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Haruya Ishida, Shuhei Miyakawa, [Hajime Shigemitsu](https://orcid.org/0000-0002-3104-049X), Kaori Fukuzawa, Toshiyuki Kida

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[Formation of hierarchical supramolecular microstructures from 6-                    <i>O</i>                    -alkylated α-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters](https://mdr.nims.go.jp/datasets/a6ecc1fa-a022-4429-b8d8-a7837cc5f091)

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Formation of hierarchical supramolecular microstructures from 6-O-alkylated α-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid estersRSC AdvancesPAPERPublished on 06 July 2026Licensed under CC-BY-NC 4.0Formation of hieaDepartment of Applied Chemistry, GraduatOsaka, 2-1 Yamada-oka, Suita, Osaka 565-0bGraduate School of Pharmaceutical Sciencoka, Suita, Osaka 565-0871, JapancNational Institute for Materials Science (NI0047, JapandIntegrated Frontier Research for MedicalTransdisciplinary Research Initiatives (OTRoka, Suita, Osaka 565-0871, Japan. E-mail:Cite this: RSC Adv., 2026, 16, 38221Received 20th May 2026Accepted 27th June 2026DOI: 10.1039/d6ra04383frsc.li/rsc-advances© 2026 The Author(s). Published byrarchical supramolecularmicrostructures from 6-O-alkylated a-cyclodextrinand their application to the selective extraction oflong-chain unsaturated fatty acid estersHaruya Ishida, a Shuhei Miyakawa, b Hajime Shigemitsu, c Kaori Fukuzawa band Toshiyuki Kida *adWe successfully fabricated rhombic plate-likemicrostructures composed of layered assemblies of head-to-head supramolecular dimers of 6-O-methylated and 6-O-ethylated a-cyclodextrins (6-Me-a-CD and 6-Et-a-CD, respectively). 6-Me-a-CD selectively extracted methyl elaidate (trans) over methyl oleate (cis)in methanol via microstructure formation driven by inclusion complexation between the 6-Me-a-CDdimer and fatty acid esters, whereas 6-Et-a-CD exhibited the opposite selectivity. These resultsdemonstrate that subtle modulation of the alkyl chain length at the 6-O position of a-CD enablesreversal of cis/trans selectivity in supramolecular extraction behavior. The origin of this selectivity wasfurther elucidated by theoretical calculations based on density functional theory (DFT) and fragmentmolecular orbital (FMO) interaction energy analysis.IntroductionSupramolecular assemblies constructed through the self-assembly of molecular building blocks have attracted consid-erable attention across diverse elds, including materialsscience,1,2 biotechnology3,4 and environmental science.5,6Among these systems, supramolecular assemblies derived frommacrocyclic host molecules such as cyclodextrins, calixarenes,pillar[n]arenes and cucurbit[n]urils have been extensivelyinvestigated in host-guest chemistry,7 separation science,8,9analytical chemistry,10 organic synthesis11,12 and photochem-istry13,14 owing to their well-dened internal cavities that enableselective guest recognition and stabilization of reaction inter-mediates. Representative examples highlight the functionalsignicance of conned supramolecular spaces. Manna et al.demonstrated that a hexameric resorcinarene capsule canstabilize reactive carbocationic intermediates, thereby enablingmild and selective Friedel–Cras reactions within its connedcavity.15 In another notable study, nonporous adaptive crystalsof pillar[6]arene derivatives were shown to undergo guest-e School of Engineering, The University of871, Japane, The University of Osaka, 1-6 Yamada-MS), 1-2-1 Sengen, Tsukuba, Ibaraki 305-Science Division, Institute for Open andI), The University of Osaka, 2-1 Yamada-kida@chem.eng.osaka-u.ac.jpthe Royal Society of Chemistryinduced structural transformations, allowing selective adsorp-tion of bromoalkane through distinct host-guest bindingmodes.16 Furthermore, pillar[5]arene-incorporated metal–organic frameworks have recently emerged as supramoleculardocking platforms that enable single-crystal structure determi-nation of alkyl-bearing molecules, including natural