Constitutional Isomers of Pentahydroxy-Functionalized Pillar[5]arenes: Synthesis, Characterization, and Crystal Structures

Article abstract of DOI:10.1021/acs.joc.7b01837

We herein report the preparation of constitutional isomers of pentahydroxy-functionalized pillar[5]arenes via the deprotection of their benzylated derivatives by catalytic hydrogenation. The structures of the obtained isomers were then established using single crystal X-ray diffraction. We also found that the yield distribution of the different constitutional isomers was dependent on the nature of the substitution, as revealed by HPLC analysis of the crude mixture. Finally, further characterization of the separated constitutional isomers indicated that they possess different melting points, NMR spectra, crystal structures, and stacking patterns in the solid state.

Full text of DOI:10.1021/acs.joc.7b01837

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Article
Constitutional Isomers of Pentahydroxy-functionalized
Pillar[5]arenes: Synthesis, Characterization, and Crystal Structures
Talal F. Al-Azemi, Mickey Vinodh, Fatemeh H. Alipour, and Abdirahman A. Mohamod
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01837 • Publication Date (Web): 29 Sep 2017
Downloaded from http://pubs.acs.org on September 29, 2017
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Constitutional Isomers of Pentahydroxyꢀfunctionalized Pillar[5]arenes:
Synthesis, Characterization, and Crystal Structures
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Talal F. AlꢀAzemi,* Mickey Vinodh, Fatemeh H. Alipour and Abdirahman A. Mohamod
Chemistry Department, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
Email: t.alazemi@ku.edu.kw
Abstract
We herein report the preparation of constitutional isomers of pentahydroxyꢀfunctionalized
pillar[5]arenes via the deprotection of their benzylated derivatives by catalytic hydrogenation.
The structures of the obtained isomers were then established using single crystal Xꢀray
diffraction. We also found that the yield distribution of the different constitutional isomers was
dependent on the nature of the substitution, as revealed by HPLC analysis of the crude mixture.
Finally, further characterization of the separated constitutional isomers indicated that they
possess different melting points, NMR spectra, crystal structures, and stacking patterns in the
solid state.
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Introduction
Macrocyclic oligomers such as crown ethers, calixarenes, cucurbiturils, cyclodextrins,
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–3
4–7
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10–12
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3–15
and cyclophanenes
are attractive receptors that possess the ability to recognize nonꢀ
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covalently bound guest molecules through multipoint interactions. Recently, pillar[n]arenes,
which are a relatively new class of macrocyclic compounds with unique structural features, have
been reported to exhibit the exceptional ability to selectively encapsulate different kinds of guest
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6–20
molecules.
To date, a range of pillar[n]arenes composed of different ring sizes have been
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reported, including pillar[5]arenes (i.e., containing a 5ꢀmembered ring),
pillar[6]arenes, and
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pillar[7]arenes. In addition, larger pillar[n = 6–15]arenes have also been synthesized recently
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through the ring expansion of pillar[5]arenes. Due to their ease of formation compared to larger
pillararenes, pillar[5]arene and its derivatives have received the most attention to date. In
addition, as the negatively charged pillar[5]arene cavity favors the binding of positively charged
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guests, pillar[5]arene and its analogs have been demonstrated to act as hosts toward a range of
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organic compounds, including viologens, alkanediamines, dinitrobenzenes, azobenzene
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derivatives, and neutral molecules.
The incorporation of functional groups into pillararenes also enables further modification of its
macrocycle structure and expands the functionality of the system through alteration of its
physical properties such as its solubility, optical response, and crystallinity. Indeed, many
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32–39
functionalized pillar[5]arenes bearing bromo, amino, alkyne, and hydroxyl moieties
have been reported thus far. A range of different strategies has been developed for the synthesis
of hydroxyꢀfunctionalized pillararenes. For example, monohydroxy pillar[5]arene has been
synthesized by controlling the deꢀOꢀmethylation of permethylated pillar[5]arene using 0.9 eq. of
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BBr . In addition, an oxidationꢀreduction strategy has been employed to synthesize diꢀ and
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tetrahydroxy pillar[5]arenes.
Another approach involved the synthesis of monoꢀ and A1/A2ꢀ
dihydroxyꢀfunctionalized pillar[5]arenes through the coꢀcyclization of 1,4ꢀdimethoxybenzene
and 1,4ꢀbis(3ꢀbromopropoxy)benzene, followed by an elimination reaction to yield the diallyl
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ether and subsequent deprotection to give the desired product.
Thus, we herein report the synthesis of pentahydroxyꢀfunctionalized pillar[5]arenes through the
condensation of nonsymmetrical hydroquinone derivatives of 1ꢀ(benzyloxy)ꢀ4ꢀalkoxybenzene
followed by the removal of the benzyl groups through catalytic hydrogenation. Separation of the
constitutional isomers and their resulting isomeric yield distributions are also investigated for the
supramolecular system. In addition, the obtained constitutional isomers are characterized by
NMR spectroscopy and Xꢀray single crystal diffraction studies. To the best of our knowledge,
this is the first report on the synthesis of pentahydroxyꢀfunctionalized pillar[5]arenes through the
deprotection of their benzylated equivalents using a catalytic hydrogenation strategy.
Results and discussion
Pillararenes synthesized using asymmetric hydroquinone derivatives are known to yield four
constitutional isomers, namely the 1,3ꢀalternate, 1,2ꢀalternate, partial cone, and cone isomers,
and the successful separation of these isomers depends on the nature of the substituents and the
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substitution pattern employed. In addition, the introduction of functional groups into this
macrocyclic system expand the functionality of the system, thereby enabling a wide range of
chemical modifications, such as in the case of the propargylꢀfunctionalized pillar[5]arene, which
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1
was previously prepared from the 1ꢀdecyloxyꢀ4ꢀpropargyloxybenzene monomer. In addition,
this constitutional isomer with C symmetry has also been further modified via the copper(I)ꢀ
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catalyzed alkyneꢀazide 1,3ꢀdipolar cycloaddition reaction to obtain the sugarꢀfunctionalized
amphiphilic pillar[5]arene.
