{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:49:32Z","timestamp":1791809372798,"version":"4.3.4"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"40","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008476","name":"University of California, Irvine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008476","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM050781"],"award-info":[{"award-number":["GM050781"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM141948"],"award-info":[{"award-number":["GM141948"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The transformations that occur at metalloenzyme active sites during catalysis are inextricably coupled to secondary-sphere interactions with surrounding amino acids and water molecules. Probing the elemental steps of these in vitro reactions remains a formidable challenge; their inherent catalytic velocity frequently prevents the isolation or detection of transient intermediates. Mapping distinct oxidation events, coupled with proton transfer steps, provides a clear pathway to elucidating these overarching catalytic mechanisms. High-valent iron-oxido and hydroxido species are key intermediates in oxidative processes catalyzed by nonheme iron proteins. Here, we employ structurally characterized bioinspired diiron complexes to systematically probe these elemental processes. We have spectroscopically characterized six distinct oxidation and protonation states of a single, asymmetric diiron core. Density functional theory calculations corroborate these findings, demonstrating strong agreement with the experimental electronic parameters and provide insight into the energetics governing individual electron and proton transfers. Reactivity profiling demonstrates that the synthesized FeIIIFeIV complex efficiently abstracts a hydrogen atom from a phenolic substrate via a proton-coupled electron transfer (PCET) pathway that takes advantage of secondary sphere hydrogen bond interactions provided by the ligand framework. This process mimics the native tyrosyl radical generation observed in intermediate X of RNR, a key enzyme in DNA biosynthesis.<\/jats:p>","DOI":"10.1021\/acs.inorgchem.6c04733","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:30:18Z","timestamp":1790317818000},"page":"24067-24081","source":"Crossref","is-referenced-by-count":0,"title":["Redox-Triggered\nProton Transfer in Synthetic Models\nfor Non-Heme Diiron Enzymes: Spectroscopic, Computational, and Mechanistic\nInsights"],"prefix":"10.1021","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8207-1272","authenticated-orcid":true,"given":"Justin L.","family":"Lee","sequence":"first","affiliation":[{"name":"University of California , , 1102 Natural Sciences II , , ,","place":["Irvine, California, United States, 92697"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saborni","family":"Biswas","sequence":"additional","affiliation":[{"name":"Carnegie Mellon University , , 4400 Fifth Avenue , , ,","place":["Pittsburgh, Pennsylvania, United States, 15213"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria F.","family":"Oswald","sequence":"additional","affiliation":[{"name":"University of California , , 1102 Natural Sciences II , , ,","place":["Irvine, California, United States, 92697"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7404-950X","authenticated-orcid":true,"given":"Joseph W.","family":"Ziller","sequence":"additional","affiliation":[{"name":"University of California , , 1102 Natural Sciences II , , ,","place":["Irvine, California, United States, 92697"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5049-9952","authenticated-orcid":true,"given":"A. S.","family":"Borovik","sequence":"additional","affiliation":[{"name":"University of California , , 1102 Natural Sciences II , , ,","place":["Irvine, California, United States, 92697"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5125-265X","authenticated-orcid":true,"given":"Emile L.","family":"Bominaar","sequence":"additional","affiliation":[{"name":"Carnegie Mellon University , , 4400 Fifth Avenue , , ,","place":["Pittsburgh, Pennsylvania, United States, 