Two new metaleorganic framework compounds based on natural b-cyclodextrin molecules (b-CD) andalkali metals (Naþ/Kþ) were synthesized and characterized by elemental analyses, IR, XPRD and 1HNMR.Single-crystal X-ray diffraction analysis reveals that compounds 1 and 2 possess the bowl-like pore andthe “8” type double channels configuration. Due to the [blow þ channel] double configuration, 5-Fluorouracil (5-FU) and Quercetin inclusion complexes of compound 1 are studied, and the resultsshow that the two kinds of drug with different structure and size can be included into the compound atthe same time, which is expected to become a new type of multi-functional green crystalline solidmaterial.
Green chemistry has become a central issue in both academicand industrial research in 21st century, involving organic synthesis,material chemistry and biochemistry. The metaleorganic frame-works (MOFs), a new class of crystalline solid materials consistingof metal ions and organic ligands, are being evaluated for diversepotential applications, such as gas adsorption [1e8], storage ofclean gas fuels [9,10], separations [11e13], and drug delivery[14e16]. However, the vast majority of MOFs reported to date arecomposed of organic subunits derived from non-renewablepetrochemical feedstocks and transition metals. Once these MOFsare applied to the industrialization, some urgent problems mayappear as follow: 1) High costs make it difficult to large-scale ap-plications in the industry; 2) Pollution control during the synthesis;3) Non-renewable ingredients. Therefore, it is necessary that thepreparing MOFs from natural products derive environmentallybenign, clean synthetic procedures, and renewable materials.
As a special class of carbohydrates [17,18], cyclodextrin (CD)consists of six, seven or eight a-1,4-linked D-glucopyranosylrepeating units and displays theeOCCO- bindingmotif on both theirprimary and secondary faces auguring well for forming extended
structures with Group IA and IIA metal. These characteristics of CDscan merge into metaleorganic frameworks (named as CD-MOFs)with alkali metals as organic candidates to contribute the naturalporous materials [19e23]. More importantly, CD-MOFs are inex-pensive and “green” in the sense, because they can be synthesizedfrom renewable sources that are themselves derived from water,CO2, and nontoxic metal salts. On the other hand, the hosteguestcomplexes of CDs have been studied extensively over a long perioddepending on their natural flexible porosities, and such complexesare used in the pharmaceutical and food industries [24e26].Although many CD-MOFs assembled form a-, b-, and g- CD werereported, and their structures exhibit the barrel, the cage, the inde-pendent double CD and three-leaf oar, and so on, but the 2D bowl-like structure was rarely reported.
On the basis of the above considerations, to seek the greennatural porous material, and to isolate the suitable crystals of CD-MOF with different structure, herein, we report the unprece-dented and rapid formation of a well-defined porous materialsconstituted by natural b-cyclodextrin (b-CD) molecules and alkalimetals (Naþ/Kþ) via a pollution-free method. Our success owes tothe C7 symmetric of b-CD with causing the asymmetric coordi-nating mode with alkali metals. Due to the interesting[blow þ channel] double configuration of CD-MOF, the drug (5-FUand Quercetin) inclusion complexes of CD-MOFs are studied(shown in Scheme 1).
Scheme 1. Schematic representation of CD-MOF with double configuration and the drug inclusion complexes of CD-MOFs.
J.-Q. Sha et al. / Journal of Molecular Structure 1101 (2015) 14e20 15
2. Experimental section
2.1. General information
All reagents were purchased commercially and used withfurther purification. Elemental analyses (C and H) were performedon a PerkineElmer 2400 CHN Elemental Analyzer. The IR spectrawere obtained on an Alpha Centaurt FT/IR spectrometer with KBrpallet in the 400e4000 cm�1 region. Chromatography work wasperformed using the HPLC-1100 system (Agilent, CA, USA). ThermalAnalysis DSC-Q100 differential scanning calorimeter was per-formed on a Thermal Analysis Ltd Co, USA. The X-ray powderdiffraction (XRPD) patterns were obtained with a Rigaku D/max2500 V PC diffractometer with Cu-Ka radiation, the scanning rate is4�/s, 2q ranging from 5 to 40�. The 1HNMR spectra obtained on aBruker AV400 instrument with deuterate dimethyl sulphoxide(DMSO) as solvent.
