Synthesis of elongated cavitands via click reactions and their use as chemosensors

Article abstract of DOI:10.1016/j.tet.2013.07.044

A very efficient modular reaction protocol was developed to attach various functionalities to a rigid cavitand scaffold. In this way, aryl, iodoaryl, benzyl, pyrrolidylmethyl groups, as well as a polyethylene-glycol chain were attached to the 'triazol-level' of the cavitand. The palladium-catalyzed ethynylation of the iodoarene moieties, followed by the copper(I)-catalyzed azide-alkyne cycloaddition produced novel cavitands with significantly elongated binding pockets. The dimensions of these molecules are calculated to be at least 9 ?×18 ?, which place them amongst the largest unimolecular hosts obtained by pure covalent synthesis. A cavitand-based click conjugate is used for selective complexation of Cu²⁺ and Fe ³⁺, providing significant fluorescent quenching.

Full text of DOI:10.1016/j.tet.2013.07.044

Tetrahedron 69 (2013) 8186e8190
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of elongated cavitands via click reactions and their use as
chemosensors
a
,
d
,
a
,
,
d
c
b,d
*
ꢀ
ꢀ
d
€
ꢀ
*
ꢀ
Zsolt Csok
, Tímea Kegl d, Yin Li b , Rita Skoda-Foldes , Laszlo Kiss
,
,
e
a,d,
ꢀ
ꢀ
ꢀ ꢀ b
ꢀ
ꢀ
ꢀ
Sandor Kunsagi-Mate , Matthew H. Todd , Laszlo Kollar
Department of Inorganic Chemistry and MTA-PTE Research Group for Selective Chemical Synthesis, University of Pecs, H-7624 Pecs,
a
ꢀ
ꢀ
P.O. Box 266, Hungary
b
ꢀ
ꢀ ꢀ
ꢀ
Department of General and Physical Chemistry, University of Pecs, Ifjusag 6., H-7624 Pecs, Hungary
c
ꢀ
Department of Organic Chemistry, Institute of Chemistry, University of Pannonia, Egyetem 10., H-8200 Veszprem, Hungary
Janos Szentagothai Research Center, Ifjusag 20., H-7624 Pecs, Hungary
d
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
e School of Chemistry, University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2013
Received in revised form 17 June 2013
Accepted 11 July 2013
Available online 18 July 2013
A very efficient modular reaction protocol was developed to attach various functionalities to a rigid
cavitand scaffold. In this way, aryl, iodoaryl, benzyl, pyrrolidylmethyl groups, as well as a polyethylene-
glycol chain were attached to the ‘triazol-level’ of the cavitand. The palladium-catalyzed ethynylation of
the iodoarene moieties, followed by the copper(I)-catalyzed azideealkyne cycloaddition produced novel
cavitands with significantly elongated binding pockets. The dimensions of these molecules are calculated
ꢁ
ꢁ
to be at least 9 Aꢀ18 A, which place them amongst the largest unimolecular hosts obtained by pure
Keywords:
Cavitand
Azideealkyne cycloaddition
Copper
Iron
covalent synthesis. A cavitand-based click conjugate is used for selective complexation of Cu2þ and Fe3þ
,
providing significant fluorescent quenching.
Ó 2013 Published by Elsevier Ltd.
Palladium
1. Introduction
alternatively, for covalently linking two macrocycle units.12,13
Herein, we expand further the applicability of this versatile meth-
odology by the synthesis of a novel series of elongated cavitands.
Click-derived triazoles have recently emerged as potential che-
mosensors due to their ability to bind both cations and anions.
Sensitive reporting signals may arise from a binding event,
a chemical reaction, a redox process or a conformational change.14
Calixarenes are known to provide a convenient platform for posi-
tioning two15e18 or four19 triazole units in close proximity. These
conjugates obtained by click chemistry were used to detect various
metal ions including Hg2þ, Cu2þ, Cr3þ, Pb2þ, Zn2þ and Cd2þ through
a photophysical change upon a binding event. The selectivity of the
designed chemosensors greatly depended on the specific structural
motifs that were incorporated into the macrocycle.
