Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 5467−5473
Synthesis and Binding Properties of Monohydroxycucurbit[7]uril: A Key Derivative for the Functionalization of Cucurbituril Hosts Nan Dong,*,†,‡ Jing He,† Tao Li,† Andrea Peralta,§ Mehdi Rashvand Avei,§ Mingfang Ma,§ and Angel E. Kaifer*,§ †
School of Chemistry and Chemical Engineering, Guizhou University, Guiyang 550025, China Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province, Guiyang 550025, China § Department of Chemistry, University of Miami, Coral Gables, Florida 33124-0431, United States ‡
S Supporting Information *
ABSTRACT: We present a simple, direct method to prepare monohydroxylated cucurbit[7]uril (CB7-OH) through the direct oxidation of its precursor host, cucurbit[7]uril (CB7). Although the conversion takes place in low yield (14%), the isolation of CB7-OH from the reaction mixture is straightforward, and the unreacted CB7 can be easily recovered. ITC measurements with several selected guests confirmed that CB7-OH binds all of them in aqueous solution with similar, albeit slightly lower, binding affinities than those observed with the unmodified CB7 host. ESI mass spectrometric competition experiments are consistent with the ITC measurements. A variety of spectroscopic and voltammetric measurements also verify that the CB7-OH complexes exhibit properties essentially identical to those of the CB7 complexes. DFT computational data also confirm the similar thermodynamic stabilities and structures of the CB7-OH and CB7 inclusion complexes. Finally, the high thermodynamic stability of the CB7-OH complexes was used to improve on the extraction efficiency of stir bar sorptive extraction methods after suitable modification of the active coating with CB7-OH.
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INTRODUCTION The family of cucurbit[n]uril (CBn) receptors1−4 is attracting considerable attention essentially because their inclusion complexes with suitable guests can reach extremely high binding affinities in aqueous solution.5 Host−guest complexes with high levels of thermodynamic stability were previously thought to be possible only if one of the partners, host or guest, was of biological origin. Particularly with the cucurbit[7]uril (CB7) host, binding affinities in the nanomolar and picomolar regimes are not uncommon, and in very specific cases, higher affinities have been reported.6 The CBn receptors are composed of n glycoluril units interconnected by double methylene bridges, leading to a barrel-shaped macrocyclic structure with two identical openings (portals) to the internal cavity (Figure 1). Unfortunately, the functionalization of these structures has not proven easy, as CBn receptors are rather stable and unreactive. Functionalization is extremely important to prepare CBn derivatives that could be useful for the attachment of these hosts to surfaces, nanoparticles, and polymer chains, which constitute desirable goals for the development of analytical, biomedical, and material science applications. Kim and co-workers developed a synthetic method for the perhydroxylation of CBn hosts, which relies on the oxidation of the methyne protons on the outer equator of these macrocycles using K2S2O8 as the oxidant.7,8 This method allows the © 2018 American Chemical Society
Figure 1. Structures of CB7 and its monohydroxylated derivative.