2.2. Synthesis
2.2.1. Synthesis of NaOH (C42H70O35)·9H2O (Na-CD-MOF)b-Cyclodextrin (1.135 g, 1 mmol) and NaOH (0.32 g, 8 mmol)
were dissolved in deionized H2O (15 ml) and C2H5OH (5 ml), andthe resulting solution was stirred for 1 h. The solution was filteredthrough PTFE membrane. After two week, colorless crystals wereisolated, washed with C2H5OH, and dried at room temperature.Yield: ca. 76%. Elemental analysis (%) calcd. for Na(C42H70O35)$OH$9H2O: C 37.69, H 6.71; found: C 37.59; H 6.75.
2.2.2. Synthesis of KOH (C42H70O35)·9H2O (K-CD-MOF)b-Cyclodextrin (1.135 g, 1 mmol) and KOH (0.448 g, 8 mmol)
were dissolved in deionized H2O (15 ml) and C2H5OH (5 ml), andthe resulting solution was stirred for 1 h. The solution was filteredthrough PTFE membrane. After two week, colorless crystals wereisolated, washed with EtOH, and dried at room temperature. Yield:ca. 74%. Elemental analysis (%) calcd. for K(C42H70O35)$OH$9H2O: C37.27, H 6.58; found: C 37.24; H 6.61.
2.3. Preparation of drug-CD-MOF inclusion complexes
Drug-CD-MOF inclusion complexes were prepared by grindingmethod at room temperature. In brief, 5-FU, Quercetin and CD-MOFwere accurately weighted at a molar ration of 1:1:1, respectively.The result compounds were grinded with absolute alcohol aswetter. After grinding for 1 h, the products were rinsed 3 times byusing certain amount of absolute alcohol. The inclusion complexeswere desiccated at 60 �C until constant weight was obtained.
2.4. X-ray single crystal diffraction analysis
Structural measurements for Na/K-CD-MOF were performed ona Rigaku RAXIS RAPID IP diffractometer with Mo-Ka mono-chromatic radiation (l ¼ 0.71069 Å) at 293 K. The structures weresolved by the directed methods and refined by full matrix least-squares on F2 using the SHELXTL crystallographic software pack-age [27]. All non-hydrogen atoms in 1 and 2 were refined aniso-tropically. The positions of hydrogen atoms on carbon atoms werecalculated theoretically. The crystal data for 1 and 2 are summa-rized in Table 1. Since the metrical parameters associated withthese structures are unexceptional, full listings of bond lengths andangles for theM sites and for the CD are given in the supplementarytables only. Crystallographic data for the structure reported in thispaper have been deposited in the Cambridge Crystallographic DataCenter with CCDC Number 1041731 for 1 and 1041782 for 2.
3. Results and discussion
3.1. Crystal structures of compounds 1 and 2
Single crystal X-ray diffraction analysis reveals that compounds1 and 2 are isostructural, and each consists of one b-CD, one Naþ ionfor 1 and one Kþ ion for 2 and nine lattice waters and one OH� ion(Fig. 1a). Here, the structure of compound 1 is discussed as anexample. There is a crystallographically independent Naþ ion,which is six-coordinated by six oxygen atoms from four contiguousCD molecules, namely, four secondary hydroxyls, one primary hy-droxyl and one ring oxygen atom. The NaeO bond distances are inrange of 2.730 Åe2.985 Å (Fig. 1b). The b-CD adopts four coordi-nated mode linking with four Na ions via a-, b- and D-glucopyr-anosyl (Fig. 1c). . To the best of our knowledge, the coordinatedmode of CD has never been found in the other CD based compound.
The prominent structure feature of compound 1 is the presenceof the bowl-like pore (size ca.6.0� 5.8Å) via “T” arrangements of b-CDs and the “8” type double channels (size ca.5.6 � 5.4 Å), whichcan be understood from Fig. 2. Two adjacent b-CDs link with Naions forming the “T” shape structure with unique bowl-like pore, inwhich one b-CD uses its 2, 3eOH groups from a- and D-glucopyr-anosyl and another uses its 6-OH and 2, 3-OH groups from b- and D-glucopyranosyl (Fig. 2a). Furthermore, these “T” shape structureunits array along the b-axis forming the “8” type double channels(Fig. 2b). Note that such an unusual coordination mode has notbeen found in CD chemistry hitherto. Finally, each of the doublechannels units held together along the a-axis via interactions ofNaeO leading to the formation of 2D layers in ab plans (Fig. 3). Thesolvent-accessible volume of the unit cell is estimated, (PLATON
Table 1Crystallographic and structural refinement data of 1 and 2.
