Application of Statistical Design of Experiment in the Screening of Carbon–Carbon Cross-Coupling Reactions

Application of Statistical Design of Experiment in the Screening of Carbon–Carbon Cross-Coupling Reactions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Application of Statistical Design of Experiment in the Screening of Carbon–Carbon Cross-Coupling Reactions Fulufhelo Radzilani, Orpah Zinyemba, Reinout Meijboom This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7306688/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract The statistical design of experiment (sDoE) enables efficient investigation of a large experimental space by screening multiple factors simultaneously, overcoming the limitations of the one-factor-at-a-time (OFAT) approaches. The Plackett-Burman design (PBD) was applied in screening four factors: electronic effect and Tolman's cone angle of phosphine ligands (4), catalyst loading (2), bases (2), and solvent polarity (2) across twelve (12) C–C cross-coupling reactions for the Mizoroki-Heck, Suzuki-Miyaura, and Sonogashira-Hagihara reactions. The main effects of the factors were used to identify optimal conditions. The preferred ligand for each reaction is tris(pentafluorophenyl)phosphine, tricyclohexylphosphine, and triphenylphosphite, respectively. Optimal catalyst loadings are 1 mol% K 2 PdCl 4 (Mizoroki-Heck and Suzuki-Miyaura) and 5 mol% Pd(CH 3 COO) 2 (Sonogashira-Hagihara reaction), with NaOH and DMSO as the optimal base and solvent, respectively. This study demonstrates the power of PBD in reaction screening and optimisation, providing an advantage in catalyst discovery, chemical synthesis, and process development. Physical sciences/Chemistry Physical sciences/Materials science Statistical Design of Experiment (sDoE) Plackett-Burman Design (PBD) One-Factor-At-A-Time (OFAT) Catalysis Mizoroki-Heck Reaction Suzuki-Miyaura Reaction Sonogashira-Hagihara Reaction Full Text Additional Declarations No competing interests reported. Supplementary Files SuppinfoDoECarbonCarbonCrossCouplingReactions.docx Cite Share Download PDF Status: Published Journal Publication published 28 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 12 Sep, 2025 Reviews received at journal 05 Sep, 2025 Reviewers agreed at journal 04 Sep, 2025 Reviews received at journal 21 Aug, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviewers invited by journal 17 Aug, 2025 Editor invited by journal 11 Aug, 2025 Editor assigned by journal 08 Aug, 2025 Submission checks completed at journal 07 Aug, 2025 First submitted to journal 06 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7306688","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":504259135,"identity":"6f106c2b-7423-49b6-a8f0-8a7a64bfd855","order_by":0,"name":"Fulufhelo Radzilani","email":"","orcid":"","institution":"University of Johannesburg","correspondingAuthor":false,"prefix":"","firstName":"Fulufhelo","middleName":"","lastName":"Radzilani","suffix":""},{"id":504259136,"identity":"2804e239-87d3-4702-97bc-46debedae0d6","order_by":1,"name":"Orpah Zinyemba","email":"","orcid":"","institution":"University of Johannesburg","correspondingAuthor":false,"prefix":"","firstName":"Orpah","middleName":"","lastName":"Zinyemba","suffix":""},{"id":504259137,"identity":"79dc3b07-4f5d-4146-8fa1-e28827cced46","order_by":2,"name":"Reinout Meijboom","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYJCCA5INQJK9gcGARC08B0jQwsAI0iKRQKRq82mHDx6w3GEjpzvzjUEBQ40dg3z7AfxaZG6nJRyQPJNmbHY7x8CA4VgyA2MPAeskpHMMDki2HU7cBtbCdoCBmYGglvwPEC03zwC1/DvAwMb/gKAtDBAtN3gMDBjbDjDwEAoHCek0A4hfzqQVGCT2JfNISBC0JfnxZ0lgiJkdP7zN4MM3Ozn5fgK2gACzBIRmMwAq5iGsHggYP0C1EnDRKBgFo2AUjFQAAFETQPhf9661AAAAAElFTkSuQmCC","orcid":"","institution":"University of Johannesburg","correspondingAuthor":true,"prefix":"","firstName":"Reinout","middleName":"","lastName":"Meijboom","suffix":""}],"badges":[],"createdAt":"2025-08-06 07:08:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7306688/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7306688/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-27005-w","type":"published","date":"2025-11-28T15:58:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":97178665,"identity":"9befdac8-8153-4037-a2f2-6e0f196887f6","added_by":"auto","created_at":"2025-12-01 16:12:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":766282,"visible":true,"origin":"","legend":"","description":"","filename":"DoECarbonCarbonCrossCouplingReactions.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7306688/v1_covered_7f348cd0-e5bf-4e68-a5f5-a828933aa941.pdf"},{"id":89828342,"identity":"33ba8d72-76a5-4ca6-a7c1-826083d3bb39","added_by":"auto","created_at":"2025-08-25 13:02:12","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":824718,"visible":true,"origin":"","legend":"","description":"","filename":"SuppinfoDoECarbonCarbonCrossCouplingReactions.docx","url":"https://assets-eu.researchsquare.com/files/rs-7306688/v1/bc0f81fe57230166a669e7a9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eApplication of Statistical Design of Experiment in the Screening of Carbon–Carbon Cross-Coupling Reactions\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Statistical Design of Experiment (sDoE), Plackett-Burman Design (PBD), One-Factor-At-A-Time (OFAT), Catalysis, Mizoroki-Heck Reaction, Suzuki-Miyaura Reaction, Sonogashira-Hagihara Reaction","lastPublishedDoi":"10.21203/rs.3.rs-7306688/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7306688/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe statistical design of experiment (sDoE) enables efficient investigation of a large experimental space by screening multiple factors simultaneously, overcoming the limitations of the one-factor-at-a-time (OFAT) approaches. 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