Here we report the first cavitand-based click conjugate that is
used for selective complexation of Cu2þ and Fe3þ. These redox
active metals undergo redox cycling reactions producing highly
reactive radicals, which may eventually lead to oxidative stress
in humans.20 Therefore, it is very important to be able to mon-
itor the presence of such metals. In contrast to the calixarene-
based fluorescent probes that contained pendant functionalities
for metal detection,15e19 in our design the four triazole binding
sites are attached on a more rigid cavitand framework, which
Cavitands are a class of molecular hosts containing sizeable in-
ternal cavities suitable for reversible molecular inclusion.1 Cav-
itands and related cage-like structures show promise with
potential applications as gas sensors, fluorescent probes, nano-
reactors and drug delivery systems.2,3 In our current research
program, we aim to extend the inner cavity of such molecular
containers through a modular strategy.4,5 Click reactions, both
minimizing the generation of hazardous substances and maxi-
mizing the reaction efficiency, are excellent representatives of the
‘green chemistry’ approach, an important contribution to sustain-
able development. The synthetic utility and simplicity of the
very efficient copper(I)-catalyzed azideealkyne cycloaddition
(CuAAC),6e8 coupled with a wide variety of readily available azi-
de derivatives, opens up the avenue to the facile synthesis of
highly extended macrocycles. The click coupling has recently been
applied to cavitands for attaching guanosine9 or uridine10 moieties
as well as macromolecular side chains11 via triazole linkers, or
ꢀ
* Corresponding authors. E-mail addresses: zscsok@gamma.ttk.pte.hu (Z. Csok),
kollar@ttk.pte.hu (L. Kollar).
ꢀ
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.07.044

ꢀ
Z. Csok et al. / Tetrahedron 69 (2013) 8186e8190
8187
may create a more rigid, pre-organized, electron-rich binding
pocket.
of 7 revealed an average molecular weight of Mn¼5800 along with
a narrow polydispersity (1.11), and the average number of repeat
units was calculated to be n¼25. Both the GPC and NMR analysis
confirmed the quantitative coupling between cavitand 3 and the
linear PEG chains. It is important to note that all reactions afforded
the expected cavitand-based conjugates in good yields (58e82%),
and in the course of this multistep synthesis starting from the
condensation reaction of 2-methylresorcinol and acetaldehyde, no
time-consuming chromatography was needed. Simple trituration of
the products with MeOH usually afforded sufficiently pure mate-
rials. The developed procedure allowed us to extend significantly
the inner cavity of these cavitands, and furthermore, incorporate
various functionalities, such as additional aromatic walls (4, 5, 6),
long PEG chains (7) and stereogenic centres (8). This study proved
very well the high versatility and functional group tolerance of the
CuAAC reaction on our macrocyclic platform. Moreover, it was ex-
pected that the addition of PEG side chains to the cavitand core
could cause a change in its solubility in water. Indeed, unlike the
other novel cavitand derivatives, the PEGylated cavitand (7)
exhibited enhanced solubility in water (>25 mg mLꢁ1). On the other
hand, the synthesis of a cavitandearyl iodide conjugate (5) offers
promise for further extension of this cavitand skeleton.
2. Results and discussion
Tetraiodocavitand (1), bearing four excellent leaving groups, was
synthesized in four consecutive steps according to our well-
established protocol.5 Trimethylsilyl-ethynyl functionalities were
placed on the upper rim of the cavitand scaffold under typical
Sonogashira-coupling conditions (2, Scheme 1.). Deprotection of 2
with TBAF$3H2O in tetrahydrofuran afforded the corresponding
tetra(ethynyl)cavitand (3) that was subsequently used as a coupling
partner in fourfold CuAAC reactions. In this study, the commercially
available azidobenzene, 1-azido-4-iodobenzene, benzyl azide,
poly(ethylene glycol) methyl ether azide (PEG average Mn 1000) and
(R)-2-(azidomethyl)-1-Boc-pyrrolidine were used in the click cou-
pling procedure in the presence of CuI at rt. In all cases, the 1H NMR
resonance corresponding to the terminal alkyne (3.01 ppm) was
completely lost and replaced by the resonances of the aromatic
protons of the triazole rings in the range of 7.70e9.14 ppm. All de-
rivatives were fully characterized by IR,1H and 13C NMR as well as by
MS techniques (see Experimental section). The GPC characterization
Scheme 1. Synthetic route to the novel click-based cavitands (4e8).