J.-Q. Sha et al. / Journal of Molecular Structure 1101 (2015) 14e2016
program) to be 589.2 Å3, which is approximately 19.5% of the unit-cell volume (3027Å3). Additionally, to obtain the information aboutsurface area of the CD-MOFs, the N2 adsorption/desorption wasperformed, and the results shows poor uptakes of N2. Maybebecause the 2D layer in CD-MOF are stacked in parallel staggeringfashion, the vacancies in a layer are covered by CD of adjacent layersin this stack style, which is of disadvantage for gas absorption(Fig. S1). The XRPD pattern undergoes partial after experiment
Fig. 1. Ball and stick representation of the asymmetric of Na-CD-MO
(Fig. S2), suggesting that phase transition or framework collapsehappens during N2 absorption process.
As is known to all, the formation of the barrel or three leafblade structures are easy when cyclodextrins are connected be-tween the tail and end via the secondary hydroxyls. But theasymmetric coordination modes of the b-CD in Na/K-CD-MOF,namely, a-, b- and D-glucopyranosyl coordination mode concen-trate in the side of the ring, not only lead to the above structure
F (a); the coordination environment of Na ions (b) and b-CD(c).
Fig. 2. Ball and stick representation of the “T” shape structure with unique bowl-like pore (a) and the “8” type double channels (b).
J.-Q. Sha et al. / Journal of Molecular Structure 1101 (2015) 14e20 17
feature, but also prevent the formation of the 3D framework. As aresult, Na/K-CD-MOF contains [blow þ channel] double configu-ration, which allows for the enclosing two types of small molec-ular drugs at the same time.
Fig. 3. Stick representation of 2D layers (left) and schematic of [blow þ channel] do
3.2. Spectroscopic properties
The IR spectra (Fig. S3) of compounds 1 and 2 show prominentcharacteristic absorption bands at 3392 cm�1 (for eOH stretching
uble configuration for the enclosing two types of small molecular drug (right).
J.-Q. Sha et al. / Journal of Molecular Structure 1101 (2015) 14e2018
vibrations of multi-association body), 2930 cm�1 (for CeHstretching vibrations of eCH3 and eCH2), 1419, 1157 cm�1 (for eOHbending vibration), 1080, 1030 cm�1 (for CeC, CeO or CeCeOstretching vibrations), which indicates that Na-CD-MOF and K-CD-MOF keep the skeleton structure of the b-CD. By comparison, thespectra of two compounds are very similar except for the CeO andOeH stretching vibration region with a slight difference perhapsdue to the formation of MeO bond.
3.3. XRPD pattern analyses
The X-ray powder diffraction (XRPD) pattern for compounds 1and 2 is presented in Fig. S4. The diffraction peaks of both simulatedand experimental patterns match well, thus indicating that thephase purity of the compounds is good. The difference in reflectionintensities between the simulated and the experimental patterns isdue to the different orientation of the crystals in the powdersamples.
3.4. Study about drug-b-CD-MOF inclusion compounds
To study inclusion properties of compounds 1 and 2, we usethem as inclusion materials to include drug molecules, owing totheir special cavity structure. On the one hand, compound 1 isisomorphous with compound 2, therefore their inclusion proper-ties are explored using compound 1 as an example. On the otherhand, the structure of compounds 1 and 2 possesses[blow þ channel] double configuration, which is favor of inclusionand loading two types of small molecular drugs at the same time.As a result, compounds 1 and 2 are expected to become a new typeof multi-functional green materials in drug delivery.
3.4.1. HPLC assayThe Quercetin and 5-Fu content of the inclusion complexes was
determined by HPLC shown in Fig. 4. The HPLC system consisted ofa water1525 Binary HPLC Pump with a Water 2487 Dual l Absor-bance Detector, and a C18 Phenomenex column (5 mm,4.60 mm � 250 mm). The mobile phase included methanol: water(50:50/V:V), running at a flow rate of 1.0 mL min�1. The injectedvolumewas 10 mL and the detectionwavelength was 270 nm, whilethe column temperature was set at 25 �C. The standard 5-FU,Quercetin and inclusion complexes were detected by this condi-tion. The results show that the pure 5-FU retention time was3.12 min, and the pure Quercetin retention timewas 16.42min. Theinclusion complexes have two absorption peaks in 2.71 min and15.40min, which belong to that of 5-FU and Quercetin, respectively.The change of retention time of 5-FU and Quercetin in the inclusion
Fig. 4. HPLC chromatograms of 5-FU (1), Quercetin (2) and inclusion complexes (3).
complex indicates that there is a force between the host and guestand the formation of inclusion complexes.