Based on such systems, we synthesized constitutional isomers of pentahydroxyꢀpillar[5]arenes
using the strategy outlined in Scheme 1. Initially, the pillar[5]arene derivatives bearing benzyl
groups (i.e., Pillars 1a–1b, 2a–2b, 3a–3b, and 4a–4b) were synthesized by the condensation of
asymmetric hydroquinone derivatives of 1ꢀ(benzyloxy)ꢀ4ꢀalkoxybenzene and paraformaldehyde
in the presence of BF ·OEt . The hydroxylated pillar[5]arene analogs (i.e., Pillars 1aʹ–1bʹ, 2aʹ–
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2bʹ, 3aʹ–3bʹ, and 4aʹ–4bʹ) were obtained following removal of the benzyl protecting groups
under mild catalytic hydrogenation conditions.
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SCHEME 1. Synthesis of the asymmetric pentahydroxyꢀfunctionalized pillar[5]arenes
R
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OBn
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a = R = CH3
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(a'-b')
4(a'-b')
The total yield of all benzyloxyꢀhydroxypillar[5]arene isomers (i.e., the yield of the isomeric
mixture) prior to separation was 10%. As expected, TLC analysis of the asymmetric
pillar[5]arenes synthesized using the 1ꢀbenzyloxyꢀ4ꢀmethoxybenzene monomer produced four
spots. Column chromatography using a dichloromethane/hexane mixture (60:40 v/v) was then
employed to separate the isomeric mixture, and gave the four isomers (i.e., Pillars 1a–4a) as
white solids (Scheme 1). Analysis by HRMS confirmed the presence of a signal at m/z
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+
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153.4923 for all isomers, which corresponded to [M+Na] . However, the melting points of the
four isomers differed significantly (i.e., Pillar 1a = 157 °C; Pillar 2a = 129 °C; Pillar 3a =
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17 °C; and Pillar 4a = 114 °C), as did their H NMR spectra, as shown in Figure 1. The signals
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corresponding to the benzyl methylene, phenyl, methylene, and methoxy protons for the Pillar
1a–3a isomers were observed as multiplets (Figures 1(a)–1(c)), due to the lack of symmetry,
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thereby rendering complete assignment of their structures from the HNMR spectra particularly
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challenging. In contrast, the C symmetrical isomer Pillar 4a was easily identified from its H
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NMR spectrum (Figure 1(d)). Thus, the structures of the different isomers were assigned using
single crystal Xꢀray diffraction, which clearly confirmed their corresponding substitution
patterns (see the insets of Figure 1). To obtain suitable crystals for analysis, single crystals of
Pillars 1a, 2a, and 4a were grown by the slow evaporation of a solution of each isomer in a
mixture of dichloromethane/nꢀhexane, while a single crystal of Pillar 3a was obtained using a
mixture of ethyl acetate and nꢀhexane. In the solid state, these four constitutional isomers were
found to stack either in the edgeꢀtoꢀedge (registered) style (i.e., Pillars 1a and 4a) or the cornerꢀ
toꢀedge style (i.e., Pillars 2a and 3a), which is a similar trend to the styles adopted by the
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asymmetric pillar[5]arene isomers prepared from the 1ꢀbutoxyꢀ4ꢀmethoxybenzene monomer
Figure S31).
(
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Figure 1. H NMR spectra (400 MHz, CDCl ) of the four constitutional isomers of Pillars 1a–
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4a and insets showing the Xꢀray single crystal diffraction structures. (a) The 1,3ꢀalternate isomer,
Pillar 1a, (b) the 1,2ꢀalternate isomer, Pillar 2a, (c) the partialꢀcone isomer, Pillar 3a, and (d)
the cone isomer, Pillar 4a.
When 1ꢀ(benzyloxy)ꢀ4ꢀ(octyloxy)benzene was employed under the same reaction conditions,
only three spots were detected by TLC analysis, and these were isolated by column
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chromatography using a mixture of dichloromethane/nꢀhexane (20:80 v/v). The H NMR spectra
of three isolated products are shown in Figure 2. As before, the C symmetrical isomer (i.e.,
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Pillar 4b) was easily identified by H NMR spectroscopy (Figure 2(c)), and its structure was
confirmed by single crystal Xꢀray diffraction (Figure 3). In addition, Pillar 1b exhibited a high
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degree of multiplicity for the benzyl methylene, phenyl, methylene bridge, and methoxy
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hydrogen signals in its H NMR spectrum (Figure 2(a)). The structure of the Pillar 1b isomer
was also determined by single crystal Xꢀray diffraction following the growth of a suitable crystal
by the slow evaporation method (Figure 3).
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Figure 2. H NMR spectra (400 MHz, CDCl ) and corresponding structures for the compounds
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present in the three fractions obtained following separation of the isomeric mixture by column
chromatography. (a) The first fraction, isomer 1b, (b) the second fraction, isomers 2b and 3b,
and (c) the third fraction, isomer 4b.
Further examination of the second (mixed) fraction by ESIꢀMS confirmed the presence of a peak
+
at m/z 1644.2 [M+Na] , which was also observed for the other two fractions. However, upon
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closer inspection of the aromatic region of the H NMR spectrum (i.e., 6.70–7.1 ppm) shown in
Figure 2(b), a significantly higher multiplicity was observed compared to that of isomer 1b,
thereby indicating that the second fraction is a mixture of two isomers, namely Pillars 2b and 3b
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(
Figure S27).
Figure 3. Crystal structures of the 1,3ꢀalternate isomer (Pillar 1b) and the cone isomer (Pillar
b) obtained from single crystal Xꢀray diffraction analysis.
4
The constitutional isomers of the asymmetrical pillar[5]arenes were then examined by HPLC,
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and their isomeric yield distribution was compared to the theoretical prediction of 5:5:5:1. Due
to small differences between the retention factors (R values) of the different constitutional
f
isomers, the estimation of their distribution following separation by column chromatography is
rather difficult. Control experiments were therefore conducted using both monomers (i.e., 1ꢀ
(benzyloxy)ꢀ4ꢀmethoxybenzene and 1ꢀ(benzyloxy)ꢀ4ꢀ(octyloxy)benzene), and the crude reaction
mixtures were passed through silica gel plugs and eluted with dichloromethane prior to HPLC
analysis. For the asymmetrical pillar[5]arenes prepared using the 1ꢀ(benzyloxy)ꢀ4ꢀ
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methoxybenzene monomer, the yield distribution obtained from HPLC analysis of the crude
reaction mixture was in agreement with the theoretical yield distribution for the Pillar 1a, 2a, 3a,
and 4a isomers (Figure 4(a)). This peak assignment was based on a comparison with the
retention times of the pure isomers (Figures S29 and S30). In contrast, HPLC analysis of the
crude isomeric mixture obtained for the pillar[5]arenes prepared using 1ꢀ(benzyloxy)ꢀ4ꢀ
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(octyloxy)benzene produced three signals with an isomeric distribution of 2:4:1, which
corresponded to the Pillar 1b, 2b+3b, and 4b isomers, respectively (Figure 4(b)). This result
differs significantly from the predicted theoretical yield distribution, likely due to the isomeric
distribution being dependent on the nature of the substituents present on the pillar[5]arene
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Figure 4. HPLC chromatograms for the crude reaction mixtures of the asymmetric
pillar[5]arenes synthesized from (a) 1ꢀ(benzyloxy)ꢀ4ꢀmethoxybenzene, and (b) 1ꢀ(benzyloxy)ꢀ4ꢀ
(octyloxy)benzene.