ꢀ
Z. Csok et al. / Tetrahedron 69 (2013) 8186e8190
8188
To the best of our knowledge, the largest covalently linked su-
pramolecular systems containing multiple cavitand subunits fea-
binding constant by one order of magnitude than that of cavitand
4eCu2þ. The thermodynamic studies suggested that the complex
formations of cavitand 4 with both Cu2þ and Fe3þ are mainly
entropy-driven processes (Table 1).
ture molecular dimensions of 10 Aꢀ25 A21,22 or an internal volume
ꢁ
ꢁ
of up to 1050 A for the so-called superbowls.23,24 Self-assembled
capsules through metaleligand interactions, and mainly, hydro-
gen bonding also plays a crucial part in constructing large molec-
ular containers with internal cavities of similar volumes.24e29 All
our efforts to obtain crystals suitable for X-ray analysis were un-
successful. However, the dimensions of cavitand 4 were found to be
9 Aꢀ18 A by using a semiempirical RM1 method, which place it
amongst the largest unimolecular hosts obtained by pure covalent
synthesis. The energy-minimized structure of cavitand 4 is shown
in Fig. 1. The angles between the neighbouring rings are approxi-
mately 90ꢂ, while the dihedral angles between the vertically po-
sitioned rings B/C and C/D vary in the range of 30.7e32.8ꢂ and
160.0e165.4ꢂ, respectively.
3
ꢁ
30
ꢁ
ꢁ
Fig. 2. Changes in fluorescence emission intensities of cavitand 4 (9.0
mM) in the
presence of various metal ions (1000 M) in various solvents. Black bar, DMF/water
m
(90%/10%, vol/vol); red bar: DMF/0.01 M HCl (aq) (90%/10%, vol/vol); grey bar: pure
DMF.
Fig. 1. The energy-minimized structure of cavitand 4.
A DMF/water solvent mixture was used to screen the fluores-
cence responses of cavitand 4 upon the addition of large excess of
metal ions, according to literature procedures (Fig. 2).15e17 A simi-
lar, but less effective, quenching ability of cavitand 6 towards Cu2þ
and Fe3þ was observed, therefore, all further investigations were
focused on compound 4. It should be noted that in pure DMF, the
Fig. 3. Fluorescence emission response of cavitand 4 (50
upon increasing concentrations of Cu2þ (0
M, 200 M, 250
500 M, 600 M, 750 M, 900 M, 1000 M, 1250 M, 1500
m
M) in pure DMF at 25 ꢂC
M, 300 M, 400 M,
M, 2000 M).
m
m
m
m
m
m
m
m
m
m
m
m
m
required salt concentrations could only be reached for La3þ, Co2þ
,
Cr3þ, Cu2þ and Fe3þ. A DMF/HCl solvent system was used for Zn2þ
and Fe3þ in order to avoid hydrolysis in aquatic solutions. Cavitand
4 provided significant quenching in emission intensity in the
presence of Cu2þ and Fe3þ. The titration profiles of cavitand 4 for
the addition of Cu2þ and Fe3þ in DMF are shown in Figs. 3 and 4,
respectively. When the concentration of Cu2þ was increased to
3. Conclusion
Multi-level extended cavitands were synthesized in palladium-
catalyzed Sonogashira-reaction followed by copper-catalyzed azi-
deealkyne 3þ2 cycloaddition reactions. The excellent selectivities
and yields make these reactions a powerful synthetic methodology
for the functionalization of deepened cavitands. These cavitand
hosts feature significantly enlarged molecular dimensions of at
2000
mM, a complete fluorescence quenching was observed. Simi-
larly, a significant decrease in fluorescent intensity occurred, when
the concentration of Fe3þ was enhanced up to 400
mM. The binding
constants of the complex formation of cavitand 4 with Cu2þ and
Fe3þ were evaluated by using Hyperquad 200631 assuming 1:1
stoichiometry at various temperatures. The thermodynamic pa-
rameters were obtained according to van’t Hoff theory (Fig. 5). The
results indicated that the cavitand 4eFe3þ complex has higher
least 9 Aꢀ18 A. All of these cavitands, possessing highly different
groups on the ‘upper level’ (upper portal), might serve as flexible
binding pockets in ‘hosteguest’ chemistry. Water-soluble ana-
logues are being prepared in our laboratory that would consider-
ably enhance their applicability in biological systems.
