{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T02:17:32Z","timestamp":1774837052446,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/00100\/2020, UIDB\/04565\/2020, PTDC\/MEC-ONC\/29327\/2017; SFRH\/BD\/129323\/2017"],"award-info":[{"award-number":["UIDB\/00100\/2020, UIDB\/04565\/2020, PTDC\/MEC-ONC\/29327\/2017; SFRH\/BD\/129323\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K2CO3 in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (1H, 13C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.<\/jats:p>","DOI":"10.3390\/molecules26061503","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T20:51:42Z","timestamp":1615409502000},"page":"1503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Conventional vs. Microwave- or Mechanically-Assisted Synthesis of Dihomooxacalix[4]arene Phthalimides: NMR, X-ray and Photophysical Analysis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8727-7077","authenticated-orcid":false,"given":"Alexandre","family":"Miranda","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Faculdade de Ci\u00eancias da Universidade de Lisboa, Edif\u00edcio C8, 1749-016 Lisboa, Portugal"},{"name":"IBB-Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-5139","authenticated-orcid":false,"given":"Paula","family":"Marcos","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Faculdade de Ci\u00eancias da Universidade de Lisboa, Edif\u00edcio C8, 1749-016 Lisboa, Portugal"},{"name":"Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5535-2500","authenticated-orcid":false,"given":"Jos\u00e9","family":"Ascenso","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Complexo I, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8200-6910","authenticated-orcid":false,"given":"M.","family":"Robalo","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Complexo I, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"},{"name":"\u00c1rea Departamental de Engenharia Qu\u00edmica, Instituto Superior de Engenharia de Lisboa, Instituto Polit\u00e9cnico de Lisboa, Rua Conselheiro Em\u00eddio Navarro, 1, 1959-007 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2349-8473","authenticated-orcid":false,"given":"Vasco","family":"Bonif\u00e1cio","sequence":"additional","affiliation":[{"name":"IBB-Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-1498","authenticated-orcid":false,"given":"M\u00e1rio","family":"Berberan-Santos","sequence":"additional","affiliation":[{"name":"IBB-Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1271-5719","authenticated-orcid":false,"given":"Neal","family":"Hickey","sequence":"additional","affiliation":[{"name":"Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, via L. Giorgieri 1, 34127 Trieste, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0711-5113","authenticated-orcid":false,"given":"Silvano","family":"Geremia","sequence":"additional","affiliation":[{"name":"Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, via L. Giorgieri 1, 34127 Trieste, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"ref_1","unstructured":"Gutsche, C.D. (2008). Calixarenes, an Introduction, The Royal Society of Chemistry. [2nd ed.]. Monographs in Supramolecular Chemistry."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Neri, P., Sessler, J.L., and Wang, M.-X. (2016). Calixarenes and Beyond, Springer International Publishing.","DOI":"10.1007\/978-3-319-31867-7"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8038","DOI":"10.1021\/acs.chemrev.5b00099","article-title":"Applications of supramolecular anion recognition","volume":"115","author":"Busschaert","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.chempr.2016.08.004","article-title":"Anion receptor chemistry","volume":"1","author":"Gale","year":"2016","journal-title":"Chem"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0040-4039(00)83996-9","article-title":"The use of microwave ovens for rapid organic synthesis","volume":"27","author":"Gedye","year":"1986","journal-title":"Tetrahedron Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4945","DOI":"10.1016\/S0040-4039(00)85103-5","article-title":"Application of commercial microwave ovens to organic synthesis","volume":"27","author":"Giguere","year":"1986","journal-title":"Tetrahedron Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1071\/CH08375","article-title":"A strategic, \u201cgreen\u201d approach to organic chemistry with microwave assistance and predictive yield optimization as core, enabling technologies","volume":"62","author":"Strauss","year":"2009","journal-title":"Aust. J. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1016\/j.tet.2009.01.105","article-title":"Microwave enhanced synthesis","volume":"65","author":"Caddick","year":"2009","journal-title":"Tetrahedron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1021\/ar400309b","article-title":"Microwave-assisted chemistry: Synthetic applications for rapid assembly of nanomaterials and organics","volume":"47","author":"Gawande","year":"2014","journal-title":"Acc. Chem. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100076","DOI":"10.1016\/j.mtnano.2020.100076","article-title":"Microwave chemistry, recent advancements, and eco-friendly microwave-assisted synthesis of nanoarchitectures and their applications: A review","volume":"11","author":"Kumar","year":"2020","journal-title":"Mater. Today Nano"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1039\/c0cs00195c","article-title":"Ball milling in organic synthesis: Solutions and challenges","volume":"40","author":"Stolle","year":"2011","journal-title":"Chem. Soc. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1039\/C1CS15171A","article-title":"Mechanochemistry: Opportunities for new and cleaner synthesis","volume":"41","author":"James","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7668","DOI":"10.1039\/c3cs35526h","article-title":"Mechanochemical organic synthesis","volume":"42","author":"Wang","year":"2013","journal-title":"Chem. Soc. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"030014","DOI":"10.1063\/5.0018078","article-title":"Gree synthetic approaches for practically relevant (hetero)macrocycles: An overview","volume":"2280","author":"Rahman","year":"2020","journal-title":"AIP Conf. Proc."},{"key":"ref_15","first-page":"70","article-title":"Microwave-assisted synthesis of p-alkylcalix[n]arene catalysed by KOH","volume":"2","author":"Baozhi","year":"2005","journal-title":"Eur. J. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1039\/b801715h","article-title":"Rapid and convenient laboratory method for the preparation of p-tert-butylcalix[4]arene using microwave irradiation","volume":"10","author":"Takagaki","year":"2008","journal-title":"Green Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1080\/00397910701397086","article-title":"Microwave-assisted synthesis of azocalixarenes","volume":"37","author":"Agrawal","year":"2007","journal-title":"Synth. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13232","DOI":"10.1002\/chem.200901799","article-title":"Achieving high affinity towards a bacterial lectin through multivalent topological isomers of calix[4]arene glycoconjugates","volume":"15","author":"Cecioni","year":"2009","journal-title":"Chem. Eur. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1134\/S0012500818040079","article-title":"Synthesis of tetraazide derivatives of p-tert-butylcalix[4]arene using copper-catalyzed nucleophilic aromatic substitution","volume":"479","author":"Fatykhova","year":"2018","journal-title":"Dokl. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3184\/174751915X14307583240337","article-title":"Microwave-assisted synthesis of bidentate chiral unsymmetrical urea derivatives of p-tert-butylcalix[4]arene and their anion recognition properties","volume":"39","author":"Wang","year":"2015","journal-title":"J. Chem. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tetlet.2011.10.142","article-title":"Microwave-assisted synthesis of 1,3-dialkyl ethers of calix[4]arenes: Application to the synthesis of cesium selective calix[4]crown-6 ionophores","volume":"53","author":"Nayak","year":"2012","journal-title":"Tetrahedron Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.mencom.2013.03.022","article-title":"Microwave-assisted alkylation of p-tert-butylcalix[4]arene lower rim: The effect of alkyl halides","volume":"23","author":"Burilov","year":"2013","journal-title":"Mendeleev Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1080\/10610278.2019.1650179","article-title":"Syntheses of ester and amide derivatives of calix[6]arene and their complexation affinities towards La3+, Eu3+, and Yb3+","volume":"31","author":"Bakic","year":"2019","journal-title":"Supramol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gal\u00e1n, H., de Mendoza, J., and Prados, P. (2010). Microwave-assisted synthesis of a nitro-m-xylylenedioxycalix[6]arene building block functionalized at the upper rim. Eur. J. Org. Chem., 7005\u20137011.","DOI":"10.1002\/ejoc.201000954"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1021\/ol9908272","article-title":"Convergent synthesis of p-benzylcalix[7]arene: Condensation and UHIG of p-benzylcalix[6 or 8]arenes","volume":"1","author":"Atwood","year":"1999","journal-title":"Org. Lett."},{"key":"ref_26","first-page":"4947","article-title":"Mechanochemical synthesis of p-nitro calix[6]arene","volume":"22","author":"Chennakesavulu","year":"2010","journal-title":"Asian J. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1021\/jo4026012","article-title":"Bidentate urea derivatives of p-tert-butyldihomooxacalix[4]arene: Neutral receptors for anion complexation","volume":"79","author":"Marcos","year":"2014","journal-title":"J. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6497","DOI":"10.1016\/j.tet.2014.07.020","article-title":"Synthesis and anion binding properties of new dihomooxacalix[4]arene diurea and dithiourea receptors","volume":"70","author":"Marcos","year":"2014","journal-title":"Tetrahedron"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Augusto, A.S., Miranda, A.S., Ascenso, J.R., Miranda, M.Q., F\u00e9lix, V., Brancatelli, G., Hickey, N., Geremia, S., and Marcos, P.M. (2018). Anion recognition by partial cone dihomooxacalix[4]arene-based receptors bearing urea groups: Remarkable affinity for benzoate ion. Eur. J. Org. Chem., 5657\u20135667.","DOI":"10.1002\/ejoc.201800880"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"758","DOI":"10.3389\/fchem.2019.00758","article-title":"Ditopic receptors based on dihomooxacalix[4]arenes bearing phenylurea moieties with electron-withdrawing groups for anions and organic ion pairs","volume":"7","author":"Miranda","year":"2019","journal-title":"Front. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Miranda, A.S., Marcos, P.M., Ascenso, J.R., Berberan-Santos, M.N., Schurhammer, R., Hickey, N., and Geremia, S. (2020). Dihomooxacalix[4]arene-based fluorescent receptors for anion and organic ion pair recognition. Molecules, 25.","DOI":"10.3390\/molecules25204708"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Barboso, S., Carrera, A.G., Matthews, S.E., Arnaud-Neu, F., Bohmer, V., Dozol, J.F., Rouquette, H., and Schiwing-Weill, M.J. (1999). Calix[4]arenes with CMPO functions at the lower rim. Synthesis and extraction properties. J. Chem. Soc. Perkin Trans. 2, 719\u2013723.","DOI":"10.1039\/a900210c"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Marcos, P.M., Ascenso, J.R., and Pereira, J.L.C. (2002). Synthesis and NMR conformational studies of p-tert-butyldihomooxacalix[4]arene derivatives bearing pyridyl pendant groups at the lower rim. Eur. J. Org. Chem., 3034\u20133041.","DOI":"10.1002\/1099-0690(200209)2002:17<3034::AID-EJOC3034>3.0.CO;2-I"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1021\/jo00010a036","article-title":"Carbon-13 NMR chemical shifts. A single rule to determine the conformation of calix[4]arenes","volume":"56","author":"Jaime","year":"1991","journal-title":"J. Org. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s10847-016-0687-z","article-title":"Synthesis and crystal structures of p-tert-butyldihomooxa-calix[4]arene mono-Schiff bases","volume":"87","author":"Liu","year":"2017","journal-title":"J. Incl. Phenom. Macrocycl. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5967","DOI":"10.1039\/C7NJ00652G","article-title":"Fluorescence properties of p-tert-butyldihomooxacalix[4]arene derivatives and the effect of anion complexation","volume":"41","author":"Miranda","year":"2017","journal-title":"New J. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S1010-6030(99)00180-X","article-title":"Laser flash photolysis study of N-alkylated phathalimides","volume":"129","author":"Griesbeck","year":"1999","journal-title":"J. Photochem. Photobiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Valeur, B., and Berberan-Santos, M.N. (2012). Molecular Fluorescence. Principles and Applications, Wiley-VCH. [2nd ed.].","DOI":"10.1002\/9783527650002"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1042\/bj0750335","article-title":"Fluorescence-polarization spectrum and electronic-energy transfer in tyrosine, tryptophan and related compounds","volume":"75","author":"Weber","year":"1960","journal-title":"Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9247","DOI":"10.1021\/jp5065352","article-title":"UV transition moments of tyrosine","volume":"118","author":"Fornander","year":"2014","journal-title":"J. Phys. Chem. B"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6427","DOI":"10.1021\/ja00042a021","article-title":"Multichromophoric cyclodextrins. 1. Synthesis of O-naphthoyl beta cyclodextrins and investigation of excimer formation and energy hopping","volume":"114","author":"Canceill","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1107\/S0907444909047374","article-title":"Integration, scaling, space-group assignment and post-refinement","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT\u2013integrated space-group and crystal-structure determination","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallog. Sect. A Found. Crystallogr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Crystallog. Sect. A Found. Crystallogr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1107\/S0021889812029111","article-title":"WinGX and ORTEP for windows: An update","volume":"45","author":"Farrugia","year":"2012","journal-title":"J. Appl. Crystallog."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:36:00Z","timestamp":1760160960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,10]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["molecules26061503"],"URL":"https:\/\/doi.org\/10.3390\/molecules26061503","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,10]]}}}