The isolated constitutional isomers were then subjected to catalytic hydrogenation over
palladium on charcoal in anhydrous ethyl acetate under mild reaction conditions to conduct the
debenzylation reaction and produce the corresponding pentahydroxyꢀfunctionalized
pillar[5]arenes isomers. All products were isolated in quantitative yields as white solids (Scheme
1
1). In the H NMR spectra (CDCl ) of isomers Pillar 1aʹ–4aʹ, the absence of resonances
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corresponding to the benzylic methylene protons (i.e., PhꢀCH ) at 4.50–4.90 ppm and the phenyl
2
groups (Ph) at 7.20–7.40 ppm indicated successful removal of the benzyl groups. A broad
resonance centered at 8.40 ppm was also indicative of the newly formed free phenolic hydroxy
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groups (i.e., ArOH). In addition, the methoxy protons (OCH ) and the methylene bridge protons
3
1
3
(ꢀCH ꢀ) were observed at 4.25 and 1.20 ppm, respectively. Furthermore, in the C NMR spectra,
2
the resonances corresponding to the aromatic carbon atoms of the benzyl groups at ~128 ppm
were greatly reduced in intensity, while the absence of the benzylic methylene signal at ~70 ppm
confirmed the successful deprotection. Similar results were observed when isomers Pillar 1b and
4b were subjected to the catalytic hydrogenation protocol. However, even following the
successful removal of the benzyl groups for the isomeric mixture of Pillars 2b+3b, separation of
the individual isomers by column chromatography remained problematic. Furthermore, only
three single crystals suitable for analysis by Xꢀray diffraction were obtained: Pillars 1aʹ, 2aʹ, and
1bʹ (Figure 5). Crystals of 1aʹ and 1bʹ were grown by slow evaporation of solutions of the
individual isomers in mixtures of ethyl acetate/nꢀhexane, while single crystals of 2aʹ were
obtained by slow evaporation from a solution of the isomer in ethanol.
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Figure 5. Crystal structures of three pentahydroxyꢀfunctionalized pillar[5]arene isomers, namely
the 1,3ꢀalternate isomer Pillar 1aʹ, the 1,2ꢀalternate isomer Pillar 2aʹ, and the 1,3ꢀalternate
isomer Pillar 1bʹ.
We also found that the crystal packing of 2aʹ is particularly unique, in that the unit cell is
relatively large, and contains six ethanol molecules and six pillar[5]arene moieties (Figure S32).
The four pillar[5]arene moieties containing ethanol encapsulated inside the cavity form two
dimeric headꢀtoꢀhead assemblies induced by hydrogenꢀbonding interactions. In addition, two
empty pillar[5]arene moieties are aligned perpendicularly to the supramolecular dimer in the
crystal lattice. This dimer is hydrogen bonded to a free pillar[5]arene unit, and the presence of an
ethanol molecule outside the cavity results in the formation of an interesting supramolecular
assembly, which is depicted in Figure 6.
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Figure 6. Xꢀray single crystal structure of the macrocyclic Pillar 2aʹ arrangement. (a) The
supramolecular dimeric headꢀtoꢀhead assembly induced by hydrogen bonding, where ethanol is
trapped inside the cavity, and (b) the supramolecular network crystal packing viewed along the
crystallographic bꢀaxis.
The crystal structure of the 1,3ꢀalternate isomer Pillar 1bʹ adopts the form of a supramolecular
doubleꢀthreaded dimer where one of the octyl chains is threaded inside the cavity of the adjacent
pillar[5]arene unit (Figure 7). In this case, dimer formation is induced by CꢀH···π interactions
between the octyl chain and the host. Indeed, similar pillar[5]arene supramolecular dimers have
been reported in the solid state for copillar[5]arenes based on 1,4ꢀdimethoxybenzene and 1ꢀ((10ꢀ
4
1
bromodecyl)oxy)ꢀ4ꢀmethoxybenzene.
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Figure 7. Supramolecular doubleꢀthreaded dimer of the 1,3ꢀalternate isomer Pillar 1bʹ. (a) The
top view, and (b) the side view.
Conclusion
In conclusion, a series of pentahydroxyꢀfunctionalized pillar[5]arenes were synthesized through
the simple benzylic deprotection of their corresponding asymmetric pillar[5]arenes, which were
prepared from hydroquinone derivatives of 1ꢀ(benzyloxy)ꢀ4ꢀalkoxybenzenes. A catalytic
hydrogenation method was employed for the deprotection, which required only mild reaction
conditions. Separation of the four constitutional asymmetric pillar[5]arene isomers by column
chromatography was attempted, and its success was found to be dependent on the nature of the
alkyl substitution, which also influenced the theoretical yield distribution of the constitutional
isomers. HPLC analysis of the crude pillararene mixture prepared from 1ꢀ(benzyloxy)ꢀ4ꢀ
methoxybenzene confirmed that the product distribution corresponded with the theoretical yield
distribution, while the crude mixture prepared from 1ꢀ(benzyloxy)ꢀ4ꢀ(octyloxy)benzene
produced a significantly different pattern due to the different alkyl substituents present and also
because of the unsuccessful separation of two of the isomers. Characterization of the prepared
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and isolated constitutional isomers revealed that they exhibited different melting points, NMR
spectra, crystal structures, and stacking patterns in the solid state. Our future work will focus on
the modification and application of the synthesized pentahydroxyꢀfunctionalized amphiphilic
pillar[5]arenes.
