{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T10:31:33Z","timestamp":1791369093983,"version":"4.3.1"},"reference-count":108,"publisher":"Wiley","issue":"40","license":[{"start":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T00:00:00Z","timestamp":1725235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K06489"],"award-info":[{"award-number":["21K06489"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23KF0093"],"award-info":[{"award-number":["23KF0093"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Polyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three\u2010component 1,2\u2010halo\u2010halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF<jats:sub>2<\/jats:sub>X) and halogen (X\u2019) groups in the desired combination of X and X\u2019 are lacking. To address this gap, for the first time, we report a three\u2010component halo\u2010halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF<jats:sub>2<\/jats:sub>XCO)<jats:sub>2<\/jats:sub>O, X=Cl and Br) and alkali metal halides (X\u2019=Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl\u2010based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C\u2212X and C\u2212X\u2019 bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions.<\/jats:p>","DOI":"10.1002\/anie.202407150","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T10:21:04Z","timestamp":1720520464000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Ligand\u2010Controlled Copper\u2010Catalyzed Halo\u2010Halodifluoromethylation of Alkenes and Alkynes Using Fluorinated Carboxylic Anhydrides"],"prefix":"10.1002","volume":"63","author":[{"given":"Subrata","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Catalysis and Integrated Research Group RIKEN Center for Sustainable Resource Science  2-1 Hirosawa Wako Saitama 351-0198 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuma","family":"Aoki","sequence":"additional","affiliation":[{"name":"Catalysis and Integrated Research Group RIKEN Center for Sustainable Resource Science  2-1 Hirosawa Wako Saitama 351-0198 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7422-837X","authenticated-orcid":false,"given":"Shintaro","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Catalysis and Integrated Research Group RIKEN Center for Sustainable Resource Science  2-1 Hirosawa Wako Saitama 351-0198 Japan"},{"name":"Synthetic Organic Chemistry Laboratory RIKEN Cluster for Pioneering Research  2-1 Hirosawa Wako Saitama 351-0198 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1344-364X","authenticated-orcid":false,"given":"Mikiko","family":"Sodeoka","sequence":"additional","affiliation":[{"name":"Catalysis and Integrated Research Group RIKEN Center for Sustainable Resource Science  2-1 Hirosawa Wako Saitama 351-0198 Japan"},{"name":"Synthetic Organic Chemistry Laboratory RIKEN Cluster for Pioneering Research  2-1 Hirosawa Wako Saitama 351-0198 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,2]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"Examples include:"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/md10092089"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/md13074044"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1071\/EN15002"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201506388"},{"key":"e_1_2_7_6_1","unstructured":"Recent 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halo-halodifluoromethylation:"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00013a051"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1139(93)03051-M"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.2533\/000942904777678163"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201900839"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/cctc.201902276"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201901896"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1039\/C9CC09517A"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1039\/D1CC01609A"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.0c02637"},{"key":"e_1_2_7_27_1","unstructured":"Examples of three-component halo-trifluoromethylations capable of installing few types of halogen functional groups depending on the 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of radical fluoroalkylation of alkenes using fluorinated carboxylic anhydrides:"},{"key":"e_1_2_7_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8919"},{"key":"e_1_2_7_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chempr.2016.08.002"},{"key":"e_1_2_7_66_2","volume":"17","author":"Giri R.","year":"2022","journal-title":"Angew. Chem. Int. Ed."},{"key":"e_1_2_7_67_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202109235"},{"key":"e_1_2_7_68_1","unstructured":"The numbering of compounds was determined by the combination of the substrate structure (alphabetic letter) and the halogen substitution pattern of the resulting product (Arabic number): i.e. CF2Br\/CHCl=2 CF2Br\/CHBr=3 CF2Cl\/CHCl=4 CF2Cl\/CHBr=5 CF3\/CHCl=6 CF3\/CHBr=7 C2F5\/CHCl=8 C3F7\/CHCl=9 CF2Cl\/Csp2Cl=10 and CF2Br\/Csp2Cl=11."