productsand drugs that are otherwise difficult to crystallize.17Cyclodextrins (CDs) are well-known macrocyclic hosts thatform inclusion complexes with a wide range of guest moleculesin both aqueous18 and organic media.19 In the solid state, CDstypically adopt three characteristic assembly modes—cage-type,channel-type and layer-type assemblies—primarily formedthrough hydrogen bonding between the hydroxyl groups on theupper and lower rims of the CD rings and/or host-guest inter-actions.20 Exploiting these assembly characteristics, a variety ofCD-based supramolecular nano- andmicrostructures have beensuccessfully fabricated.21–25 For instance, Jiang et al. reportedthat b-CD forms head-to-head supramolecular dimers viaintermolecular hydrogen bonding between secondary hydroxylgroups in water upon complexation with sodium dodecylsulfate.26 These dimers further assemble into higher-orderarchitectures such as tubular structures and multilamellarvesicles.27 Such studies clearly demonstrate that dimer forma-tion can serve as a critical intermediate step in hierarchical CD-based self-assembly in water.In this study, we focus on 6-O-alkylated CDs, specically 6-O-methylated and 6-O-ethylated a-CD (6-Me-a-CD and 6-Et-a-CD,respectively), as molecular building blocks for constructingwell-dened supramolecular architectures. These modied CDsRSC Adv., 2026, 16, 38221–38227 | 38221http://crossmark.crossref.org/dialog/?doi=10.1039/d6ra04383f&domain=pdf&date_stamp=2026-08-01http://orcid.org/0009-0007-4648-7650http://orcid.org/0009-0005-6275-5550http://orcid.org/0000-0002-3104-049Xhttp://orcid.org/0000-0001-5357-8250http://orcid.org/0000-0002-5777-8580https://creativecommons.org/licenses/by-nc/4.0/RSC Advances Paperare capable of forming head-to-head dimeric assemblies inorganic solvents through intermolecular hydrogen bondingbetween the secondary hydroxyl groups, analogous to thebehavior previously reported for 6-O-triisopropylsilylated b-CD.28 We hypothesized that such preorganized dimeric unitscould undergo controlled secondary assembly to generate uni-que supramolecular microstructures. Herein, we report thefabrication of well-regulated rhombic plate-like supramolecularmicrostructures from 6-Me-a-CD and 6-Et-a-CD (Fig. 1), as wellas their selective extraction behavior toward long-chain unsat-urated fatty acid esters. The observed selectivity originates frominclusion complexation between fatty acid esters and the CDdimers, coupled with supramolecular microstructure forma-tion. Notably, subtle modulation of the alkyl chain length at the6-O position enables reversal of cis/trans selectivity. To the bestof our knowledge, this work represents the rst example ofsupramolecular structure formation achieved throughcontrolled secondary assembly of supramolecular dimersderived from chemically modied CDs.Experimental sectionHexakis(6-O-methyl)-a-CD (6-Me-a-CD) and hexakis(2,3-di-O-benzyl)-a-CD were purchased from Cyclodextrin-Shop (Nether-lands). Hexakis(6-O-ethyl)-a-CD (6-Et-a-CD) was synthesizedfrom hexakis(2,3-di-O-benzyl)-a-CD in two steps with referenceto the reported method29 (Schemes S1–3).Preparation of supramolecular structures from 6-Me-a-CD6-Me-a-CD (2.0 mg, 1.9 × 10−3 mmol), which was dried at 80 °Cfor 12 h in vacuo before use, was dissolved in methanol (1.0 mL)to prepare a 6-Me-a-CD/methanol solution (1.9 mmol L−1). Thissolution (0.5 mL) was added dropwise to a poor solvent (1.0 mL)and stirred at 500 rpm at 25 °C for 24 h. The resulting precip-itate was collected by centrifugation and subsequently driedunder a nitrogen ow. The obtained solids were analyzed withpowder X-ray diffraction (PXRD) and scanning electronmicroscopy (SEM).Preparation of supramolecular structures from 6-Et-a-CD6-Et-a-CD (5.0 mg, 4.4 × 10−3 mmol), which was dried at 80 °Cfor 12 h in vacuo before use, was dissolved in methanol (1.0 mL)to prepare a 6-Et-a-CD/methanol solution (4.4 mmol L−1). Thissolution (0.2 mL) was added dropwise to a poor solvent (0.4 mL)and stirred at 500 rpm at 25 °C for 24 h. The resulting precip-itate was collected by centrifugation and subsequently driedFig. 