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Experimental section
Materials and methods
NMR spectroscopy was carried out by on Bruker Avance II 600 MHz and Bruker Avance DPX
400 spectrometers (Bruker, Germany). Electron impact (EI) mass spectrometry was performed
using a DFS High Resolution GC/MS (Thermo Scientific, Germany). Electrospray ionization
was carried out in high resolution mode using a Waters Xevo G2ꢀS QTOF LCꢀMS/MS (Waters,
Germany). As detailed later, single crystal Xꢀray diffraction was carried out using an RꢀAXIS
RAPID II diffractometer (Rigaku, Japan), and the data were collected at −123 °C (Oxford
Cryosystems, UK). LC was carried out using an instrument equipped with a photodiode array
detector (LCꢀMS/MS, Thermo Scientific, Germany). Flash column chromatography was
performed using silica gel (silica gel 60, 40–60 mesh ASTM, EMD Millipore, Merck KGaA,
Germany). Dimethylformamide, dichloroethane, and ethyl acetate were employed in the
hydrogenation reaction and were distilled prior to use. All other reagents and solvents were of
reagent grade purity and were used without further purification. HPLC was carried out using a
Waters HPLC system equipped with a 1525 binary pump, a 2487 dual absorbance detector, a 717
plus autosampler, and Breeze software (Waters, German). Pillars 1a–4a were separated using a

Waters Spherisorb 5 ꢁm NH column using hexane:chloroform (85:15 v/v) as the eluent, with a
2
run time of 20 min and a flow rate of 1 mL/min. Pillars 1b–4b were separated using a Supelco
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Astec Cellulose DMP column (5 ꢁm) using hexane:isopropanol (99:1 v/v) as the eluent, with a
run time of 10 min and a flow rate of 1 mL/min.
1ꢀ(Benzyloxy)ꢀ4ꢀmethoxybenzene: 4ꢀMethoxyphenol (4.96 g, 40 mmol) was dissolved in
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acetone (100 mL) at room temperature, and potassium carbonate (8.28 g, 60 mmol) was added
with stirring. The resulting solution was stirred for ~30 min then heated to reflux prior to the
addition of benzyl bromide (4.76 mL, 40 mmol). The reaction was allowed to stir under reflux
overnight, after which time the solvent was removed by evaporation under reduced pressure and
the crude product was extracted with dichloromethane. Purification was by column
chromatography using dichloromethane/nꢀhexane (60:40 v/v) to give the desired product as a
1
white solid (7.80 g, 90%). H NMR (400 MHz, CDCl ) δ: 3.79 (s, 3H), 5.04 (s, 2H), 6.90 (m,
3
13
4
1
4
H), 7.35 (m, 5H); C NMR (150 MHz, CDCl ) δ: 55.7, 70.7, 114.7, 115.9, 127.5, 127.9, 128.6,
3
37.3, 153.0, 154.0.
ꢀ(Octyloxy)phenol: Hydroquinone (6.60 g, 60 mmol) was dissolved in acetone (120 mL) at
room temperature, and potassium carbonate (12.42 g, 90 mmol) was added. The resulting
solution was heated under reflux overnight following the addition of bromooctane (10.36 mL,
40 mmol). After this time, the solvent was removed by evaporation under reduced pressure and
the crude product was extracted with dichloromethane. The obtained 4ꢀ(octyloxy)phenol was
then purified by column chromatography using dichloromethane/nꢀhexane (80:20 v/v) to give the
1
desired product as a white solid (9.45 g, 71%). H NMR (400 MHz, CDCl ) δ: 0.91 (t, 3H, J =
3
13
6
.8 Hz), 1.33 (m, 8H), 1.45 (m, 2H), 1.77 (m, 2H), 3.92 (t, 2H, J = 6.8 Hz), 6.79 (m, 4H); C
NMR (100 MHz, CDCl ) δ: 14.1, 22.7, 26.0, 29.2, 29.4, 31.8, 68.7, 115.6, 116.0, 149.3, 153.3.
3
1ꢀ(Benzyloxy)ꢀ4ꢀ(octyloxy)benzene: 4ꢀ(Octyloxy)phenol (8.9 g, 40 mmol) was dissolved in
acetone (100 mL) at room temperature, and potassium carbonate (8.28 g, 60 mmol) was added.
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After stirring the resulting solution for ~30 min, it was heated to reflux prior to the addition of
benzyl bromide (4.76 mL, 40 mmol). The reaction system was then stirred under reflux
overnight. After this time, the reaction solvent was removed by evaporation under reduced
pressure and the crude product was extracted with dichloromethane. Purification was by column
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chromatography using dichloromethane/nꢀhexane (40:60 v/v) to give the desired product as a
1
white solid (10.35 g, 83%). H NMR (400 MHz, CDCl ) δ: 0.92 (t, 3H, J = 7.2 Hz), 1.33 (m,
3
8
5
1
H), 1.46 (m, 2H), 1.78 (m, 2H), 3.92 (t, 2H, J = 6.4 Hz), 5.04 (s, 2H), 6.88 (m, 4H), 7.40 (m,
1
3
H); C NMR (100 MHz, CDCl ) δ: 14.1, 22.7, 26.1, 29.2, 29.4, 31.8, 68.6, 70.1, 115.4, 115.8,
3
27.5, 127.8, 128.5, 137.3, 152.8, 153.5.
Synthesis of the asymmetric benzoxymethoxypillar[5]arenes 1a–4a. Paraformaldehyde
1.86 g, 60.0 mmol) was added to a solution of 1ꢀ(benzyloxy)ꢀ4ꢀmethoxybenzene (4.28 g,
0.0 mmol) in dry dichloroethane (40 mL) under a nitrogen atmosphere. Boron trifluoride
etherate [(BF ·OEt ), 2.5 mL, 20.0 mmol] was then added to the solution and the mixture was
(
2
3
2
stirred at room temperature for 30 min. After this time, methanol (50 mL) was poured into the
reaction mixture and the solution was concentrated then dissolved in dichloromethane (100 mL).
The resulting organic solution was washed with aqueous NaHCO (2 × 50 mL) and H O
3
2
(
50 mL), then dried over anhydrous Na SO , concentrated under reduced pressure, and subjected
2 4
to purification by silica gel chromatography (dichloromethane/hexanes (60:40 v/v)) to give a
mixture of isomers 1a–4a (0.490 g, 10%).