15213"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4775-0389","authenticated-orcid":true,"given":"Michael P.","family":"Hendrich","sequence":"additional","affiliation":[{"name":"Carnegie Mellon University , , 4400 Fifth Avenue , , ,","place":["Pittsburgh, Pennsylvania, United States, 15213"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"2026101208095034400_cit1","doi-asserted-by":"publisher","first-page":"15558","DOI":"10.1021\/jacs.5b10763","article-title":"Composition and\nStructure of the Inorganic Core of Relaxed Intermediate X(Y122f) of Escherichia coli Ribonucleotide Reductase","volume":"137","author":"Doan","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit2","doi-asserted-by":"publisher","first-page":"4559","DOI":"10.1021\/jacs.1c12888","article-title":"Bioinspired Di-Fe Complexes: Correlating Structure\nand Proton Transfer over Four Oxidation States","volume":"144","author":"Lee","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit3","doi-asserted-by":"publisher","first-page":"11804","DOI":"10.1021\/jacs.0c03085","article-title":"Effects of Noncovalent Interactions on High-Spin Fe(IV)-Oxido\nComplexes","volume":"142","author":"Oswald","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit4","doi-asserted-by":"publisher","first-page":"4733","DOI":"10.1021\/ic010250w","article-title":"Hydrogen-Bonding\nCavities about Metal Ions: Synthesis, Structure, and Physical Properties\nfor a Series of Monomeric M-Oh Complexes Derived from Water","volume":"40","author":"MacBeth","year":"2001","journal-title":"Inorg. Chem."},{"key":"2026101208095034400_cit5","doi-asserted-by":"publisher","first-page":"8656","DOI":"10.1021\/ic101408e","article-title":"Synthesis and Stabilization of a\nMonomeric Iron(II) Hydroxo Complex via Intramolecular Hydrogen Bonding\nin the Secondary Coordination Sphere","volume":"49","author":"Kendall","year":"2010","journal-title":"Inorg.\nChem."},{"key":"2026101208095034400_cit6","doi-asserted-by":"publisher","first-page":"8111","DOI":"10.1039\/D1DT01021B","article-title":"Stepwise\nAssembly of Heterobimetallic\nComplexes: Synthesis, Structure, and Physical Properties","volume":"50","author":"Lee","year":"2021","journal-title":"Dalton Trans."},{"key":"2026101208095034400_cit7","first-page":"287","article-title":"Aspects\nof 57Fe Mo\u0308ssbauer Spectroscopy","volume-title":"Physical Methods in Bioinorganic Chemistry","author":"Mu\u0308nck","year":"2000"},{"key":"2026101208095034400_cit8","doi-asserted-by":"publisher","first-page":"12009","DOI":"10.1021\/jacs.7b06546","article-title":"Spectroscopy and DFT Calculations\nof a Flavo-Diiron Enzyme Implicate New Diiron Site Structures","volume":"139","author":"Weitz","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit9","doi-asserted-by":"publisher","first-page":"14807","DOI":"10.1021\/jacs.8b08349","article-title":"Structures, Spectroscopic\nProperties, and Dioxygen Reactivity of 5- and 6-Coordinate Nonheme\nIron(II) Complexes: A Combined Enzyme\/Model Study of Thiol Dioxygenases","volume":"140","author":"Gordon","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit10","doi-asserted-by":"publisher","first-page":"3688","DOI":"10.1021\/ja00062a039","article-title":"Mo\u0308ssbauer,\nEpr, and Endor Studies of the Hydroxylase and Reductase Components\nof Methane Monooxygenase from Methylosinus Trichosporium Ob3b","volume":"115","author":"Fox","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit11","doi-asserted-by":"publisher","first-page":"6769","DOI":"10.1021\/ja00489a046","article-title":"Structural Changes Upon Oxygenation\nof an Iron(II)(Porphyrinato)(Imidazole) Complex","volume":"100","author":"Jameson","year":"1978","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit12","doi-asserted-by":"publisher","first-page":"12188","DOI":"10.1021\/ja1047818","article-title":"Formation, Structure, and Epr Detection\nof a High Spin Fe(IV)-Oxo Species Derived from Either an Fe(III)-Oxo\nor Fe(III)-Oh Complex","volume":"132","author":"Lacy","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit13","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1021\/ja207048h","article-title":"A High-Spin Iron(IV)-Oxo\nComplex