},{"key":"e_1_2_7_69_1","unstructured":"In the control experiment performed under optimal conditions without the catalyst and LiCl 3\u2009awas obtained in a 35\u2009% yield."},{"key":"e_1_2_7_70_1","unstructured":"The ratios of halogen scrambling for the chloro-bromodifluoromethylation and bromo-chlorodifluoromethylation of alkenes were summarized in Table\u2005S4."},{"key":"e_1_2_7_71_1","unstructured":"Unsuccessful attempts are described in Figure\u2005S1."},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1039\/B711844A"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201200202"},{"key":"e_1_2_7_74_1","unstructured":"For a discussion of the unique effects of fluorine atom on the selectivity see"},{"key":"e_1_2_7_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/poc.3382"},{"key":"e_1_2_7_76_2","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS00564B"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b03867"},{"key":"e_1_2_7_78_1","unstructured":"For details of reaction condition optimization see Scheme\u2005S1."},{"key":"e_1_2_7_79_1","unstructured":"\u00a0"},{"key":"e_1_2_7_80_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0035-1562786"},{"key":"e_1_2_7_81_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c02331"},{"key":"e_1_2_7_82_1","unstructured":"\u00a0"},{"key":"e_1_2_7_83_2","doi-asserted-by":"publisher","DOI":"10.1039\/b714578k"},{"key":"e_1_2_7_84_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b02158"},{"key":"e_1_2_7_85_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c05364"},{"key":"e_1_2_7_86_1","unstructured":"According to the proposed mechanism the Cu(I) catalyst can promote the reaction without the initiation step. However the reaction using CuCl instead of CuCl2showed a lower efficiency (Table\u2005S1). This behavior may reflect the fact that in the case of CuCl the alkyl radical generated by the background decomposition of the diacyl peroxide cannot be transformed."},{"key":"e_1_2_7_87_1","unstructured":"\u00a0"},{"key":"e_1_2_7_88_2","doi-asserted-by":"publisher","DOI":"10.1039\/DT9730002293"},{"key":"e_1_2_7_89_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.catcom.2007.05.040"},{"key":"e_1_2_7_90_2","doi-asserted-by":"publisher","DOI":"10.3390\/ma14010113"},{"key":"e_1_2_7_91_1","unstructured":"NBO analysis of the intermediateCsuggested the carboxylate acts as an innocent ligand as almost no spin density is located on the carbonyl oxygen. See"},{"key":"e_1_2_7_92_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.2c01356"},{"key":"e_1_2_7_93_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.organomet.2c00663"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-023-01236-8"},{"key":"e_1_2_7_95_1","unstructured":"The sums of the free energies of [Cu(II)Cl(4 4\u2032-Br2bpy)2]+and anions were compared."},{"key":"e_1_2_7_96_1","unstructured":"The open-shell singlet transition structures of XAT were obtained using the broken symmetry method and the radical nature of these structures was confirmed through Mulliken spin density analysis (Figure\u2005S3). While triplet transition states might offer a more favorable pathway via the minimum energy crossing point singlet biradical structures were chosen for the purpose of energy comparison with the other pathways in this study."},{"key":"e_1_2_7_97_1","unstructured":"The solubility of copper intermediates may also influence reactivity and product selectivity. See"},{"key":"e_1_2_7_98_2","doi-asserted-by":"publisher","DOI":"10.1021\/ma021418f"},{"key":"e_1_2_7_99_2","doi-asserted-by":"publisher","DOI":"10.1021\/ie061506e"},{"key":"e_1_2_7_100_2","doi-asserted-by":"publisher","DOI":"10.3390\/polym6102552"},{"key":"e_1_2_7_101_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00002a004"},{"key":"e_1_2_7_102_1","unstructured":"\u00a0"},{"key":"e_1_2_7_103_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200500265"},{"key":"e_1_2_7_104_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.327"},{"key":"e_1_2_7_105_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201910085"},{"key":"e_1_2_7_106_1","unstructured":"The values of the Laplacian of the electron density (\u22072${{\\nabla }^{2}}$\u03c1) for the Cu\u2013Cl and Cu\u2013O bonds in the 4 4\u2019-Br2bpy-ligating complexes (A\u2019 andC respectively) obtained through quantum theory of atoms in molecules (QTAIM) analysis were 0.2528 and 0.3752 respectively and indicated charge-shift bonding. Topological electron density analyses were performed using the Multiwfn program."},{"key":"e_1_2_7_107_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.22885"},{"key":"e_1_2_7_108_2","volume-title":"Atoms in Molecules: A Quantum Theory","author":"Bader F. 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