functionalization of CB6 to CB6-(OH)12 in reasonable yield, but similar reactions with the larger CB7 and CB8 hosts suffered from impractically low yields. Scherman and coworkers modified Kim’s method in two ways: (1) They used the more water-soluble (NH4)2S2O8 as the oxidant and (2) carried out the reaction on CB6 inclusion complexes, which exhibited higher water solubility than uncomplexed CB6. With these modifications, they were able to improve control on the reaction and isolate monohydroxycucurbit[6]uril9 (CB6-OH). Received: February 8, 2018 Published: April 16, 2018 5467
DOI: 10.1021/acs.joc.8b00382 J. Org. Chem. 2018, 83, 5467−5473
Article
The Journal of Organic Chemistry
reaction mechanism is not clear. Perhaps the free radical formed during the redox reaction between NaHSO3 and NH4S2O8 could further promote the generation of OH radical to oxidize CB[7] and to obtain more CB7-OH. Second, we controlled the ratio between CB7 and NH4S2O8 to be 1:1.5. If the ratio exceeds 1:2, the quantity of CB7-(OH)2 and CB7(HO)3 will increase (Figure S1B), leading to a lower yield of CB7-OH and to a more difficult separation during the purification steps. Third, we decreased the reaction temperature from 85 to 65 °C, which seems to depress the production of CB7-(OH)n (n > 1) and yield more than CB7-OH in shorter reaction times (Figure S1B). Finally, the reaction time was kept to 12 h. Under these conditions, reversed-phase chromatography, using CHP20P gel as the stationary phase and water as the mobile phase, results in a 14% isolated yield for the CB7OH target host. Unreacted CB7 can be easily recovered and reused. Figures 2 and 3 show the 1H NMR and 13C NMR spectra of CB7-OH. When compared to unmodified CB7, the symmetry
Isaacs and co-workers took advantage of their extensive mechanistic studies on the formation of CBn receptors to prepare an open hexameric derivative, which they reacted with a previously derivatized glycoluril derivative to yield functionalized CB7 derivatives.10 These derivatives can be further modified with relative synthetic ease. While this approach can become very useful, we also wanted to explore further the oxidation of preformed CBn hosts. In particular, since CB7 has greater aqueous solubility than CB6, we thought that we could directly react CB7 with (NH4)2S2O8 in order to prepare the monohydroxylated derivative of CB7 (CB7-OH). This methodology might be more accessible than Isaacs’ for groups with limited synthetic expertise, since the key starting material is CB7 itself, and the product should be readily converted into a variety of more elaborate CB7 derivatives. We should point out that CB7-OH has been synthesized by Kim’s group11 and used to prepare some CB7 derivatives, but more synthetic and purification details will be a welcome addition to the literature. In 2015, Ouari and co-workers reported the almost quantitative conversion of CB7 to CB7-OH by a photochemical method,12 but they corrected their results later and recognized that their yields were modest and in line with previous reports.13 Very recently, the Scherman group has reported a more detailed account on the oxidation of CB7 to CB7-OH and the factors that limit the reaction yields.14 This manuscript provides an account of our results on the hydroxylation reaction of CB7 and an investigation of the binding properties of CB7-OH compared to those of unmodified CB7.
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RESULTS AND DISCUSSION Synthesis. The efficient monohydroxylation of CB7 constitutes a difficult synthetic challenge because the equatorial outer surface of CB7 contains 14 identical methyne protons that can undergo oxidation to hydroxyl groups. Clearly, if the challenge [oxidant]/[CB7] ratio is below unity, the reaction will exhibit low yields. If the equilibrium is shifted to the product side by increasing the challenge ratio beyond unity, a mixture containing unreacted CB7, CB7-OH, CB7-(OH)2, and other derivatives with multiple hydroxyl groups is obtained. Since the derivatives containing more than one hydroxyl group may exist as multiple isomers, the ensuing purification problem quickly becomes intractable. The progress of this reaction can be easily followed by MALDI-TOF mass spectrometry, which detects either the protonated forms of CB7 and its hydroxylated derivatives or their sodium ion adducts. Surprisingly, the same is not true in ESI mass spectrometric experiments, and addition of a positively charged guest is necessary for the observation of the corresponding complexes. For instance, methyl viologen works very well as an additive to monitor the hydroxylation reaction via the ESI-MS observation of doubly charged methyl viologen complexes of CB7, CB7OH, etc. We first tried the oxidation of CB7 with 1.0 equiv of NH4S2O8 as the oxidizing agent, but the results were not promising as shown in Figure S1B. We looked for conditions that would maximize the yield of CB7-OH while minimizing the range of multihydroxylated derivatives. Tan reported the synthesis of linear CB[7] pendant copolymers based on the redox reaction with NH4S2O8 and NaHSO3.15 Initially, NaHSO3 was added into the reaction mixture in a 1:1 ratio with NH4S2O8. MALDI-TOF MS experiments showed that the concentration of CB7-OH was increased as compared to that obtained without addition of NaHSO3 (Figure S1A). The
Figure 2. Partial 1H NMR spectrum (D2O, 400 MHz) of CB7-OH.