ꢁ
ꢁ

ꢀ
Z. Csok et al. / Tetrahedron 69 (2013) 8186e8190
8189
The 13C chemical shifts are referenced to the carbon resonance of
CDCl3 (77.00 ppm) or to that of DMSO-d6 (39.52 ppm), respectively.
4.2. Synthesis and characterization of cavitands 2e8
Cavitand 2: Cavitand 1 (1.00 g, 0.658 mmol), Pd(OAc)2 (16.5 mg,
0.073 mmol), PPh3 (40 mg, 0.153 mmol) and CuI (135 mg,
0.709 mmol) were weighed, placed under an inert atmosphere into
a Schlenk-tube, and deoxygenated THF (35 mL) was added. Tri-
methylsilylacetylene (1.1 mL, 7.784 mmol), K2CO3 (1.10 g,
7.959 mmol) dissolved in deoxygenated water (15 mL) was added
to the reaction mixture, and then stirred at 65 ꢂC for 16 h. The
reaction mixture was partitioned between CH2Cl2 (50 mL) and
water (50 mL). The organic phase was separated, and the aqueous
phase was extracted with another portion of CH2Cl2 (20 mL). The
combined organic phases were washed with water (50 mL), dried
over MgSO4 and evaporated to dryness. The residue was treated
with MeOH (5 mL), the resulting precipitate was collected by fil-
tration, and dried in vacuo. Off-white solid (760 mg, 82%), mp
184e185 ꢂC. Anal. Calcd for C84H88O12Si4: C, 71.96; H, 6.33. Found:
C, 72.25; H, 6.41. nmax (KBr): 843, 868, 976, 1248, 1506, 1604,
Fig. 4. Fluorescence emission response of cavitand 4 (50
upon increasing concentrations of Fe3þ (0
M, 40 M, 60
150 M, 200 M, 250 M, 300 M, 400 M).
m
M) in pure DMF at 25 ꢂC
M, 80 M, 100 M, 125 M,
m
m
m
m
m
m
m
m
m
m
m
2157 cmꢁ1
; dH (400.13 MHz, CDCl3): 0.25 (36H, s, Si(CH3)3), 1.82
(12H, d, J 7.2 Hz, CH3CH), 4.61 (4H, d, J 7.2 Hz, inner of OCH2O), 4.90
(8H, s, ArCH2O), 5.08 (4H, q, J 7.2 Hz, CH3CH), 5.74 (4H, d, J 7.2 Hz,
outer of OCH2O), 6.81 (8H, d, J 11.8 Hz, Ar), 7.37 (4H, s, Ar), 7.39 (8H,
d, J 11.8 Hz, Ar). dc (100.6 MHz, CDCl3): 0.1 (Si(CH3)3), 16.2 (CH3CH),
31.2 (CH3CH), 60.6 (ArCH2O), 92.8 (C^CeSiR3), 100.0 (OCH2O),
105.0 (AreC^C), 114.3, 115.9, 120.7, 122.4, 133.6, 139.0, 154.0, 158.7.
MS: 1424.43 [Mþ23]þ.