1 Chemical structures of the 6-O-alkylated a-cyclodextrins.38222 | RSC Adv., 2026, 16, 38221–38227under a nitrogen ow. The obtained solids were analyzed withPXRD and SEM.Theoretical calculationsEnergy-minimized structures of the inclusion complexesbetween the 6-O-alkylated a-CD dimers and the unsaturatedfatty acid methyl esters (methyl elaidate andmethyl oleate) wererst explored by molecular mechanics calculations using theOPLS4 force eld30 in the gas phase. The framework of the 6-O-alkylated a-CD dimer used in these calculations was derivedfrom the single-crystal X-ray structure of the 6-Me-a-CD dimercrystallized from amethanol/water/diethyl carbonate solution.31Initial host-guest geometries were generated by conformationalsampling using the Mixed torsional/Low-mode sampling(MTLMOD) method, which efficiently explores both torsionaldegrees of freedom and large-scale low-frequency motions.32 Inthis procedure, the placement of the unsaturated fatty acidmethyl esters was systematically varied at several plausiblebinding sites of the a-CD dimer, including the primary-rimcavity and the internal space between the two a-CD units.These structures were employed as starting points for subse-quent density functional theory (DFT) optimizations includingsolvent effects. From the resulting conformational ensemble,the three lowest-energy structures were selected and subse-quently optimized by DFT calculations using the B3LYP-D3functional33–35 with the 6-31G(d) basis set, as implemented inthe Gaussian 16 program package.36 Solvent effects were takeninto account by employing the IEFPCM implicit solvationmodel37 (methanol) during geometry optimization. The DFT-optimized structures were conrmed to have no imaginaryfrequencies, and the lowest-energy structure was taken as therepresentative inclusion complex. To further investigate thestability differences among the inclusion complexes, interac-tion energy analyses were performed for the optimized struc-tures using the Fragment Molecular Orbital (FMO) method.38,39FMO calculations were carried out at the second-order Møller–Plesset perturbation theory (MP2) level40,41 with the 6-31G(d)basis set, and inter-fragment interaction energy (IFIE) and PairInteraction Energy Decomposition Analysis (PIEDA) were usedto quantitatively evaluate the detailed host-guest interactionswithin the inclusion complexes.42Results and discussionPreparation of supramolecular structures from 6-O-alkylateda-CDSupramolecular structures were prepared by adding a methanolsolution of 6-O-alkylated a-CD dropwise into poor solvents suchas hexane or cyclohexane, followed by standing at 25 °C for 24 h.The resulting precipitates were collected by ltration and driedunder an N2 ow prior to PXRD and SEM analyses.Fig. 2A and B show SEM images of the precipitates obtainedfrom mixtures of 6-Me-a-CD/methanol with hexane and cyclo-hexane as poor solvents, respectively. In both cases, rhombicmicroplates with lateral dimensions of 1–2 mm and thicknessesof 0.1–0.2 mm were observed. Fig. 2C shows the SEM image of© 2026 The Author(s). Published by the Royal Society of ChemistryFig. 2 SEM images of precipitates formed by dropwise addition of a 6-Me-a-CD/methanol solution into (A) hexane and (B) cyclohexane,followed by standing at 25 °C for 24 h. (C) SEM image of precipitatesformed by adding a 6-Et-a-CD/methanol solution into hexane, fol-lowed by standing at 25 °C for 24 h.Paper RSC Advancesthe supramolecular structures formed from a combination of 6-Et-a-CD/methanol and hexane (a poor solvent). Similar rhombicmicroplates were observed; however, their lateral dimensions(0.2–0.5 mm) were clearly smaller than those observed for 6-Me-a-CD, whereas their thicknesses remained comparable (0.1–0.2mm) (Fig. 2A), suggesting that the ethyl substituents may hindercrystal growth along the lateral direction compared with themethyl substituents.The PXRD pattern of the rhombic microplates formed from6-Me-a-CD in methanol/hexane is shown in Fig. 3A. Diffractionpeaks were observed at 2q = 5.1°, 7.6°, 10.2°, 12.9° and 19.9°.The reections at 2q= 5.1° (d= 17.4 Å) and 10.2° (d= 8.7 Å) canbe assigned to diffraction from the [001] and [002] planes of thehead-to-head assembly of 6-Me-a-CD (Fig. 3D),24 respectively,which is consistent with the formation of supramolecularFig. 