Figure 3. Partial 13C NMR spectrum (D2O, 400 MHz) of CB7-OH.
and electron density distribution are perturbed by the additional group, especially the electronic environment near the hydroxyl oxygen. Proton H3, located close to the oxygen through space, experiences a 0.29 ppm downfield shift compared to less affected H7, indicating the decrease of electron density around H3. At the same time, the electron density around H2 and C4 is increased as proton H2 exhibits an upfield shift of 0.29 ppm, and C4 also shifts upfield in comparison with the unperturbed H6 and C7. Therefore, the electron density distribution for H3−C2−H2 bonds are partially polarized in the presence of the hydroxyl oxygen. This 5468
DOI: 10.1021/acs.joc.8b00382 J. Org. Chem. 2018, 83, 5467−5473
Article
The Journal of Organic Chemistry functional group also has an inductive effect toward the C1−C2 bond, resulting in their downfield shifts as shown in Figure 3. The upfield shift of proton H1 is 0.25 ppm compared to the less affected proton H8. The small singlets around H8 arise from the other equatorial protons, also affected by the hydroxyl group. Complex Formation by CB7-OH. CB7 derivatives are commonly used in the assumption that they will behave like unmodified CB7 in terms of host binding properties. While this assumption is reasonable, given that the replacement of one of the equatorial methyne protons of CB7 by more elaborate substituents should not change the size of the host cavity, the covalently attached functionalities may exert electronic effects whose magnitude is yet to be assessed in some detail. Initially, we carried out a series of NMR spectroscopic studies in D2O solution to assess the formation of host−guest complexes between CB7-OH and various guests. Our data (Figure S4) reveal that CB7-OH behaves in the same manner as CB7 as a supramolecular host. Therefore, we decided to carry out quantitative studies to determine, using ITC experiments, the equilibrium association constants (K) of CB7 and CB7-OH with a group of selected guests, shown in Chart 1. These guests
Table 1. Thermodynamic Parameters for the Association between Selected Guests and the Hosts CB7 and CB7-OH in Pure Water at 25 °C (A) Host: CB7 a
(3.3 (3.5 (2.8 (7.9 (1.4 (1.8 (4.0 (1.1
3 4·H22+ 5·H22+ 6·H22+ 7·H+ 8·H+
Chart 1. Structures of Guests Selected for This Study
± ± ± ± ± ± ± ±
0.4) 0.5) 0.4) 0.4) 0.3) 0.2) 0.2) 0.7)
× 109 −42.2 ± × 106 −36.1 ± × 107 −44.1 ± × 105 −12.6 ± × 108 −31.6 ± × 106 −18.2 ± × 105 −23.2 ± × 1011 −49.6 ± (B) Host: CB7-OH
Ka (M−1)
guest 1·H22+ 2·H22+ 2+
ΔH (kJ/mol)
K (M )
guest 1·H22+ 2·H22+ 32+ 4·H22+ 5·H22+ 6·H22+ 7·H+ 8·H+
−1
(1.4 (2.1 (1.6 (6.0 (1.2 (1.4 (3.8 (9.4
± ± ± ± ± ± ± ±
0.7) 0.2) 0.5) 0.7) 0.3) 0.3) 0.2) 0.6)
× × × × × × × ×
0.4 0.7 0.9 0.5 0.6 0.4 0.3 1.1
ΔH (kJ/mol) 109 106 107 105 108 106 105 1010
−56.2 −36.1 −30.8 −13.7 −47.8 −30.1 −29.1 −70.1
± ± ± ± ± ± ± ±
1.2 0.6 0.8 1.4 0.7 0.4 0.4 0.8
TΔS (kJ/mol) 12.1 1.21 −1.61 21.1 14.9 17.3 8.77 13.4
± ± ± ± ± ± ± ±
0.8 0.7 0.6 0.6 0.5 0.5 0.4 1.3
TΔS (kJ/mol) −2.69 −0.06 10.3 19.3 −1.74 5.01 2.72 −7.51
± ± ± ± ± ± ± ±
1.0 0.6 0.5 1.6 0.6 0.5 0.5 0.7
K values under 107 M−1 were determined by direct ITC titration. Higher K values were determined by competition experiments (see the Supporting Information for more details). a
Mass Spectrometric Competition Experiments. As mentioned before, the composition of mixtures of CB7, CB7OH and other hydroxylated derivatives of CB7 can be assessed using MALDI-TOF mass spectrometry. In contrast, these hosts are not easily detected in ESI mass spectrometric experiments, but signals for their charged complexes are readily observed (Figure S5). We decided that it would be instructive to run a series of competition experiments in which solutions containing 1 equiv each of CB7, CB7-OH, and a charged guest would be submitted to ESI conditions, and the resulting relative intensities of the mass spectrometric signals corresponding to the two complexes could be taken as an approximate reflection of their concentrations in the solution phase. We carried out these experiments with three guests: p-xylylenediamine (guest 1·H22+ in Chart 1), methyl viologen (guest 32+ in Chart 1), and cobaltocenium (Cob+). The latter guest, although not shown in Chart 1, forms a very stable inclusion complex with CB7, in which the guest is fully encapsulated in the host cavity.16,17 The results of these experiments are summarized in Table 2. The results of these mass spectrometric experiments are in very good agreement with the K values found in the ITC