Supported by a Trigonal Nonheme Pyrrolide Platform","volume":"134","author":"Bigi","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit14","doi-asserted-by":"publisher","first-page":"11880","DOI":"10.1021\/ja2040909","article-title":"A More Reactive Trigonal-Bipyramidal\nHigh-Spin Oxoiron(IV) Complex with a Cis-Labile Site","volume":"133","author":"England","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit15","doi-asserted-by":"publisher","first-page":"3622","DOI":"10.1002\/anie.200900863","article-title":"A Synthetic High-Spin\nOxoiron(IV) Complex: Generation, Spectroscopic Characterization, and\nReactivity","volume":"48","author":"England","year":"2009","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026101208095034400_cit16","doi-asserted-by":"publisher","first-page":"6752","DOI":"10.1002\/anie.202015896","article-title":"A Pseudotetrahedral Terminal Oxoiron(IV)\nComplex: Mechanistic Promiscuity\nin C-H Bond Oxidation Reactions","volume":"60","author":"Warm","year":"2021","journal-title":"Angew. Chem.,\nInt. Ed."},{"key":"2026101208095034400_cit17","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.1021\/ja511757j","article-title":"Modeling Taud-J: A High-Spin Nonheme Oxoiron(IV) Complex with High\nReactivity toward C-H Bonds","volume":"137","author":"Biswas","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit18","doi-asserted-by":"publisher","first-page":"21637","DOI":"10.1021\/jacs.1c10051","article-title":"A Reactive, Photogenerated\nHigh-Spin (S = 2) Fe(IV)(O) Complex via O2 Activation","volume":"143","author":"Gordon","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit19","doi-asserted-by":"publisher","first-page":"7551","DOI":"10.1021\/ja960399k","article-title":"Reconsideration of X, the Diiron\nIntermediate Formed During Cofactor Assembly in E. coli Ribonucleotide Reductase","volume":"118","author":"Sturgeon","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit20","doi-asserted-by":"publisher","first-page":"7497","DOI":"10.1021\/bi030011f","article-title":"The First Direct Characterization\nof a High-Valent Iron Intermediate in the Reaction of an Alpha-Ketoglutarate-Dependent\nDioxygenase: A High-Spin Fe(IV) Complex in Taurine\/Alpha-Ketoglutarate\nDioxygenase (Taud) from Escherichia Coli","volume":"42","author":"Price","year":"2003","journal-title":"Biochemistry"},{"key":"2026101208095034400_cit21","doi-asserted-by":"publisher","first-page":"6871","DOI":"10.1002\/anie.200502686","article-title":"Aqueous Fe(IV) = O:\nSpectroscopic Identification and Oxo-Group Exchange","volume":"44","author":"Pestovsky","year":"2005","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026101208095034400_cit22","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1126\/science.6306767","article-title":"Ribonucleotide Reductase--a Radical Enzyme","volume":"221","author":"Reichard","year":"1983","journal-title":"Science"},{"key":"2026101208095034400_cit23","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1006\/jmbi.1993.1374","article-title":"Structure and Function of the Escherichia coli Ribonucleotide Reductase Protein R2","volume":"232","author":"Nordlund","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2026101208095034400_cit24","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/S1367-5931(03)00025-5","article-title":"Di-Iron-Tyrosyl\nRadical Ribonucleotide Reductases","volume":"7","author":"Stubbe","year":"2003","journal-title":"Curr. Opin\nChem. Biol."},{"key":"2026101208095034400_cit25","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1146\/annurev.biochem.75.103004.142443","article-title":"Ribonucleotide Reductases","volume":"75","author":"Nordlund","year":"2006","journal-title":"Annu.\nRev. Biochem."