3 (A) PXRD patterns of precipitates obtained by dropwise additionof a 6-Me-a-CD/methanol solution into hexane, followed by standingat 25 °C for 24 h. (B) Simulated PXRD pattern based on the single-crystal structure of 6-Me-a-CD obtained from a methanol/water/DECsystem. (C) PXRD patterns of precipitates formed by dropwise additionof a 6-Et-a-CD/methanol solution into hexane followed by standing at25 °C for 24 h. (D, E) Schematic illustrations of the (D) head-to-headarrangement and (E) lateral hexagonal packing of 6-Me-a-CD.© 2026 The Author(s). Published by the Royal Society of Chemistrydimers. Peaks at 2q = 7.6° [110], 12.9° [200] and 19.9° [310] areattributable to a laterally aligned hexagonal arrangement of thedimers (Fig. 3E).43 The PXRD pattern of the rhombic micro-plates obtained from 6-Et-a-CD (Fig. 3C) was similar to that of 6-Me-a-CD, indicating comparable supramolecular packing.These results suggest that the rhombic plate-like microstruc-tures are constructed from head-to-head supramoleculardimers of 6-Me-a-CD and 6-Et-a-CD, which are laterally orga-nized into hexagonal arrays.A single crystal of 6-Me-a-CD was obtained by standinga methanol/water/diethyl carbonate (DEC) solution of 6-Me-a-CD at 80 °C for one week. X-ray crystallographic analysisrevealed that 6-Me-a-CD molecules form head-to-head dimersvia intermolecular hydrogen bonding between the 3-OH groups,with an H/O distance of 2.16 Å (Fig. 4A and B).31 These dimersfurther assemble into layered structures featuring a lateralhexagonal packing and a slightly offset vertical alignment(Fig. 4C and S7). The hexagonal arrangement is stabilized byintermolecular hydrogen bonding between the 2-OH groups ofadjacent 6-Me-a-CDmolecules, with an H/O distances of 1.86–1.95 Å (Fig. 4D). Although themolecules adopt locally hexagonalpacking within each layer, the layered stacking is considered toinduce anisotropic crystal growth. The resulting directionalimbalance in growth suppresses the development of a hexag-onal morphology and instead favors the formation of rhombicplate-like assemblies.44The PXRD pattern simulated from the single-crystal data of6-Me-a-CD (Fig. 3B) is consistent with the experimental PXRDpattern of the supramolecular structures formed from 6-Me-a-CD (Fig. 3A), indicating that the microstructures consist oflayered assemblies of head-to-head supramolecular 6-Me-a-CDdimers.We next investigated the formation of supramolecularstructures from 6-O-alkylated a-CD by mixing its methanolFig. 4 Crystal structure of the 6-Me-a-CD assembly. (A and B) sideviews; (C and D) top views. 6-Me-a-CD molecules are displayed usinga cylinder representation. Color labels: white, hydrogen; gray, carbon;red, oxygen. In (A), selected 6-Me-a-CD molecules are illustrated asyellow trapezoids, while in (C) and (D), selected 6-Me-a-CDmoleculesare shown as yellow circles. Darker yellow indicates the top-mostlayer. Methanol and DEC molecules are omitted for clarity.RSC Adv., 2026, 16, 38221–38227 | 38223Fig. 6 (A and B) SEM images of precipitates obtained by dropwiseaddition of an equimolar mixture of methyl oleate and methyl elaidateinto (A) a 6-Me-a-CD/methanol solution or (B) a 6-Et-a-CD/methanolsolution, followed by standing at 25 °C for 24 h. (C) Extraction rates ofmethyl elaidate (blue) and methyl oleate (orange) in methanol throughsupramolecular structure formation induced by inclusion complexesbetween the 6-O-alkylated a-CD dimer and the fatty acid esters.RSC Advances Papersolution with long-chain unsaturated fatty acid esters, such asmethyl elaidate (trans) and methyl oleate (cis). These fatty acidesters can act not only as poor solvents but also as potentialguest molecules for the CD. Rhombic supramolecular micro-plates were also obtained when either methyl elaidate or methyloleate (0.33 mL, 9.7 × 10−4 mmol) was added dropwise toa methanol solution of 6-Me-a-CD (1.0 mL, 1.9 mmol L−1)(Fig. 5). In both cases, the resulting microplates (lateraldimensions of 5–10 mm and thicknesses of 0.3–0.5 mm) werelarger than those obtained when hexane or cyclohexane wasused as the poor solvent, suggesting that these fatty acid estersenhance the supramolecular assembly process of 6-Me-a-CD,possibly by promoting the formation of 6-Me-a-CD dimers inmethanol. Moreover, the yield of the microstructures washigher when methyl elaidate was used (1.6 mg) than whenmethyl oleate was employed (1.1 mg), although their sizes werecomparable. This nding suggests that methyl elaidate moreeffectively promotes the formation of supramolecular structuresthan methyl oleate, possibly by enhancing the initial inclusioncomplex formation between the 6-Me-a-CD dimer and the fattyacid esters in methanol. PXRD and NMR analyses conrmedthat these rhombic microplates are composed of a 1 : 1 inclu-sion complex between head-to-head supramolecular dimers of6-O-alkylated a-CD and the fatty acid ester guests (Fig. S8, S11and S12).Selective extraction of unsaturated fatty acid estersBased on the above-mentioned observations, we investigatedthe cis/trans-selective extraction of unsaturated fatty acid estersfrom an equimolar mixture of methyl elaidate andmethyl oleateby utilizing the formation of inclusion complexes between the 6-O-alkylated a-CD dimers and the fatty acid esters, followed bytheir supramolecular assembly. Aer addition of a mixture offatty acid esters (0.33 mL) to a methanol solution of 6-Me-a-CD(1.0 mL, 1.9 mmol L−1), the resulting solution was stirred at 25 °C and then allowed to stand for 24 h, leading to the formation ofrhombic microplates composed of supramolecular assembliesof the corresponding CD dimers (Fig. 6A, S9 and S10), similar tothe results described above. The concentrations of theremaining fatty acid esters in the supernatant separated fromthe precipitate, were quantied by GC-MS to determine theextraction percentage of each ester. In this case, methyl elaidatewas preferentially extracted into the supramolecular assembliesFig. 5 (A and B) SEM images of precipitates obtained by dropwiseaddition of (A) methyl oleate and (B) methyl elaidate into a 6-Me-a-CD/methanol solution, followed by standing at 25 °C for 24 h.38224 | RSC Adv., 2026, 16, 38221–38227over methyl oleate, with an extraction amount approximatelytwice that of methyl oleate (Fig. 6C). Similarly, addition ofa mixture of fatty acid esters (0.81 mL) to a methanol solution of6-Et-a-CD under otherwise identical conditions yielded rhombicmicroplates as precipitates (Fig. 6B). In contrast, GC-MS anal-ysis of the supernatant revealed that 6-Et-a-CD selectivelyextracted methyl oleate (Fig. 6C). These results demonstratethat the cis/trans-selective extraction of long-chain unsaturatedfatty acid esters is achieved through a supramolecular assemblyprocess driven by inclusion complex formation between 6-O-alkylated a-CD dimers and the fatty acid ester guests. Notably,modulation of the alkyl chain length at the 6-O position of a-CDenables a reversal of cis/trans selectivity in the supramolecularextraction behavior.DFT-based evaluation of binding selectivityTo elucidate the origin of the cis/trans-selective extraction oflong-chain unsaturated fatty acid esters through the supramo-lecular assembly process of 6-O-alkylated a-CD, density func-tional theory (DFT) calculations were performed to evaluate theoptimized structures of the inclusion complexes between 6-O-alkylated a-CD dimers and the corresponding fatty acid esterguests, as well as their binding stabilization energies (Fig. 7Aand B and Tables S1–S12). The optimized structures of the 6-Me-a-CD dimer complexes with methyl oleate and methyl elaidaterevealed that the long alkyl chains of both fatty acid methylesters were accommodated within the dimer cavity. The estercarbonyl group of each guest was positioned near the terminalmethoxy groups of the dimer, suggesting attractive interactionsthat induce bending of the alkyl chain. A similar inclusionmode was observed for the 6-Et-a-CD dimer, in which the alkyl© 2026 The Author(s). Published by the Royal Society of ChemistryFig. 