were chosen to cover a range of chemical structures, charges, and binding affinities. The measured thermodynamic parameters are given in Table 1. Based on these data, we can conclude that CB7-OH forms complexes with all of the guests, exactly as CB7, and the binding affinities of any of the guests with both hosts are similar. However, the K values measured with CB7OH tend to be slightly lower than those measured with CB7, which may reflect the existence of small electronic effects induced by the −OH substituent, as mentioned before. This matter will be revisited later in the manuscript, when we describe our computational results. The ITC data also show that complex formation is primarily driven by enthalpy, as the ΔH values are negative and much larger than the corresponding TΔS values. The entropic contributions, while generally smaller, are all positive in the case of CB7, but they are either positive or negative in the case of CB7-OH. The positive TΔS values correspond to the less stable complexes. In spite of the variations observed on the enthalpic and entropic contributions as we move from CB7 to CB7-OH with the same guest, the overall change in the K value is relatively small. The measured changes in the enthalpic and entropic contributions are more difficult to justify and may be related to differences in the solvation of the host equatorial surface, which is obviously more polar in the case of CB7-OH as compared to CB7.
Table 2. Relative Signal Intensities Obtained Using Equimolar Amounts of the Selected Guest, CB7, and CB7OH in ESI Mass Spectrometric Experiments [CB7-OH]/[CB7]/ [guest]
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guest
1:1:1
Cob+
1:1:1 1:1:1 0.5:1:1 1.5:1:1 2:1:1
32+ 1·H22+ 32+ 32+ 32+
CB7-OH to CB7 complex signal ratios
avg ratio
0.94, 0.50, 0.67 0.69, 0.71, 0.68 0.74,0.97 0.70, 0.54, 0.69 0.54 0.67, 0.66, 0.73 0.32 1.04, 1.04, 1.08 1.06 1.40
0.74 0.62 0.69 0.32 1.06 1.40
DOI: 10.1021/acs.joc.8b00382 J. Org. Chem. 2018, 83, 5467−5473
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The Journal of Organic Chemistry
CB7 has a pronounced effect on the emission of fluorescent guests upon complexation. For instance, the emission of the dye berberine is strongly enhanced in its complex with CB7.18 Similarly, CB7-OH has an essentially identical effect on the fluorescent emission of this dye (Figures S6 and S7). These spectroscopic data suggest that the light absorption and emission properties of CB7 and CB7-OH complexes are generally expected to be quite similar. The voltammetric properties of guests may also be considerably affected by CB7 inclusion. For instance, complexation of (ferrocenylmethyl)trimethylammonium by CB7 leads to a substantial shift (ca. 120 mV) of its oxidation potential to more positive values and a concomitant decrease of the current levels in the voltammetric response.19,20 While the latter is the result of the larger size and lower diffusivity of the CB7 complex compared to the free guest, the observed potential shift is attributed to the differential host-induced stabilization of the reduced form of the guest (neutral ferrocene) versus its oxidized form (positively charged ferrocenium). We have conducted voltammetric experiments with CB7-OH and determined that the voltammetric responses of the ferrocenylmethyltrimethylammonium complexes with CB7 and CB7OH are essentially undistinguishable from each other (Figure 5). Therefore, the electrochemical properties of the CB7 and CB7-OH complexes of this ferrocene derivative are also similar.
