Continuous flow electrochemical reactor enables chlorination with iodine(I/III) species generated in situ

Nature Communications

Date: 10 October 2024 | Category: Headline NewsNews

New Nature Communications paper: Electrocatalytic continuous flow chlorination with iodine(I/III) mediators

Authors: Tuhin Patra, Sagar Arepally, Jakob Seitz, and Thomas Wirth*

The Wirth group from the University of Cardiff have recently showcased the use of an electrocatalytic flow set-up for in situ generation of dichloroiodoarenes that can be used for a range of different reactions including mono- and dichlorination, as well as chlorocyclisation [1]. Attempts at these types of reaction in batch have proven extremely difficult, mainly due to the sluggish interfacial electron transfer rates from the electrode to the substrate and the high oxidation potential of the aryl iodides in comparison with the substrates. In this case, use of the Vapourtec Ion electrochemical reactor circumvented several problems and allowed chlorination of a range of substrates in excellent yield and reproducibility.

Vicinal dichlorination of alkenes: scope to date

Until this work was disclosed, there were very few methods for undertaking the electrocatalytic vicinal dichlorination of alkenes. The use of manganese [2], organoseleniums [3] and Willgerodt’s reagent (PhICl2) [4, 5] have all been explored, but often have drawbacks such as requirement for a toxic transition metal element or stoichiometric equivalents of the chlorinating agent itself. Wirth’s development of a catalytic Willgerodt-type reagent is therefore a valuable addition to the organic chemist’s toolkit and an excellent example of where flow can outperform batch in terms of utility.

Development of an organoiodide (I/III) electrocatalytic platform

A range of chlorides and aryliodides were screened for electrochemical generation of the requisite hypervalent iodine species. It was found that passing a mixture of 4-iodotoluene, tetramethylammonium hexafluorophosphate (Me4NPF6) and trimethylchlorosilane (TMSCl) in HFIP/MeCN through the Vapourtec Ion continuous flow electrochemical reactor in the presence of a terminal alkene generated the vicinal dichloride product. In addition, it was found that expensive electrode combinations could be replaced by more practical and cheap graphite electrodes without impact upon the yield.

A range of substrates were screened including non-activated terminal alkenes and long-chain alkenes. Esters, nitriles, alcohols, free carboxylic acids, ketones, fluoro-, chloro-, bromo- and iodoaryls, sulfones, phosphonate esters and internal alkynes were all tolerated, with good to excellent yields reported. Stereoselectivity was also possible: (E)-alkenes led to anti-product as the major species, whereas (Z)-alkenes favoured the syn-product. Trisubstituted alkenes were tolerated and chlorocyclisation of unsaturated carboxylic acids furnished lactones in good yield. Finally, monochlorination of 1,3-dicarbonyls and β-keto ester derivatives in the most acidic α-position was also facile.

Overall, the use of an electrochemical microflow reactor was key to enabling development of conditions that allowed chlorination with catalytic quantities of iodine(I/III) mediators because the Ion continuous flow electrochemical reactor:

  • Allowed generation and use of potentially unstable hypervalent dichloroarenes in situ;
  • Enabled rapid screening of a range of a reaction parameters and conditions;
  • Improved reaction kinetics and electron transfer by virtue of the small inter-electrode gap, large electrode surface-to-volume ratio, high mass transfer and intensified reaction conditions.

Prof. Wirth said “In our recent publication on chlorinations using iodine(III) mediators (Electrocatalytic continuous flow chlorinations with iodine(I/III) mediators, T. Patra, S. Arepally, J. Seitz, T. Wirth, Nat. Commun. 2024, 15, 6329. DOI), we have made use of the Vapourtec Ion reactor to generate a reactive oxidising reagent using flow electrochemistry. The close distance between the electrodes in the reactor (0.2 mm) allowed the generation of the reactive hypervalent iodine(III) reagent and the reaction with many different substrates within a short reaction time of only 12 minutes. Similar reactions in batch systems would take a much longer time. The ease of operation and the opportunity to rapidly screen and tune reaction conditions using the electrochemical Ion reactor also allowed a gram-scale synthesis of products.”

Duncan Guthrie, Vapourtec MD commented, “In early 2018 Vapourtec began a productive collaboration with Thomas Wirth’s group at Cardiff University in electrochemistry.  Thanks to the significant contribution from Prof. Wirth and his team at Cardiff, this collaboration yielded the development of the Ion electrochemical reactor.  With further developments in the pipeline the collaboration continuous to yield positive outcomes for all involved.”

References:

[1] Electrocatalytic continuous flow chlorinations with iodine(I/III) mediators (T. Patra, S. Arepally, J. Seitz, T. Wirth, Nature Comms., 2024, 15, 6329). https://www.nature.com/articles/s41467-024-50643-z

[2] Electrocatalytic Radical Dichlorination of Alkenes with Nucleophilic Chlorine Sources (N. Fu, G. S. Sauer, S. Lin, J. Am. Chem. Soc., 2017, 139 (43), 15548 – 15553). https://pubs.acs.org/doi/10.1021/jacs.7b09388

[3] The Electrochemical cis-Chlorination of Alkenes (J. Strehl, C. Fastie, G. Hilt, Chem. Eur. J., 2021, 27 (69), 17341 – 17345). https://doi.org/10.1002/chem.202103316

[4] Ueber einige aromatische Jodidchloride (C. Willgerodt, J. Prakt. Chem., 1886, 33, 154 – 160). https://doi.org/10.1002/prac.18860330117

[5] Visible-Light-Induced Cross-Dehydrogenative Coupling of Heteroarenes with Aliphatic Alcohols Mediated by Iodobenzene Dichloride (C. Yin, P. Hu, Eur. J. Org. Chem., 2023, 26 (11), e202300015). https://doi.org/10.1002/ejoc.202300015

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