3.4.2. Spectroscopic propertiesFig. 5 shows the spectra of Quercetin, 5-FU, b-CD, Na-CD-MOF,
and their physical mixture and inclusion complexes, respectively.The IR spectra of 5-FU and Quercetin show their prominent char-acteristic absorption, respectively. And the spectrum of physicalmixture shows correspondence to superposition of its parentproducts with relatively weak absorption, however, compared withits parent products, the spectrum of inclusion complexes shows arelatively large difference, namely, for 5-FU, the NeH stretchingvibration peak (3010 cm�1) disappeared, the CeF peak (1699 cm�1)is weakened; for Quercetin, the eOH stretching vibrations peak(3388 cm�1) is weakened and the stretching vibrations peak ofbenzene skeleton (1151 cm�1) shift. The changes further indicatethat 5-FU and Quercetin interact with Na-CD-MOF and formed in-clusion complexes.
The 1HNMR spectra of CD-MOF, 5-FU, Quercetin, physical mix-tures and inclusion complexes are shown in Fig. 6 and Fig. S5, and1HNMR chemical shift are listed Table S3eS5. The glucopyranosylresidues of CD-MOF in the 1HNMR spectrum produce five distinctsignals for the protons. It is clearly found that the chemical shift ofprotons is only a superposition of three substances in the 1HNMRspectra of physical mixture, but the chemical shift of protons havechanged significantly in the 1HNMR spectrum of the inclusioncomplexes. More specifically, the chemical shift of H-3 and H-5localized within the cyclodextrin cavity changed due to thescreening effect, which demonstrates 5-FU as guest moleculesenter the CD-MOF cavity. On the other hand, when Quercetinmolecule and CD-MOF interaction, hydrogen bonds between 6-OHof Quercetin and 7-OH of CD-MOF result in changing of chemicalshift of 6-OH of Quercetin and 7-OH of CD-MOF (shown in Fig. S6).This data further indicate that 5-FU, Quercetin and CD-MOF forminclusion complexes.
3.4.3. Differential scanning calorimetry (DSC)Fig. 7 shows the DSC curve of Quercetin, 5-FU, b-CD, NaeCD-
MOF, and their physical mixture and inclusion complexes, respec-tively. Na-CD-MOF has one endothermic peak at 86 �C and onemeltpeak at 315 �C; 5-FU has one sharp endothermic peak at 283 �C;Quercetin has one endothermic peak at 130 �C and a melt peak at315 �C; In DSC curve of physical mixture, all endothermic peak was
Fig. 5. IR spectra of (1) CD-MOF; (2) 5-FU; (3) Quercetin; (4) Physical mixture; (5)Inclusion complexes.
Fig. 6. 1HNMR spectra of CD-MOF, Quercetin, 5-FU; mixture product and inclusion complexes.
J.-Q. Sha et al. / Journal of Molecular Structure 1101 (2015) 14e20 19
found and weakened, which suggest the weak interaction betweenthree components without a formation of a new phase; For theinclusion complexes, the endothermic peak of 5-FU and Quercetincompletely disappeared, which indicates that the inclusion com-plexes has been formed.
4. Conclusion
In summary, two new carbohydrate metaleorganic frameworks(CD-MOF) with [blow þ channel] double configuration have beensynthesized, and their unique structure and inclusion propertieswere characterized and studied. It is interesting that this kind ofCD-MOF is favor of inclusion and loading the drug molecules withdifferent structure, different size, or different charges at the sametime, which are expected to become a new type of multi-functionalgreen material. The successfully isolation of the suitable crystals ofCD-MOF can lead to a new generation of the carbohydrate metal-eorganic frameworks with different structures.
This work is financially supported by the National Natural Sci-ence Foundation (Grant Nos. 21271089) and the Education OfficeFoundation (12511575) in Heilongjiang Province.
Appendix A. Supplementary information
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.molstruc.2015.08.020.
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