experiments. Clearly, when equal concentrations of both hosts were used, the signal intensities corresponding to CB7-OH complexes were smaller than those corresponding to the CB7 complexes. While there is significant variation of the signal ratios in individual experiments, the average values obtained after several trials exhibit values in the range 0.62−0.74, probably reflecting the slightly lower stability of the CB7-OH complexes for each of the guests compared to their CB7 complexes. Furthermore, we also carried out experiments in which we kept the same, identical concentrations of CB7 and one of the guests (32+) and varied the relative concentration of CB7-OH. Under these conditions, the measured intensities corresponding to the CB7-OH complexes follow the relative concentrations of this host, as would be expected on the basis of mass action. In general terms, it can be argued that differential solvation or ease of vaporization/ionization of the CB7 and/or CB7-OH complexes may be additional factors affecting the signal intensities measured for these complexes. These arguments cannot be entirely dispelled here, but we must note that the literature is accumulating growing evidence that signal intensities measured in ESI mass spectrometric experiments reflect reasonably well the concentrations of the corresponding species in the solution phase. Therefore, in spite of the uncertainties involved in these mass spectrometric experiments, the results are in very good agreement with the ITC results given in Table 1 and provide additional evidence for the slightly lower thermodynamic stability in aqueous solution of the CB7-OH complexes compared to their CB7 analogs. Spectroscopic and Voltammetric Properties of the CB7-OH Complexes. The complexation of Cob+ by CB7 can be followed spectrophotometrically, as the absorbance of the characteristic band of the guest at 261 nm decreases gradually in the presence of increasing concentrations of the host. This behavior, coupled to the large K value for the formation of the complex, allows the quantitative titration of Cob+ with CB7, which our group has proposed as a method for the assessment of purity in CB7 samples.17 An entirely similar behavior is observed with CB7-OH (see Figure 4), indicating that the same spectroscopic titration method can be used for the assessment of purity with the monohydroxylated host.
Figure 5. Cyclic voltammetric behavior on glassy carbon (0.07 cm2) of a 1.0 mM solution of ferrocenylmethyltrimethylammonium also containing 0.1 M NaCl in the absence (black line) and in the presence of 1.0 equiv of CB7 (red line) or 1.0 equiv of CB7-OH (blue line). Scan rate: 0.1 V s−1.
