.

# 4

Mechanistic Insights

Inspired by the successful implementation of the dual-functional group transfer strategy in dihalogenation reactions, we sought to elucidate the underlying reaction mechanism. To effectively outline the mechanistic pathway, we selected the homo-dihalogenation reaction as a representative example (Scheme [3]A). Upon irradiation at 440 nm, the photocatalyst IrIII transitions to its excited state IrIII* , capable of single-electron reduction[31] [32] [33] of the FGTR I - III . This oxidative quenching event generates the β-halo-α-carbonyl radical intermediate R1, following exergonic mesolytic cleavage of the C–X bond, concurrently forming IrIV and a halide anion X– . Intermediate R1 subsequently undergoes a rapid and reversible radical-mediated 1,2-halogen shift through a halogen-bridged three-membered transition state (TS). DFT calculations provided detailed insights into these ‘halogen dance’ events, identifying distinct transition states TS-Cl and TS-Br. Although direct oxidation of α-carbonyl radical R1 by IrIV was found to be energetically unfavorable due to the instability of the corresponding α-carbonyl carbocation, subsequent oxidation of the benzylic radical intermediate R2 is significantly more feasible. This oxidation step is exergonic, producing the benzyl cation intermediate CA and concurrently regenerating the IrIII photocatalyst. Following this, two potential pathways were identified: (a) ion-pair collapse leading either to the formation of molecular dihalogen X2 and chalcone CH, or (b) the barrierless addition of the halide anion regenerates the reagent I - III . After release of X2 , it engages in ionic addition to starting olefin S furnishing product P. By the other way, the regenerated IrIII photocatalyst initiates another catalytic cycle of radical-polar crossover dihalogen release.

Further mechanistic evidence was gathered through complementary studies, including time-resolved NMR spectroscopy, regioisomeric reagent testing (Scheme [3]D), and radical-trapping experiments. One of them is the reaction of FGTR I with a radical-trapping allyl sulfone, which exclusively yielded ionic addition product 60, while no radical addition product 61 was observed (Scheme [3]B). Additionally, a radical-clock experiment conducted with FGTR III exclusively provided uncyclized product 62, demonstrating an ionic rather than radical nature of the released dihalogen species, with no cyclized radical product 63 detected.

An H-tube experiment involving FGTR II conducted in a 7-chamber Schlenk flask demonstrated the absence of dihalogen gas transfer upon reaction with a model substrate, suggesting that the reactive X2 species remains dissolved in DMF rather than being released as the free gas (Scheme [3]C). Anticipating that low-concentration X2 species are strict in solution as complexes with the solvent, we performed computational analyses to evaluate the formation of a 1:1 complex of X2 with DMF and 1,4-dioxane. These calculations indicated that both solvents exhibit comparable abilities to form stable species with Br2, BrCl, and Cl2, as reflected by the negative association enthalpies and similar values (Scheme [3]E).


# 5

Conclusion

Our work presents unique features for achieving essential dihalogenation transfer, introducing a novel dual-functional group transfer reagent. This study comprehensively focuses on reagent design, scalable synthesis, and mild photoredox activation. These advancements may enable broad applications, including late-stage functionalization and strain release of bicyclo[1.1.0]butanes. Notably, we realized selective bromo-chlorination, a rarely explored transformation using one reagent. Mechanistically, our study revealed a unique redox catalytic cycle featuring a rare radical 1,2-halogen shift, distinguishing our approach from existing strategies.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Generous and continuous support from the University of Bern is acknowledged.


Corresponding Author

Dmitry Katayev
Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern
Freiestrasse 3, 3012 Bern
Switzerland   

Publication History

Received: 27 March 2025

Accepted after revision: 29 April 2025

Article published online:
01 July 2025

© 2025. Thieme. All rights reserved

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Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany


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Zoom Image
Egor Zhilin (left) obtained his M.S. in chemistry from Lomonosov Moscow State University in 2019. He subsequently received his Ph.D. in 2022 from the Zelinsky Institute of Organic Chemistry under the supervision of Prof. Leonid Fershtat. He is currently conducting postdoctoral research at the University of Bern in the group of Prof. Dmitry Katayev. His current interests are light-driven transformations in organic chemistry. Rahul Giri (center) was born in Jharkhand, India. He completed his B.Sc. at the University of Delhi and studied for his M.S. at IISER Bhopal in the group of Prof. Alakesh Bisai. In 2021, he joined the group of Prof. Dmitry Katayev at the University of Bern, where he obtained his Ph.D. in 2025. His research is focused on the development and application of novel reagents using photo- and electrochemical methodologies. Dmitry Katayev (right) received Ph.D. from the University of Geneva. After two postdoctoral stays at TU Kaiserslautern and ETH Zürich, funded by the Swiss National Science Foundation (SNSF), he was awarded the Ambizione and Holcim Stiftung and launched his independent research at ETH Zürich in 2018. As a recipient of the Eccellenza Professorial Grant, he joined the University of Fribourg in early 2021. Shortly thereafter, in 2022, he was appointed as an Assistant Professor with Tenure Track in Organic Chemistry at the University of Bern.
Zoom Image
Figure 1 (A) Concept of functional group transfer reagents. (B) Introduction to dual-FGTRs for the dihalogenation of olefins. Y = Ph or OH.
Zoom Image
Scheme 1 Key FGTRs for transfer dihalogenation. FGTR screening conditions: substrate (0.5 mmol, 1.0 equiv), fac-Ir(ppy)3 (1 mol%), reagent (2.0 equiv), DMF (1.0 mL), blue LEDs, rt, 24 h.
Zoom Image
Scheme 2 Substrate scope of transfer the dichlorination, bromochlorination, and dibromination reactions. Y = Ph or OH. Standard conditions: substrate (0.5 mmol, 1.0 equiv), fac-Ir(ppy)3 (1 mol%), reagent I , II or III (1.1 equiv), DMF (1.0 mL), blue LEDs, rt, 24 h.
Zoom Image
Scheme 3 (A) Proposed mechanism for transfer dihalogenation. Y = Ph or OH. (B) Additional experimental observations revealing the radical-ionic nature of dihalogen addition. Standard conditions: substrate (0.5 mmol, 1.0 equiv), fac-Ir(ppy)3 (1 mol%), reagent I or III (1.1 equiv), DMF (1.0 mL), blue LEDs, rt, 24 h. (C) Custom reaction setup design for tracking Br2, Cl2 or BrCl to be released and captured. (D) Regioisomeric reagent testing. (E) Association enthalpies (ΔH) and free Gibbs energies (ΔG) in kcal·mol–1 of various dihalide-solvent complexes, referenced to the separated reactants.