1
Isomer 1a: White solid (175 mg, 4%). Mp. 157ꢀ158 °C. H NMR (400 MHz, CDCl ) δ: 3.24 (s,
3
3H), 3.27 (s, 3H), 3.28 (s, 3H), 3.32 (s, 3H), 3.65 (s, 3H), 3.73 (s, 2H), 3.76 (s, 2H), 3.83 (s, 2H),
3.87 (d, 4H, J = 4.4 Hz), 4.53 (s, 2H), 4.84 (s, 4H), 4.86 (s, 2H), 4.91 (s, 2H), 6.76 (m, 10H),
1
3
7.31 (m, 25H). C NMR (100 MHz, CDCl ) δ: 28.7, 28.9, 30.1, 30.7, 31.0, 55.4, 55.9, 69.9,
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0.4, 70.5, 114.2, 114.4, 114.5, 114.8, 114.9, 115.1, 127.5, 127.6, 127.6, 127.6, 127.8, 127.9,
28.0, 128.1, 128.1, 128.2, 128.4, 128.6, 128.6, 138.2, 138.2, 138.3, 149.9, 150.1, 150.1, 150.2,
+
50.2, 150.7, 150.8, 150.8. HRMS (ESI/QTOF) m/z: [M + Na] Calcd for C H O Na
7
5
70 10
10
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153.4867; Found 1153.4923.
1
Isomer 2a: White solid (120 mg, 3%). Mp. 129ꢀ130 °C. H NMR (400 MHz, CDCl ) δ: 3.29 (d,
3
6
H, J = 8.4 Hz), 3.63 (s, 6H, J = 8.0 Hz), 3.71 (s, 3H), 3.81 (m, 10H), 4.46 (s, 2H), 4.52 (d, 4H, J
=
2.4 Hz), 4.94 (d, 4H, J = 7.6 Hz), 6.72 (s, 2H), 6.80 (m, 3H), 8.88 (m, 5H), 7.25 (m, 20H), 7.39
1
3
(
m, 5H). C NMR (100 MHz, CDCl ) δ: 29.1, 29.4, 29.8, 29.9, 30.1, 31.1, 55.4, 55.8, 55.8, 55.9,
3
6
9.8, 69.8, 69.9, 70.3, 70.3, 113.9, 114.1, 114.2, 114.9, 115.0, 115.1, 127.4, 127.4, 127.4, 127.5,
127.6, 127.6, 127.6, 127.7, 127.7, 127.8, 128.0, 128.1, 128.1, 128.2, 128.2, 128.4, 128.5, 128.5,
1
1
1
28.6, 128.6, 128.6, 138.2, 138.3, 138.3, 149.8, 149.8, 149.8, 150.0, 150.0, 150.8, 150.8, 150.9,
+
50.9, 151.0. HRMS (ESI/QTOF) m/z: [M + Na] Calcd for C H O Na 1153.4867; Found
75 70 10
153.4910.
1
Isomer 3a: White solid (140 mg, 3%). Mp. 117ꢀ118 °C. H NMR (400 MHz, CDCl ) δ: 3.24 (s,
3
3H), 3.32 (s, 3H), 3.63 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 3.76 (s, 2H), 3.81 (s, 2H), 3.87 (m,
6
5
2
1
H), 4.45 (s, 2H), 4.50 (s, 2H), 4.55 (s, 2H), 4.88 (s, 2H), 4.94 (s, 2H), 6.70 (s, 1H), 6.81 (m,
1
3
H), 6.87 (m, 4H), 7.28 (m, 21H), 7.37 (m, 2H), 7.44 (m, 2H). C NMR (100 MHz, CDCl ) δ:
3
8.7, 29.4, 29.5, 29.7, 30.0, 30.4, 55.2, 55.6, 55.7, 69.7, 70.2, 113.9, 114.0, 114.1, 114.2, 114.6,
14.7, 114.8, 114.9, 127.2, 127.3, 127.4, 127.5, 127,5, 127.5, 127.7, 127.8, 128.0, 128.2, 128.2,
128.3, 128.3, 128.4, 128.4, 128.4, 138.0, 138.0, 138.0, 138.1, 138.1, 149.7, 149.7, 149.7, 149.8,
+
1
49.9, 150.6, 150.7, 150.8, 150.9. HRMS (ESI/QTOF) m/z: [M + Na] Calcd for C H O Na
7
5
70 10
1153.4867; Found 1153.4918.
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Isomer 4a: White solid (55 mg, 1%). Mp. 114ꢀ115 °C. H NMR (400 MHz, CDCl ) δ: 3.72 (s,
3
1
3
15H), 3.84 (s, 10H), 4.47 (s, 10H), 6.80 (s, 5H), 6.87 (s, 5H), 7.23 (m, 25H). C NMR
(
100 MHz, CDCl ) δ: 29.8, 55.9, 69.8, 114.2, 115.0, 127.4, 127.6, 127.7, 128.3, 128.5, 138.2,
3
0
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+
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49.9, 151.0. HRMS (ESI/QTOF) m/z: [M + Na] Calcd for C H O Na 1153.4867; Found
75 70 10
1153.4924.
Synthesis of the asymmetric benzyloxyoctyloxypillar[5]arenes 1b–4b. Paraformaldehyde
(1.86 g, 60.0 mmol) was added to a solution of 1ꢀ(benzyloxy)ꢀ4ꢀ(octyloxy)benzene (6.24 g,
2
0.0 mmol) in dry dichloroethane (50 mL) under a nitrogen atmosphere. BF ·OEt (2.5 mL,
3 2
2
0.0 mmol) was then added to the solution and the mixture was stirred at room temperature for
30 min. After this time, MeOH (50 mL) was poured into the reaction mixture and the solution
was concentrated then dissolved in dichloromethane (100 mL) prior to washing with aqueous
NaHCO (2 × 50 mL) and H O (50 mL). The resulting organic layer was dried over anhydrous
3
2
Na SO , concentrated under reduced pressure, and subjected to purification by silica gel column
2
4
chromatography (hexanes/dichloromethane, 80:20) to give a mixture of isomers 1b–4b (507 mg,
16%).