Computational Results. Our experimental results with CB7-OH complexes and the fact that their thermodynamic stability was found to be similar, albeit slightly lower than that corresponding to the CB7 complexes, led us to carry out computational work to further understand these results. We optimized the structures of the CB7 and CB7-OH complexes of the methyl viologen guest through DFT calculations using the global hybrid meta M062X functional and the 6-31G(d) basis set, both of which have shown to provide highly reliable results with chemical structures in which noncovalent interactions play an important role.21 For simplicity, our computations did not take into account any solvent molecules. Frequency calculations were carried out at the same level of theory and confirmed that the found local minima possess all real frequencies. Our DFT computations reveal that the free energies associated with the formation of both complexes, 32+·CB7 and 32+·CB7-OH, from the free guest and host are identical
Figure 4. Electronic absorption spectra of Cob+ (23 μM in pure water) in the presence of various CB7-OH concentrations (0−40 μM, in the direction of the arrow). The inset presents the titration data with CB7 and CB7-OH. 5470
DOI: 10.1021/acs.joc.8b00382 J. Org. Chem. 2018, 83, 5467−5473
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efficient at extracting 4,4′-bipyridine (guest 2 in Chart 1) than other reference coatings, such as commercial PDMS, sol−gel blank PDMS, and CB6-OH/PDMS, as evidenced by our quantitative data (Figure 7) obtained using HPLC measure-
(see Table 3). Since the computations were carried out in a vacuum, the data suggest that the small stability differences Table 3. Free Energies (in Hartrees) of Formation and Complexation Calculated Using DFT Methods compd
ΔfG°
ΔcompG°
32+ CB7 CB7-OH 32+·CB7 32+·CB7-OH
−574.195 −4209.918 −4285.114 −4784.292 −4859.488
−0.178 −0.178
observed experimentally may be due to entropic effects associated with solvation of the complexes and the free hosts. In any case, the minimized structures for both complexes are very similar, as shown in Figure 6. We also calculated the electrostatic potential surfaces for both guests, and the results are shown in Figure S8. Figure 7. Comparison of extraction efficiencies with various bar coatings measured by SBSE-HPLC. Additional details are given in the Supporting Information.
ments. The analyte enrichment observed with the CB7-OH/ PDMS coating suggests that the recognition properties and the stability of the complex between the analyte and the CB7 hosts attached to the coating are responsible for the observed effect. We have also applied CB7-OH/PDMS coatings to develop analytical methodology for the determination of nonsteroidal anti-inflammatory drugs (NSAIDs) in human urine. These compounds are difficult to determine using stir bars with commercial PDMS coatings because their considerable polarities hamper their extraction and incorporation into this low polarity coating.24 However, coating functionalization with CB7-OH leads to efficient extraction. Additional details can be found in the Supporting Information. In conclusion, we report here a straightforward method for the synthesis and isolation of CB7-OH. Although the yield is unquestionably low, the isolation and purification are quite simple. Furthermore, we have compared in detail the host properties of CB7-OH with those of its precursor host and found that both exhibit similar binding affinities with a variety of guests, although CB7 forms complexes with slightly higher stability. This was supported by ITC and MS experiments as well as by DFT computational results. Our experimental results suggest that the spectroscopic and voltammetric properties of CB7-OH complexes are essentially identical to those of CB7 complexes. Finally, we have used CB7-OH to functionalize PDMS coatings, which show considerable potential in SBSEbased analytical applications.
Figure 6. Energy-minimized structures obtained for the complexes between methyl viologen and the hosts CB7 (A) and CB7-OH (B). Side views of the complexes are shown at the top, while top views are at the bottom.