},{"key":"2026101208095034400_cit26","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1016\/S0969-2126(96)00112-8","article-title":"Crystal Structure of\nReduced Protein R2 of Ribonucleotide Reductase: The Structural Basis\nfor Oxygen Activation at a Dinuclear Iron Site","volume":"4","author":"Logan","year":"1996","journal-title":"Structure"},{"key":"2026101208095034400_cit27","doi-asserted-by":"publisher","first-page":"9893","DOI":"10.1021\/ja9923686","article-title":"Formation of Fe(III)Fe(IV) Species\nfrom the Reaction between a Diiron(II) Complex and Dioxygen: Relevance\nto Ribonucleotide Reductase Intermediate X","volume":"121","author":"Lee","year":"1999","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S1570-9639(04)00054-8","article-title":"Structure,\nFunction, and Mechanism of Ribonucleotide Reductases","volume":"1699","author":"Kolberg","year":"2004","journal-title":"Biochim. Biophys. Acta, Proteins Proteomics"},{"key":"2026101208095034400_cit29","doi-asserted-by":"publisher","first-page":"15778","DOI":"10.1021\/ja050904q","article-title":"Active Site\nStructure of Class I Ribonucleotide Reductase Intermediate X: A Density\nFunctional Theory Analysis of Structure, Energetics, and Spectroscopy","volume":"127","author":"Han","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit30","doi-asserted-by":"publisher","first-page":"9049","DOI":"10.1021\/ja070909i","article-title":"Spectroscopic and Electronic Structure\nStudies of Intermediate X in Ribonucleotide Reductase R2 and Two Variants:\nA Description of the Fe(IV)-Oxo Bond in the Fe(III)-O-Fe(IV) Dimer","volume":"129","author":"Mitic\u0301","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit31","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.1073\/pnas.0536684100","article-title":"Displacement of the\nTyrosyl Radical Cofactor in Ribonucleotide Reductase Obtained by Single-Crystal\nHigh-Field Epr and 1.4-a X-ray Data","volume":"100","author":"Ho\u0308gbom","year":"2003","journal-title":"Proc. Natl.\nAcad. Sci. U.S.A."},{"key":"2026101208095034400_cit32","doi-asserted-by":"publisher","first-page":"7598","DOI":"10.1021\/ja8091938","article-title":"Elucidation of the\nProton Transport Mechanism in Human Carbonic Anhydrase II","volume":"131","author":"Maupin","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"2026101208095034400_cit33","doi-asserted-by":"publisher","first-page":"3919","DOI":"10.1021\/cr400415k","article-title":"Heme Enzyme\nStructure and Function","volume":"114","author":"Poulos","year":"2014","journal-title":"Chem. Rev."},{"key":"2026101208095034400_cit34","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1002\/zaac.201000274","article-title":"Crystal Structure of\nIron(II) Acetate","volume":"637","author":"Weber","year":"2011","journal-title":"Z. Anorg. Allg. Chem."},{"key":"2026101208095034400_cit35","doi-asserted-by":"publisher","first-page":"6086","DOI":"10.1021\/ic000531o","article-title":"N-Donor Effects\non Carboxylate Binding in Mononuclear Iron(II) Complexes of a Sterically\nHindered Benzoate Ligand","volume":"39","author":"Hagadorn","year":"2000","journal-title":"Inorg. Chem."},{"key":"2026101208095034400_cit36","unstructured":"APEX2 Version 2014.11\u20130; Bruker AXS, Inc.: Madison, WI, 2014."},{"key":"2026101208095034400_cit37","unstructured":"Sheldrick, G. 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G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; J A Montgomery, J.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.\n          Gaussian 09 Revision A.02; Gaussian, Inc.: Wallingford, CT, 2016."}],"container-title":["Inorganic Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.inorgchem.6c04733","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/inocaj\/article-pdf\/65\/40\/24067\/68646826\/acs.inorgchem.6c04733.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/inocaj\/article-pdf\/65\/40\/24067\/68646826\/acs.inorgchem.6c04733.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:25:27Z","timestamp":1791807927000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/inocaj\/article\/65\/40\/24067\/5438142\/Redox-Triggered-Proton-Transfer-in-Synthetic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":39,"journal-issue":{"issue":"40","published-online":{"date-parts":[[2026,9,25]]},"published-print":{"date-parts":[[2026,10,12]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.inorgchem.6c04733","relation":{},"ISSN":["0020-1669","1520-510X"],"issn-type":[{"value":"0020-1669","type":"print"},{"value":"1520-510X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]}}}