1
Isomer 1b: Yield (145 mg, 4%). Mp. 117ꢀ118 °C. H NMR (400 MHz, CDCl ) δ: 0.94 (m,
3
1
5H), 1.25 (m, 40H), 1.38 (m, 10H), 1.55 (m, 8H), 1.86 (m, 2H), 3.46 (m, 8H), 3.87 (m, 12H),
1
3
4
.57 (s, 2H), 4.93 (m, 6H), 5.01 (s, 2H), 6.89 (m, 10H), 7.28 (m, 17H), 7.34 (m, 8H). C NMR
(
100 MHz, CDCl ) δ: 14.3, 14.3, 14.3, 22.8, 22.9. 26.5, 26.5, 26.5, 26.6, 28.6, 28.8, 29.5, 29.7,
3
29.8, 29.8, 30.0, 30.0, 30.0, 30.1, 30.4, 30.8, 32.0, 32.0 67.9, 67.9, 68.0, 68.5, 69.6, 70.2, 70.2,
7
0.3,70.3, 114.6, 114.7, 114.7, 114.8, 114.9, 115.1, 115.2, 127.4, 127.5, 127.6, 127.6, 127.7,
27.7, 127.8. 128.0, 128.1, 128.2, 128.3. 128.5, 128.5, 128.6, 128.6, 128.7, 138.3, 138.3, 149.6,
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110 140 10
1
644.0344; Found 1644.0388.
1
Isomers 2b and 3b: Yield (305 mg, 4%). H NMR (400 MHz, CDCl ) δ: 0.88 (m, 15H), 1.23
3
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(
m, 46H), 1.56 (m, 8H), 1.84 (m, 6H), 3.39 (m, 4H), 3.84 (m, 16H), 4.51 (m, 6H), 4.89 (m, 4H),
1
3
6
.86 (m, 10H), 7.27 (m, 25H). C NMR (100 MHz, CDCl ) δ: 14.3, 14.3, 14.3, 22.8, 22.8, 22.9,
3
2
2.9, 26.4, 26.5, 26.6, 26.6, 26.7, 29.4, 29.5, 29.5, 29.7, 29.8, 29.8, 29.9, 30.0, 30.0, 30.1, 30.2,
32.0, 32.0, 67.8, 67.9, 68.0, 68.5, 68.5, 69.5, 69.5, 69.6, 70.0,70.0, 70.1, 70.1, 114.6, 114.7,
1
14.8, 114.9. 115.0, 115.1, 127.2, 127.3, 127.3, 127.3, 127.4, 127.4, 127.5, 127.5, 127.7, 127.8,
28.0, 128.0, 128.1, 128.1, 128.1, 128.2, 128.2, 128.2, 128.3, 128.4, 128.4, 128.5, 128.5, 128.6,
1
128.7, 128.7, 128.8, 138.3, 138.3, 138.3, 149.5, 149.5, 149.6, 149.6, 149.7, 149.7, 149.8, 150.0,
50.1, 150.1, 150.2, 150.2, 150.2. ESIꢀMS: m/z: 1644.2 (C H O Na).
1
1
10 140 10
1
Isomer 4b: Yield (60 mg, 4%). Mp. 160ꢀ161 °C. H NMR (400 MHz, DMSOꢀd ) δ: 0.88 (m,
6
1
6
2
1
5H), 1.33 (m, 40H), 1.47 (m, 10H), 1.74 (m, 10H), 3.52 (m, 10H), 3.91 (m, 6H), 4.13 (m, 4H),
1
3
.62 (s, 5H), 6.79 (s, 5H). C NMR (100 MHz, DMSOꢀd ) δ: 10.8, 13.8, 13.9, 22.2, 22.4, 23.3,
6
5.9, 28.4, 28.9, 29.3, 29.6, 29.8,32.0, 33.2, 38.1, 67.4, 67.5, 113.5, 114.6, 115.2, 117.6, 126.0,
+
27.8, 128.7, 131.6, 131.7, 138.8, 147.2, 148.2, 167.0. HRMS (ESI/QTOF) m/z: [M + Na]
Calcd for C H O Na 1644.0344; Found 1644.0375.
1
10 140 10
General debenzylation procedure. Isomers 1–4(a–b) (40 mg, 0.42 mmol) were dissolved in
anhydrous ethyl acetate (30 mL) to which Pd/C (25 wt%) (10 mg) was added. The reaction
apparatus for the catalytic hydrogenation process was evacuated then filled with H . Following
2
absorption of the theoretical quantity of hydrogen by the isomers, the Pd/C catalyst was removed
by filtration, then carefully washed with ethyl acetate and methanol. The combined filtrate was
subsequently evaporated to yield the deprotected pillar[5]arene isomers as white solids in
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quantitative yields. Finally, the isomers were dried to constant weight under reduced pressure,
and dissolved in a suitable deuterated solvent for NMR analysis.
1
Isomer 1aʹ: Yield (28 mg, 97%). H NMR (400 MHz, CDCl ) δ: 3.79 (m, 22H), 3.90 (s, 3H),
3
0
1
2
3
4
5
6
7
8
9
0
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.63 (m, 3H), 6.70 (s, 1H), 6.80 (s, 2H), 6.83 (s, 1H), 6.85 (s, 1H), 6.87 (s, 1H), 6.92 (s, 1H). C
NMR (100 MHz, CDCl ) δ: 26.9, 27.2, 30.3, 31.7, 31.8, 56.3, 56.6, 56.8, 56.8, 59.5, 113.4,
3
+
113.6, 113.7, 114.0, 117.4, 118.0, 118.1, 118.3, 118.5, 119.2. HRMS (ESI/QTOF) m/z: [M]
Calcd for C H O 679.2543; Found 679.2537.
4
0
39 10
1
Isomer 2aʹ: Yield (27 mg, 93%). H NMR (400 MHz, CDCl ) δ: 3.72 (m, 19H), 3.93 (d, 6H, J =
3
13
1
1.2 Hz), 6.53 (s, 1H), 6.56 (s, 1H), 6.67 (m, 6H), 6.78 (s, 1H), 6.80 (s, 1H). C NMR
(
150 MHz, CDCl ) δ: 27.2, 30.7, 30.7, 30.8, 31.6, 56.2, 56.3, 56.7, 56.9, 56.9, 112.8, 112.8,
3
113.2, 113.7, 115.6, 118.7, 118.8, 119.0, 119.1, 119.4, 124.9, 125.1, 126.2, 126.4, 126.5, 128.4,
128.5, 128.9, 130.8, 131.0, 147.1, 147.2, 147.2, 147.5, 148.4, 148.8, 149.1, 149.1, 150.7, 150.8.
