{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:41:02Z","timestamp":1785400862912,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hokkaido University of Science"},{"id":[{"id":"https:\/\/ror.org\/05gqsa340","id-type":"ROR","asserted-by":"publisher"}]},{"name":"CRILS"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Sulfonamides are a fundamental class of compounds with diverse pharmacological applications. Here, two benzene-1,3-disulfonamide-containing cycloalkyne compounds were designed to demonstrate the strained conformations due to the 11-membered ring. Their structures were experimentally analyzed using single-crystal X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. The molecules exhibit flexible sulfonamide conformations together with characteristic distortions of the benzene and alkyne moieties. Comparing the compound data obtained, the proton NMR chemical shift of hydrogen at the 2-position of the benzene ring shows a correlation of a dihedral angle involving the benzene ring and sulfonamide sulfur, and the carbon NMR shift suggests an angle distortion of the alkyne. The conformations of the crystal structure and the solution state in DMSO are supported by NOESY spectra and DFT calculations. The relative chemical shift differences were quantitatively reproduced by DFT calculations. We believe this fundamental research will contribute to the design and development of sulfonamide\u2013alkyne\u2013benzene-based medium-sized heterocyclic molecules with detailed conformation predictions.<\/jats:p>","DOI":"10.3390\/molecules31142462","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:12:53Z","timestamp":1784023973000},"page":"2462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational Analysis of Novel Benzene-1,3-Disulfonamide-Based Cycloalkynes Through X-Ray Crystallography, DFT Calculations, and NMR Spectroscopy"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-2685","authenticated-orcid":false,"given":"Kyosuke","family":"Kaneda","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1, Maeda Teine, Sapporo 006-8585, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takato","family":"Koideya","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1, Maeda Teine, Sapporo 006-8585, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1, Maeda Teine, Sapporo 006-8585, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruto","family":"Katakura","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1, Maeda Teine, Sapporo 006-8585, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Fukaya","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3148-0852","authenticated-orcid":false,"given":"Takehiro","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1, Maeda Teine, Sapporo 006-8585, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2017). Special Issue: Sulfonamides. Molecules, 22.","DOI":"10.3390\/molecules22101642"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1039\/D3MD00653K","article-title":"Unveiling sultam in drug discovery: Spotlight on the underexplored scaffold","volume":"15","author":"Chong","year":"2024","journal-title":"RSC Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1021\/acs.jmedchem.1c01509","article-title":"Discovery and Lead Optimization of Benzene-1,4-disulfonamides as Oxidative Phosphorylation Inhibitors","volume":"65","author":"Xue","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/978-94-007-5297-9_17","article-title":"Chapter 17 Validation of Quantum Chemical Calculations for Sulfonamide Geometrical Parameters","volume":"Volume 26","author":"Nishikawa","year":"2012","journal-title":"Quantum Systems in Chemistry and Physics: Progress in Methods and Applications"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Vigorito, A., Calabrese, C., Maris, A., Loru, D., Pe\u00f1a, I., Sanz, M.E., and Melandri, S. (2022). The Shapes of Sulfonamides: A Rotational Spectroscopy Study. Molecules, 27.","DOI":"10.3390\/molecules27092820"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5288","DOI":"10.1021\/acs.joc.9b03394","article-title":"Twisting and Turning the Sulfonamide Bond: A Synthetic, Quantum Chemical, and Crystallographic Study","volume":"85","author":"Blahun","year":"2020","journal-title":"J. Org. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1021\/acs.orglett.7b00123","article-title":"2-Aminobenzenesulfonamide-containing cyclononyne as adjustable click reagent for strain-promoted azide\u2013alkyne cycloaddition","volume":"19","author":"Kaneda","year":"2017","journal-title":"Org. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1002\/ajoc.201700687","article-title":"Reactivity of the Sultam and Strained Alkyne Groups in 2-Aminobenzenesulfonamide-Containing Cyclononyne (ABSACN)","volume":"7","author":"Kaneda","year":"2018","journal-title":"Asian J. Org. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1248\/yakushi.20-00139","article-title":"Synthesis of Cyclic Compounds Containing Aminobenzenesulfonamide","volume":"140","author":"Kaneda","year":"2020","journal-title":"Yakugaku Zasshi"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"upad016","DOI":"10.1093\/chemle\/upad016","article-title":"Synthesis and structural characterization of benzene-1, 3-disulfonamide-containing 11-to 13-membered heterocycles via double Mitsunobu annulation","volume":"53","author":"Kaneda","year":"2024","journal-title":"Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2164558","DOI":"10.1155\/2022\/2164558","article-title":"Carboxylic acid bioisosteres in medicinal chemistry: Synthesis and properties","volume":"2022","author":"Bredael","year":"2022","journal-title":"J. Chem."},{"key":"ref_12","first-page":"264","article-title":"Hydrolysis of sulphonamides in aqueous solutions","volume":"221","author":"Stolte","year":"2012","journal-title":"J. Hazard. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1021\/cg1012389","article-title":"K Sulfonamide molecular crystals: Thermodynamic and structural aspects","volume":"11","author":"Perlovich","year":"2011","journal-title":"Cryst. Growth Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e202217178","DOI":"10.1002\/anie.202217178","article-title":"Ring expansion strategies for the synthesis of medium sized ring and macrocyclic sulfonamides","volume":"62","author":"Yang","year":"2023","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lee, H., Kim, J., and Koh, M. (2024). Medium-Sized Ring Expansion Strategies: Enhancing Small-Molecule Library Development. Molecules, 29.","DOI":"10.3390\/molecules29071562"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/9783527615278.ch08","article-title":"Cyclic Alkynes: Preparation and Properties","volume":"27","author":"Gleiter","year":"1995","journal-title":"Mod. Acetylene Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Tobe, Y., and Sonoda, M. (2004). Cyclopynes. Modern Cyclophane Chemistry, Wiley.","DOI":"10.1002\/3527603964.ch1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.mencom.2019.05.001","article-title":"Strain and stereoelectronics in cycloalkyne click chemistry","volume":"29","author":"Harris","year":"2019","journal-title":"Mendeleev Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1246\/cl.2007.566","article-title":"Di-2-methoxyethyl azodicarboxylate (DMEAD): An inexpensive and separation-friendly alternative reagent for the Mitsunobu reaction","volume":"36","author":"Sugimura","year":"2007","journal-title":"Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1080\/00397919008053136","article-title":"(p-Dimethylaminophenyl) Diphenylphosphine: A More Practical Phosphine in the Mitsunobu Reaction","volume":"20","author":"Itzstein","year":"1990","journal-title":"Synth. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1039\/D2SC07045F","article-title":"Electrosynthesis of bridged or fused sulfonamides through complex radical cascade reactions: Divergence in medium-sized ring formation","volume":"14","author":"Zhang","year":"2023","journal-title":"Chem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5289","DOI":"10.1002\/chem.200802548","article-title":"Rhodium(I)-Catalysed Intramolecular [2+2+2] Cyclotrimerisations of 15-, 20- and 25-Membered Azamacrocycles: Experimental and Theoretical Mechanistic Studies","volume":"15","author":"Dachs","year":"2009","journal-title":"Chem. A Eur. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7169","DOI":"10.1039\/C9CP06869D","article-title":"Automated exploration of the low-energy chemical space with fast quantum chemical methods","volume":"22","author":"Pracht","year":"2020","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1021\/acs.jctc.8b01176","article-title":"GFN2-xTB\u2014An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Polarization and Density Dependent Dispersion Contributions","volume":"15","author":"Bannwarth","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1606","DOI":"10.1002\/wcms.1606","article-title":"Software update: The ORCA program system\u2014Version 5.0","volume":"12","author":"Neese","year":"2022","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1107\/S0021889808042726","article-title":"Olex2: A complete structure solution, refinement and analysis program","volume":"42","author":"Dolomanov","year":"2009","journal-title":"J. Appl. Cryst."},{"key":"ref_28","first-page":"3","article-title":"SHELXT\u2014Integrated space-group and crystal-structure determination","volume":"A71","author":"Sheldrick","year":"2015","journal-title":"Acta Cryst."},{"key":"ref_29","first-page":"3","article-title":"Crystal structure refinement with SHELXL","volume":"C71","author":"Sheldrick","year":"2015","journal-title":"Acta Cryst."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1107\/S0108767383001762","article-title":"On enantiomorph-polarity estimation","volume":"A39","author":"Flack","year":"1983","journal-title":"Acta Cryst."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/14\/2462\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:13:31Z","timestamp":1784024011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/14\/2462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":30,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["molecules31142462"],"URL":"https:\/\/doi.org\/10.3390\/molecules31142462","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]}}}