Sorptive Extraction Based on CB7-OH. Stir bar sorptive extraction (SBSE) was introduced in 1999 as a novel preparation technique by Baltussen and co-workers.22 SBSE has a number of advantages, such as high sensitivity, good reproducibility, and compatibility with aqueous solvents. It has been successfully applied to trace analysis in environmental, food, and biomedical samples.23 However, the only commercially available coating is poly(dimethylsiloxane) (PDMS), which limits the range of applications. We reasoned that CB7OH could be useful to functionalize the coating and contribute its unique recognition properties to the SBSE technique. Therefore, we used CB7-OH to functionalize a commercially available coating material, PDMS, using a well-known crosslinker, 3-(2-cyclooxypropoxyl)propyltrimethoxysilane. Hydrolysis and polycondensation reactions led to the attachment of CB7-OH to the polymer coating. As an example, the resulting CB7-OH/PDMS coating was found to be considerably more
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EXPERIMENTAL SECTION
General Information. All chemicals were reagent grade and used without further purification. MCI gel CHP20P resin was supplied by Supelco. Deuterated solvents for NMR spectroscopy were purchased from Cambridge Isotopes. A four-cartridge Barnstead system was utilized to purify distilled water to a minimum resistivity of 18.2 MΩ· cm. ITC experiments were carried out using a Model Nano-ITC instrument. Complete details on these experiments are given in the Supporting Information. Electrochemical experiments were performed with a CH Instruments system, using a single-compartment glass cell, fitted with a glassy carbon working electrode (0.071 cm2), a platinum counter electrode, and a Ag/AgCl reference electrode. The solution 5471
DOI: 10.1021/acs.joc.8b00382 J. Org. Chem. 2018, 83, 5467−5473
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The Journal of Organic Chemistry was deoxygenated by purging with purified nitrogen, and a nitrogen atmosphere was maintained above the solution throughout the experiment. Before use, the working electrode surface was polished with an aqueous slurry of alumina (0.05 μm) on a soft, felt surface. Quantitation of the SBSE experiments was carried out with an Agilent 1100 HPLC system equipped with a photodiode array detector. Synthesis of CB7-OH. CB7 (500 mg, 0.43 mmol), (NH4)2S2O8 (147 mg, 0.645 mmol), and NaHSO3 (67 mg, 0.645 mmol) were dissolved in water (60 mL), and the reaction was stirred at 65 °C for 12 h. The reaction volume was reduced to 15 mL under vacuum and loaded onto the column containing CHP20P resin for separation. (See the Supporting Information for details on column preparation and regeneration). The reaction mixture was eluted with water, and 15 mL fractions were collected and analyzed by MALDI-TOF mass spectrometry. CB7 elutes first, followed by CB7-OH and finally CB7-(OH)2. Fractions containing mixtures were discarded. The fractions containing pure CB7 were collected, and the unreacted starting material could be isolated and reused. The fractions containing pure CB7-OH were pooled and concentrated to ca. 10 mL in a rotary evaporator. A white precipitate was formed upon addition of methanol (100 mL). After centrifugation at 8500 rpm for 10 min, the supernatant was discarded, and the solid was treated with acetone (45 mL) for further washing. After a second round of centrifugation at 8500 rpm, the supernatant was discarded again, and the precipitate was dried under high vacuum at 40 °C for 48 h to give pure CB7-OH (71 mg, yield 14.1%) as a white solid, which decomposes at 387 °C. 1H NMR: (400 MHz, D2O) δH 5.73−5.62 (12H, m), 5.45−5.31 (14H, m), 5.15 (1H), 4.41−4.37 (2H, d, J = 15.37 Hz), 4.15−4.06 (12H, m). 13 C NMR: (100 MHz, D2O) δC 157.0, 152.2, 91.5, 83.3, 71.7, 52.8, 46.9. Anal. Calcd for C42H42N28O15·12H2O: C, 36.16; H, 4.77; N, 28.11. Found: C, 36.53; H, 5.02; N, 27.95. HRMS (ESI) m/z: [CB7OH + p-xylylenediamine + 2H]2+ calcd for C50H56N30O15 658.2271, found 658.2245. A similar protocol was followed with the fractions containing CB7(OH)2, which were obtained as mixtures of isomers in 5% yield.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00382. Additional spectroscopic data, experimental details, computational details, and Cartesian Coordinates (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Angel E. Kaifer: 0000-0001-7155-9889 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to the National Science Foundation of China for financial support (Nos. 811600398 and 21665005) and the US National Science Foundation for the generous support of this work (to A.E.K., CHE-1412455). N.D. and M.M. also acknowledge fellowships from the Chinese Scholarship Council.
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DOI: 10.1021/acs.joc.8b00382 J. Org. Chem. 2018, 83, 5467−5473