7 (A and B) Energy diagrams for the complex formation of (A) the6-Me-a-CD dimer with methyl oleate (MO) or methyl elaidate (ME)and (B) the 6-Et-a-CD dimer with MO or ME. Molecular sizes are notdrawn to scale. (C and D) IFIE and PIEDA energy components for theinteractions between the fatty acid esters and (C) 6-Me-a-CD and (D)6-Et-a-CD. ES: electrostatic; EX: exchange-repulsion; CT + mix:charge-transfer plus mixed; DI: dispersion.Paper RSC Advanceschains of the fatty acid esters were likewise encapsulated withinthe dimer cavity, while the ester carbonyl groups were locatednear the terminal ethoxy groups, leading to a bent molecularconformation. The calculated binding stabilization energy for© 2026 The Author(s). Published by the Royal Society of Chemistrythe methyl elaidate/6-Me-a-CD dimer complex(−77.0 kcal mol−1) was larger than that for the methyl oleatecomplex (−76.0 kcal mol−1). In contrast, for the 6-Et-a-CDdimer, the stabilization energy of the methyl oleate complex(−70.7 kcal mol−1) exceeded that of methyl elaidate(−68.8 kcal mol−1), indicating stronger host-guest interactionsbetween methyl oleate and the 6-Et-a-CD dimer. The stabiliza-tion energies of the fatty acid ester/6-Et-a-CD dimer complexeswere lower than those of the corresponding 6-Me-a-CD dimercomplexes. These results are consistent with the extractionbehavior of unsaturated fatty acid esters mediated by thesupramolecular assembly process of the 6-O-alkylated a-CDs,suggesting that the stability of the inclusion complexes between6-O-alkylated a-CD dimers and fatty acid esters contributes tothe selective extraction process. These contrasting trends inguest selectivity prompted further investigation into theunderlying host-guest interaction mechanisms using interac-tion energy analysis based on the Fragment Molecular Orbital(FMO) method.FMO interaction energy analysisTo further elucidate the differences in the stability of theinclusion complexes formed between each 6-O-alkylated a-CDdimer and the fatty acid methyl esters, we performed interac-tion energy analyses based on the Fragment Molecular Orbital(FMO) method38,39 to investigate their host-guest interactions indetail. FMO calculations of inter-fragment interaction energy(IFIE) and Pair Interaction Energy Decomposition Analysis(PIEDA) were carried out for the inclusion complexes.42 Theresults revealed substantial contributions from electrostatic(ES) and charge-transfer plus mixed (CT + mix) interactions, aswell as from dispersion (DI) and exchange-repulsion (EX)interactions, between the 6-Me-a-CD dimer and the fatty acidesters (Fig. 7C and S13-16, Tables S13 and S14). Upon changingthe guest frommethyl elaidate to methyl oleate, the ES and CT +mix terms remained nearly unchanged, and the DI contributionslightly increased. In contrast, the EX interaction increasedmarkedly, indicating enhanced steric repulsion arising from thebent alkyl chain of methyl oleate. This EX component originatesfrom the overlap of electron densities between the host andguest molecules, reecting steric repulsion caused by the closeapproach of atomic orbitals. In this CD dimer, the bentconformation of methyl oleate produced greater EX destabili-zation than the more linear methyl elaidate, rendering the latterguest intrinsically more favorable for inclusion. By comparison,in the case of the 6-Et-a-CD dimer, the DI with methyl oleatebecomes stronger than that with methyl elaidate (Fig. 7D andS17–20, Tables S15 and S16). In addition, pronounced ES andCT + mix interactions between the terminal ethoxy groups(particularly fragments 7 and 11: Fig. S17 and S19) and the estergroup of methyl oleate effectively compensate for the unfavor-able contribution of EX. As a result, the inclusion complex withmethyl oleate becomes more stable than that with methyl elai-date, leading to a reversal of selectivity. These results indicatethat, in addition