+
HRMS (ESI/QTOF) m/z: [M] Calcd for C H O 679.2543; Found 679.2540.
40
39 10
1
Isomer 3aʹ Yield (26 mg, 90%).: H NMR (400 MHz, CDCl ) δ: 3.71 (m, 20H), 3.86 (s, 5H),
3
1
3
6
.55 (m, 3H), 6.62 (s, 1H), 6.72 (m, 3H), 6.76 (s, 1H), 6.79 (s, 1H), 6.82 (s, 1H). C NMR
(
100 MHz, CDCl ) δ: 28.0, 28.4, 28.9, 29.1, 29.3, 30.6, 30.8, 31.5, 32.0, 33.0, 34.3, 38.9, 56.2,
3
56.6, 56.8, 57.0, 112.8, 113.1, 113.5, 113.7, 118.3, 118.6, 119.1, 119.2, 119.3, 125.4, 126.2,
126.9, 127.9, 128.1, 128.6, 130.0, 130.4, 131.1, 144.9, 147.5, 148.2, 148.4, 148.6, 149.0, 150.9.
+
HRMS (ESI/QTOF) m/z: [M] Calcd for C H O 679.2543; Found 679.2533.
40
39 10
1
Isomer 4aʹ Yield (25 mg, 86%).: H NMR (400 MHz, CDCl ) δ: 3.69 (s, 10H), 3.876 (s, 15H),
3
1
3
6.66 (s, 10H). C NMR (100 MHz, CDCl ) δ: 30.5, 56.6, 113.4, 118.7, 126.6, 128.0, 148.4,
3
+
1
48.7. HRMS (ESI/QTOF) m/z: [M] Calcd for C H O 679.2543; Found 679.2529.
4
0
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Isomer 1bʹ: Yield (27 mg, 93%). H NMR (600 MHz, Acetoneꢀd ) δ: 0.91 (m, 15H), 1.30 (m,
6
1
3
40H), 1.47 (m, 10H), 1.83 (m, 10H), 3.70 (s, 10H), 3.86 (s, 10H), 6.91 (m, 10H). C NMR
(
150 MHz, Acetoneꢀd ) δ: 14.1, 14.2, 23.1, 26.7, 26.8, 31.4, 32.4, 32.4, 68.8, 69.3, 113.9, 114.9,
6
10
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13
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+
1
18.8, 126.6, 126.9, 129.7, 146.9, 147.8, 150.2, 150.7. HRMS (ESI/QTOF) m/z: [M] Calcd for
C H O 1169.8021; Found 1169.8063.
75
109 10
1
Isomer 4bʹ: Yield (24 mg, 83%) H NMR (400 MHz, DMSOꢀd ) δ: 0.88 (m, 15H), 1.33 (m,
6
40H), 1.47 (m,10H), 1.74 (m, 10H), 3.52 (m, 10H), 3.91 (m, 6H), 4.13 (m, 4H), 6.62 (s, 5H),
13
6
.79 (s, 5H). C NMR (100 MHz, DMSOꢀd ) δ: 10.8, 13.8, 13.9, 22.2, 22.4, 23.3, 25.9, 28.4,
6
28.9, 29.3, 29.6, 29.8,32.0, 33.2, 38.1, 67.4, 67.5, 113.5, 114.6, 115.2, 117.6, 126.0, 127.8, 128.7,
+
1
31.6, 131.7, 138.8, 147.2, 148.2, 167.0. HRMS (ESI/QTOF) m/z: [M] Calcd for C H O
7
5
109 10
1169.8021; Found 1169.8075.
Preparation of single crystals for Xꢀray diffraction
Single crystals of the synthesized pillar[5]arenes and their inclusion complexes were grown
using either the slow solvent evaporation method or by the diffusion method using
dichloromethane and nꢀhexane. The data were collected on an RꢀAXIS RAPID diffractometer
(
Rigaku, Japan) at −123 °C using the Crystal Clear software package (Rigaku, Japan). All
structures were solved and refined using the Bruker SHELXTL Software Package (structure
solution program: SHELXSꢀ97; refinement program: SHELXLꢀ97). The crystallographic data
for all structures reported in this paper have been deposited at the Cambridge Crystallographic
Data Centre as supplementary publications (CCDC 1552627ꢀ1552637). Copies of the data can be
obtained, free of charge, upon submission of application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44(0) 1223 336033 or eꢀmail: deposit@ccdc.cam.ac.uk).
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Acknowledgments
The support received from the University of Kuwait, made available through research grant no.
SC04/16, in addition to the Collage of Graduate Studies and the facilities of RSP4 (grant nos.
GS01/01, GS03/01, GS01/03, GS01/10 and GS03/08) is gratefully acknowledged.
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Supporting Information. Crystallographic information (CIF), HPLC traces, H and C NMR
spectra for new compounds. This material is available free of charge at http://pubs.acs.org.
References
1
. Krakowiak, K. E.; Bradshaw, J. S.; ZameckaꢀKrakowiak, D. J. Chem. Rev. 1989, 89, 929–
72.
9
2
. (a) Bradshaw, J. S.; Izatt, R. M. Acc. Chem. Res. 1997, 30, 338–345. (b) Yan, X.; Xu, D.;
Chi, X.; Chen, J.; Dong, S.; Ding, X.; Yu, Y.; Huang, F. Adv. Mater. 2012, 24, 362ꢀ369. (c)
Wang, F.; Han, C.; He, C.; Zhou, Q.; Zhang, J.; Wang, C.; Li, N.; Huang, F. J. Am. Chem.
Soc. 2008, 130, 11254ꢀ11255.
3
. Gokel, G. W.; Levy, W. M.; Weber, M. E. Chem. Rev. 2004, 104, 2723–2750.
. Harada, A.; Hashidzume, A.; Yamaguchi, H.; Takashima, Y. Chem. Rev. 2009, 109, 5974–
6023.
4
5. Gutsche, C. D. Calixarenes Revisited, 2nd ed.; Royal Society of Chemistry: Cambridge,
2
000.
6
. Gutsche, C. D. Calixarenes, An Introduction; Royal Society of Chemistry: Cambridge, 2008.
