Elucidating the Mechanism and Selectivity of [3+2] Cycloaddition: A DFT and Molecular Docking Investigation of the Reaction of 6-Butoxy-5,6- Dihydro-4H-1,2-Oxazine 2-Oxide with Dimethyl Maleate

Elucidating the Mechanism and Selectivity of [3+2] Cycloaddition: A DFT and Molecular Docking Investigation of the Reaction of 6-Butoxy-5,6- Dihydro-4H-1,2-Oxazine 2-Oxide with Dimethyl Maleate | 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 Research Article Elucidating the Mechanism and Selectivity of [3+2] Cycloaddition: A DFT and Molecular Docking Investigation of the Reaction of 6-Butoxy-5,6- Dihydro-4H-1,2-Oxazine 2-Oxide with Dimethyl Maleate Haydar Mohammad-Salim, Jesus Vicente de Julián-Ortiz, Mohammad Shahidul Islam, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3870206/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Sep, 2024 Read the published version in Structural Chemistry → Version 1 posted 4 You are reading this latest preprint version Abstract The [3 + 2] cycloaddition (32CA) reactions involving 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide and dimethyl maleate are examined in this study. Molecular electron density theory (MEDT) is applied at the M06-2X/6-311G(d,p) level, coupled with the D3 dispersion correction. The nitrone species are identified as zwitterionic entities through an analysis of the electron localization function (ELF). Conceptual DFT indices are utilized to classify dimethyl maleate as the electrophilic component and the nitrone as the nucleophilic counterpart. The [3 + 2] cycloaddition processes are predominantly governed by kinetic control, as indicated by activation free energies of -23.64 and − 11.42 kcal.mol − 1 for the exo and endo pathways, respectively, aligning with experimental findings. The formation of a pseudoradical center initiates at carbon atoms C3 and C4. A subsequent docking analysis is conducted on cycloadducts 3 and 4 in relation to the main protease of SARS-CoV2 (6LU7), alongside the co-crystal ligand. The results of this analysis reveal that cycloadducts 3 exhibit higher binding energy, while cycloadducts 4 display lower binding energy compared to the co-crystal ligand. [3 + 2] cycloaddition reactions DFT Molecular Docking ELF 6-butoxy-5 6-dihydro-4H-1 2-oxazine 2-oxide Nitrone Dimethyl Maleate Molecular Electron Density Theory AIM Full Text Additional Declarations No competing interests reported. Supplementary Files SupportingInformation.doc Cite Share Download PDF Status: Published Journal Publication published 04 Sep, 2024 Read the published version in Structural Chemistry → Version 1 posted Editorial decision: Revision requested 18 Jan, 2024 Editor assigned by journal 18 Jan, 2024 Submission checks completed at journal 17 Jan, 2024 First submitted to journal 16 Jan, 2024 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. 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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-3870206","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":267904781,"identity":"dbe5e537-6fd0-4cbd-90d9-62ed2151dead","order_by":0,"name":"Haydar 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Maleate","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":"structural-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stuc","sideBox":"Learn more about [Structural Chemistry](https://www.springer.com/journal/11224)","snPcode":"11224","submissionUrl":"https://submission.nature.com/new-submission/11224/3","title":"Structural Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"[3 + 2] cycloaddition reactions, DFT, Molecular Docking, ELF, 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide, Nitrone, Dimethyl Maleate, Molecular Electron Density Theory, AIM","lastPublishedDoi":"10.21203/rs.3.rs-3870206/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3870206/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe [3\u0026thinsp;+\u0026thinsp;2] cycloaddition (32CA) reactions involving 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide and dimethyl maleate are examined in this study. Molecular electron density theory (MEDT) is applied at the M06-2X/6-311G(d,p) level, coupled with the D3 dispersion correction. The nitrone species are identified as zwitterionic entities through an analysis of the electron localization function (ELF). Conceptual DFT indices are utilized to classify dimethyl maleate as the electrophilic component and the nitrone as the nucleophilic counterpart. The [3\u0026thinsp;+\u0026thinsp;2] cycloaddition processes are predominantly governed by kinetic control, as indicated by activation free energies of -23.64 and \u0026minus;\u0026thinsp;11.42 kcal.mol\u0026thinsp;\u0026minus;\u0026thinsp;1 for the \u003cem\u003eexo\u003c/em\u003e and \u003cem\u003eendo\u003c/em\u003e pathways, respectively, aligning with experimental findings. The formation of a pseudoradical center initiates at carbon atoms C3 and C4. A subsequent docking analysis is conducted on cycloadducts \u003cb\u003e3\u003c/b\u003e and \u003cb\u003e4\u003c/b\u003e in relation to the main protease of SARS-CoV2 (6LU7), alongside the co-crystal ligand. The results of this analysis reveal that cycloadducts 3 exhibit higher binding energy, while cycloadducts 4 display lower binding energy compared to the co-crystal ligand.\u003c/p\u003e","manuscriptTitle":"Elucidating the Mechanism and Selectivity of [3+2] Cycloaddition: A DFT and Molecular Docking Investigation of the Reaction of 6-Butoxy-5,6- Dihydro-4H-1,2-Oxazine 2-Oxide with Dimethyl Maleate","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-19 05:51:26","doi":"10.21203/rs.3.rs-3870206/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-18T19:00:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-18T18:57:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-18T03:37:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Structural Chemistry","date":"2024-01-16T14:58:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"structural-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stuc","sideBox":"Learn more about [Structural Chemistry](https://www.springer.com/journal/11224)","snPcode":"11224","submissionUrl":"https://submission.nature.com/new-submission/11224/3","title":"Structural Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a723d3fd-65a0-4006-a1e8-d2831953eb63","owner":[],"postedDate":"January 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-09T16:10:48+00:00","versionOfRecord":{"articleIdentity":"rs-3870206","link":"https://doi.org/10.1007/s11224-024-02373-7","journal":{"identity":"structural-chemistry","isVorOnly":false,"title":"Structural Chemistry"},"publishedOn":"2024-09-04 15:57:09","publishedOnDateReadable":"September 4th, 2024"},"versionCreatedAt":"2024-01-19 05:51:26","video":"","vorDoi":"10.1007/s11224-024-02373-7","vorDoiUrl":"https://doi.org/10.1007/s11224-024-02373-7","workflowStages":[]},"version":"v1","identity":"rs-3870206","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3870206","identity":"rs-3870206","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}