to the van der Waals interactions between theguest alkyl chain and the cavity wall of the dimer, electrostaticRSC Adv., 2026, 16, 38221–38227 | 38225RSC Advances Paperinteractions between the terminal alkoxy groups of the dimerand the ester carbonyl group of the guest also play an importantrole in stabilizing the inclusion complexes. The cooperativeeffect of these interactions contributes to the experimentallyobserved reversal of cis/trans selectivity upon varying theterminal alkyl substituent in the dimer.ConclusionsIn this study, we successfully fabricated rhombic plate-likemicrostructures composed of layered assemblies of head-to-head supramolecular dimers derived from 6-O-alkylated a-cyclodextrins (6-Me-a-CD and 6-Et-a-CD). These well-regulatedmicrostructures were formed through the secondary assemblyof supramolecular dimers in a mixed solvent system consistingof methanol and a poor solvent (serving as a guest), and thisassembly process enabled the selective extraction of long-chainunsaturated fatty acid esters. Notably, 6-Me-a-CD preferentiallyextracted methyl elaidate (trans), whereas 6-Et-a-CD showed theopposite preference, selectively extracting methyl oleate (cis).This reversal of cis/trans selectivity demonstrates that subtlemodulation of the alkyl substituent at the 6-O position of a-CDcritically inuences host-guest interactions within the dimernanocavities. The origin of this selectivity was further eluci-dated by DFT calculations combined with FMO interactionenergy analysis, which revealed that subtle differences in thebalance of dispersion, electrostatic and exchange-repulsioninteractions govern guest recognition within the dimer nano-cavities. These ndings highlight the utility of alkylated cyclo-dextrins as tunable supramolecular hosts capable ofdiscriminating between structurally similar molecules throughcontrolled dimer assembly and microstructure formation. Theapproach presented here offers a promising strategy for theselective separation of fatty acid esters and potentially otherclosely related organic compounds.Author contributionsToshiyuki Kida: conceptualization, supervision, projectadministration, funding acquisition, writing – review and edit-ing. Haruya Ishida: investigation, formal analysis, visualization,writing – original dra. Hajime Shigemitsu: investigation,formal analysis, writing – review and editing. Shuhei Miyakawa:methodology, formal analysis, writing – review and editing.Kaori Fukuzawa: supervision, writing – review and editing.Conflicts of interestThere are no conicts to declare.Data availabilityAll other data supporting this study are included in thesupplementary information (SI). Ref. 30 and 32–42 are also citedin the SI, where they are renumbered 1–12.CCDC 2512778 contains the supplementary crystallographicdata for this paper.3138226 | RSC Adv., 2026, 16, 38221–38227Supplementary information is available. See DOI: https://doi.org/10.1039/d6ra04383f.AcknowledgementsThis work was supported by a Grant-in-Aid for ScienticResearch (No. 22H02146) from the Japan Society of thePromotion of Science and the OU Master Plan ImplementationProject at The University of Osaka. The theoretical calculationswere performed using the Fugaku supercomputer (project ID:hpci250154).Notes and references1 Y. Zhao, F. Sakai, L. SU, Y. Liu, K. Wei, G. Chen and M. Jiang,Adv. Mater., 2013, 25, 5215–5256.2 R. Bleta, A. Ponchel and E. Monier, Environ. Chem. Lett.,2018, 16, 1393–1413.3 J. Zheng, C. Zhu, X. Xu, X. Wang and J. Fu, J. Mater. Chem. B,2023, 11, 6265–6289.4 A. S. Mahadevi and G. N. Sastry, Chem. Rev., 2013, 113, 2100–2138.5 W. Chen, P. Chen, G. Zhang, Y. Feng, Y.-W. Yang andL. 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C,2013, 117, 15859–15870.RSC Adv., 2026, 16, 38221–38227 | 38227https://doi.org/10.5517/ccdc.cq2qbrc6 Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters Formation of hierarchical supramolecular microstructures from 6-O-alkylated tnqh_x03B1-cyclodextrin and their application to the selective extraction of long-chain unsaturated fatty acid esters