. Botana, E.; Da Silva, E.; BenetꢀBuchholz, J.; Ballester, P.; de Mendoza, J. Angew. Chem.,
Int. Ed. 2007, 46, 198–201.
7
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Page 25 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8
9
1
1
. Kim, K. Chem. Soc. Rev. 2002, 31, 96–107.
. Kaifer, A. E.; Li, W.; Silvi, S.; Sindelar, V. Chem. Commun. 2012, 48, 6693–6695.
0. Harada, A. Acc. Chem. Res. 2001, 34, 456–464.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. Zhu, L.; Zhang, D.; Qu, D.; Wang, Q.; Ma, X.; Tian, H. Chem. Commun. 2010, 46, 2587–
2589.
1
2. Wang, K.ꢀR.; Guo, D.ꢀS.; Jiang, B.ꢀP.; Liu, Y. Chem. Commun. 2012, 48, 3644–3646.
3. Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem. Rev. 2006, 106, 5291–
5316.
1
1
4. Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393–2402. (
5. Wang, M.ꢀX. Acc. Chem. Res. 2012, 45, 182–195.
1
16. (a) Ogoshi, T.; Kanai, S.; Fujinami, S.; Yamagishi, T. A.; Nakamoto, Y. J. Am. Chem. Soc.
008, 130, 5022–5023. (b) Zhang, Z.; Luo, Y.; Chen, J.; Dong, S.; Yu, Y.; Ma, Z.; Huang, F.
2
Angew. Chem., Int. Ed. 2011, 50, 1397ꢀ1401.
1
7. Han, C.; Ma, F.; Zhang, Z.; Xia, B.; Yu, Y.; Huang, F. Org. Lett. 2010, 12, 4360–4363.
8. Li, Z.; Yang, J.; He, J.; Abliz, Z.; Huang, F. Org, Lett. 2014, 16, 2065ꢀ2069.
1
19. Ogoshi, T.; Masaki, K.; Shiga, R.; Kitajima, K.; Yamagishi, T.ꢀA. Org. Lett. 2011, 13, 1264–
266.
1
2
2
2
0. Ogoshi, T.; Nishida, Y.; Yamagishi, T.ꢀA.; Nakamoto, Y. Macromolecules 2010, 43, 3145–
3147.
1. Ogoshi, T.; Ueshima, N.; Sakakibara, F.; Yamagishi, T.; Haino, T. Org. Lett. 2014, 16,
2
896–2899.
2. Strutt, N. L.; Forgan, R. S.; Spruell, J. M.; Botros, Y. Y.; Stoddart, J. F. J. Am. Chem. Soc.
011, 133, 5668–5671.
2
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5
5
6
2
3. Strutt, N.; FairenꢀJimenez, D.; Iehl, J.; Lalonde, M.; Snurr, R.; Farha, O.; Hupp, J.; Stoddart,
F. J. Am. Chem. Soc. 2012, 134, 17436–17439.
2
4. Ogoshi, T.; Kida, K.; Yamagishi, T. J. Am. Chem. Soc. 2012, 134, 20146–20150.
5. Li, C.; Chen, S.; Li, J.; Han, K.; Xu, M.; Hu, B.; Yu, Y.; Jia, X. Chem. Commun. 2011, 47,
11294–11296.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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5
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9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
26. Li, C.; Han, K.; Li, J.; Zhang, H.; Ma, J.; Shu, X.; Chen, Z.; Weng, L.; Jia, X. Org. Lett.
2
012, 14, 42–45.
27. Ogoshi, T.; Demachi, K.; Kitajima, K.; Yamagishi, T.ꢀA. Chem. Commun. 2011, 47, 10290–
0292.
1
2
8. Ogoshi, T.; Masaki, K.; Shiga, R.; Kitajima, K.; Yamagishi, T. Org. Lett. 2011, 13, 1264–
1266.
2
9. Ogoshi, T.; Shiga, R.; Hashizume, M.; Yamagishi, T. Chem. Commun. 2011, 47, 6927–6929.
0. Hu, W. B.; Hu, W. J.; Zhao, X. L.; Liu, Y. A.; Li, J. S.; Jiang, B.; Wen, K. J. Org. Chem.
3
2
016, 81, 3877−3881.
3
1. Yu, G.; Ma, Y.; Han, C.; Yao, T.; Tang, G.; Mao, Z.; Gao, C.; Huang, F. J. Am. Chem. Soc.
2013, 135, 10310–10313.
3
2. Ogoshi, T.; Aoki, T.; Kitajima, K.; Fujinama, S.; Yamagishi, T. A.; Nakamoto, Y. J. Org.
Chem. 2011, 76, 328–331.
33. Chen, Y.; He, M.; Li, B.; Wang, L.; Meier, H.; Cao, D. RSC Adv. 2013, 3, 21405–21408.
3
4. Han, J.; Hou, X.; Ke, C.; Zhang, H.; Strutt, N. L.; Stern, C. L.; Stoddart, J. F. Org. Lett. 2015,
7, 3260–3263.
1
3
5. Han, C.; Zhang, Z.; Yu, G.; Huang, F. Chem. Commun. 2012, 48, 9876–9878.
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7
8
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3
6. Ogoshi, T.; Yamafuji, D.; Kotera, D.; Aoki, T.; Fujinami, S.; Yamagishi, T.ꢀA. J. Org. Chem.
2012, 77, 11146–11152.
3
3
7. Pan, M.; Xue, M. Eur. J. Org. Chem. 2013, 22, 4787–4793.
10
11
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8. Strutt, N. L.; Forgan, R. S.; Spruell, J. M.; Botros, Y. Y.; Stoddart, J. F. J. Am. Chem. Soc.
2011, 133, 5668–5671.
39. Strutt, N. L.; FairenꢀJimenez, D.; Julien Iehl, J.; Lalonde, M. B.; Snurr, R. Q.; Farha, O. K.;
Hupp, J. T.; J.; Stoddart, J. F. J. Am. Chem. Soc. 2012, 134, 17436–17439.
40. Zhang, Z.; Luo, Y.; Xia, B.; Han, C.; Yu, Y.; Chena, X.; Huang, F. Chem. Commun. 2011,
7, 2417–2419.
4
41. Zhang, Z.; Yu, G.; Han, C.; Liu, J.; Ding, X.; Yu, Y.; Huang, F. Org. Lett. 2011, 13, 4818–
4821.
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