Cavitand 3: To the THF (30 mL) solution of cavitand 2 (760 mg,
0.542 mmol) was added TBAF$3H2O (1.35 g, 4.279 mmol), and the
reaction mixture was stirred for 30 min at rt. The solvent was
evaporated, the residue was dissolved in CH2Cl2 (30 mL), and
washed with 10% HCl (30 mL). The organic phase was dried over
MgSO4, and the solvent was removed on a rotary evaporator. The
residue was treated with MeOH (10 mL), the resulting precipitate
was collected by filtration, and dried in vacuo. Greenish-grey solid
(550 mg, 91%), mp>350 ꢂC (dec). Anal. Calcd for C72H56O12: C,
77.78; H, 5.07. Found: C, 77.98; H, 5.15. nmax (KBr): 974, 1246, 1506,
1604, 2106, 3286 cmꢁ1
; dH (400.13 MHz, CDCl3): 1.83 (12H, d, J
7.2 Hz, CH3CH), 3.01 (4H, s, C^CH), 4.63 (4H, d, J 7.2 Hz, inner of
OCH2O), 4.92 (8H, s, ArCH2O), 5.09 (4H, q, J 7.2 Hz, CH3CH), 5.76
(4H, d, J 7.2 Hz, outer of OCH2O), 6.84 (8H, d, J 8.8 Hz, Ar),
7.39e7.43 (12H, m, Ar), dc (100.6 MHz, CDCl3): 16.1 (CH3CH), 31.2
(CH3CH), 60.6 (ArCH2O), 76.1 (C^CH), 83.3 (ArC^C), 100.0
(OCH2O), 114.4, 114.8, 120.7, 122.3, 133.7, 138.9, 153.9, 158.9. MS:
1135.37 [Mþ23]þ.
Fig. 5. van’t Hoff plots for the complexations of cavitand 4eFe3þ and cavitand 4eCu2þ
.
Table 1
Thermodynamic parameters for the complexations of cavitand 4eFe3þ and cavitand
4eCu2þ
4.2.1. General synthesis for cavitands 4e8. Cavitand 3 (250 mg,
0.225 mmol) and CuI (13 mg, 0.068 mmol) were weighed, placed
under an inert atmosphere into an Schlenk-tube, then a mixture of
deoxygenated CH2Cl2/H2O (8 mL/1 mL) was added. The methyl tert-
butyl ether (for 4 and 5) or CH2Cl2 (for 6, 7 and 8) solution of the
corresponding organic azide derivative (0.9 mmol) and NEt3
(0.31 mL, 2.25 mmol) were added, then the reaction mixture was
stirred for 16 h at rt. Distilled water (5 mL) was added at the end of
the reaction, the organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (2ꢀ5 mL). The combined organic
phases were washed with water (10 mL), dried over MgSO4 and
evaporated to dryness.
Log K
D
H
DS
15 ꢂC
25 ꢂC
35 ꢂC
45 ꢂC
kJ molꢁ1
J molꢁ1 Kꢁ1
Cu2þ
Fe3þ
3.48(7)
4.47(5)
3.46(8)
4.41(8)
3.45(9)
4.38(9)
3.41(10)
4.31(10)
ꢁ3(1)
ꢁ9(1)
57(2)
54(3)
4. Experimental
4.1. General information
Chemicals were either purchased or purified by standard tech-
niques. Tetraiodocavitand (1) was prepared as previously de-
Cavitand 4, trituration with MeOH affords off-white solid
(290 mg, 81%), mp 250e255 ꢂC. Anal. Calcd for C96H76N12O12: C,
72.53; H, 4.82; N, 10.57. Found: C, 72.36; H, 4.71; N, 10.39. nmax
13
scribed.5 1H and C NMR spectra were recorded at 25 ꢂC in CDCl3
(or in DMSO-d6) on a 400 MHz spectrometer. The 1H chemical shifts
(KBr): 973, 1246, 1494, 1598 cmꢁ1
; dH (400.13 MHz, CDCl3): 1.87
(
d
), reported in parts per million (ppm) downfield, are referenced to
(12H, d, J 7.2 Hz, CH3CH), 4.77 (4H, d, J 7.2 Hz, inner of OCH2O), 5.03
(8H, s, ArCH2O), 5.14 (4H, q, J 7.2 Hz, CH3CH), 5.82 (4H, d, J 7.2 Hz,
the residual protons (7.26 ppm for CDCl3 and 2.50 for DMSO-d6).

