{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:09:00Z","timestamp":1790053740282,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ton Duc Thang University","id":[{"id":"https:\/\/ror.org\/01drq0835","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01drq0835","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Norwegian University of Science and Technology","id":[{"id":"https:\/\/ror.org\/05xg72x27","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05xg72x27","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017881","name":"Research Council of Norway","doi-asserted-by":"publisher","award":["262644"],"award-info":[{"award-number":["262644"]}],"id":[{"id":"10.13039\/100017881","id-type":"DOI","asserted-by":"publisher"}]},{"award":["262644"],"award-info":[{"award-number":["262644"]}],"id":[{"id":"https:\/\/ror.org\/00epmv149","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>4-Mercaptoimidazole (4MC) is the minimal parent scaffold of the ovothiol family of redox-active mercaptohistidines. We present a DFT study of the tautomerism, copper coordination, redox chemistry, and electronic structure of 4MC and its C2-substituted derivatives in aqueous solution. Twelve parent species (neutral tautomers, anions, disulfides, and Cu(I)\/Cu(II) complexes) were optimised at BP86\/def2-SVP with single-point energies at BP86\/def2-TZVP\/IEFPCM(water). The thione tautomer (N3-H) and its anion dominate (\u0394G=\u22122.56\u00a0kJmol\u22121 and \u221214.63\u00a0kJmol\u22121), leaving N1 free for copper coordination; the cis-(N3) Cu(II) isomer is the global minimum (81%). The disulfide\/thiol and Boltzmann-weighted Cu(II)\/Cu(I) reduction potentials are E\u2218=0.286\u00a0V and 0.828\u00a0V vs. SHE, giving a positive EMF of 0.542\u00a0V comparable to the natural ovothiols. An M06-2X functional benchmark quantifies the method contribution, raising the copper potential to 1.063\u00a0V and confirming that the residual offset to the ovothiol literature values reflects the minimal scaffold. Three C2 derivatives (CH3, Cl, NO2; \u03c3p from \u22120.17 to +0.78) show weak Hammett correlations for both redox couples, yet the EMF remains positive for all of them (0.302 to 0.738 V), indicating that C2 substitution tunes the thermodynamic coupling between the thiol\u2013disulfide and copper centres without disrupting it. Electronic structure analysis (NBO, QTAIM) reveals polar covalent Cu\u2013S bonding, spin delocalisation onto sulfur in Cu(II) complexes, and Cu\u2013S dissociation with a switch to Cu\u2013N coordination in the NO2 derivative. The core mercaptoimidazole scaffold thus retains the essential ovothiol redox chemistry, and C2 modification offers a genuine handle for modulating the driving force of the redox cycle.<\/jats:p>","DOI":"10.3390\/molecules31183331","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:12:09Z","timestamp":1789999929000},"page":"3331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DFT Investigation of 4-Mercaptoimidazole\u2013Copper(I\/II) Redox Chemistry and C2-Substituent Effects: A Minimal Scaffold Study of Ovothiol-Type Redox Cycling"],"prefix":"10.3390","volume":"31","author":[{"given":"Do Tuong","family":"Ha","sequence":"first","affiliation":[{"name":"Group of Applied Research in Advanced Materials for Sustainable Development, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 70000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1721-6786","authenticated-orcid":false,"given":"Thuat T.","family":"Trinh","sequence":"additional","affiliation":[{"name":"Porelab, Department of Chemistry and Biomedical Science, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.1021\/bi00387a043","article-title":"Ovothiols, a Family of Redox-Active Mercaptohistidine Compounds from Marine Invertebrate Eggs","volume":"26","author":"Turner","year":"1987","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21506","DOI":"10.1038\/srep21506","article-title":"Shedding Light on Ovothiol Biosynthesis in Marine Metazoans","volume":"6","author":"Castellano","year":"2016","journal-title":"Sci. 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