ꢀ
Z. Csok et al. / Tetrahedron 69 (2013) 8186e8190
8190
outer of OCH2O), 7.00 (8H, d, J 8.0 Hz, Ar), 7.40e7.55 (16H, m, Ar),
7.75e7.90 (16H, m, Ar), 8.27 (4H, s, C]CH), dc (100.6 MHz, CDCl3):
16.2 (CH3CH), 31.3 (CH3CH), 60.6 (ArCH2O), 100.2 (OCH2O), 115.0,
117.1, 120.4, 120.6, 122.8, 123.4, 127.4, 128.5, 129.6, 137.1, 138.9, 148.1,
154.1, 158.8. MS: 1611.60 [Mþ23]þ.
120.6, 122.6, 123.8, 127.1, 138.9, 147.5, 154.0, 154.7, 158.6. MS:
2018.93 [M]þ.
Acknowledgements
Cavitand 5, trituration with MeOH and reprecipitation from
CH2Cl2/MeOH affords pale yellow solid (273 mg, 58%),
mp>350 ꢂC (dec). Anal. Calcd for C96H72I4N12O12: C, 55.08; H,
3.47; N, 8.03. Found: C, 55.36; H, 3.51, N, 7.91. nmax (KBr): 974,
Financial support for the ‘Synthesis of supramolecular systems,
examination of their physicochemical properties and their utiliza-
tion for separation and sensor chemistry’ project (SROP-4.2.2.A-11/
1/KONV-2012-0065) is gratefully acknowledged. Z.C. thanks the
Bolyai Grant of the Hungarian Academy of Sciences.
1246, 1489, 1616 cmꢁ1
; dH (400.13 MHz, DMSO-d6): 1.91 (12H, d, J
6.8 Hz, CH3CH), 4.56 (4H, d, J 7.0 Hz, inner of OCH2O), 4.92 (12H,
br s, ArCH2O overlapping with CH3CH), 5.87 (4H, d, J 7.0 Hz,
outer of OCH2O), 7.06 (8H, d, J 8.4 Hz, Ar), 7.70 (8H, d, J 8.4 Hz,
Ar), 7.82 (8H, d, J 8.3 Hz, Ar), 7.93e7.97 (12H, br s, Ar), 9.13 (4H, br
s, C]CH), dc (100.6 MHz, DMSO-d6): 16.1 (CH3CH), 31.3 (CH3CH),
60.5 (ArCH2O), 94.1, 99.4 (OCH2O), 115.1, 118.4, 121.7, 122.4, 122.7,
122.9, 126.8, 136.2, 138.5, 139.0, 147.2, 153.1, 158.5. MS: 2116.80
[Mþ23]þ.
Supplementary data
The details of the fluorescent measurements, the binding con-
stant evaluation and the computational study as well as the 1H and
13C NMR spectra of compounds 2e8 are available. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.07.044.
Cavitand 6, trituration with MeOH affords off-white solid
(260 mg, 70%), mp 220e225 ꢂC. Anal. Calcd for C100H84N12O12: C,
72.98; H, 5.14; N, 10.21. Found: C, 73.12; H, 5.16, N, 10.14. nmax (KBr):
References and notes
972, 1245, 1497, 1615 cmꢁ1
; dH (400.13 MHz, CDCl3): 1.83 (12H, d, J
1. Cram, D. J.; Karbach, S.; Kim, H. E.; Knobler, C. B.; Maverick, E. F.; Ericson, J. L.;
Helgeson, R. C. J. Am. Chem. Soc. 1988, 110, 2229e2237.
2. Cram, D. J.; Cram, J. M. Container Molecules and their Guests; Royal Society of
Chemistry: Cambridge, 1994.
7.2 Hz, CH3CH), 4.69 (4H, d, J 7.2 Hz, inner of OCH2O), 4.95 (8H, s,
ArCH2O), 5.09 (4H, q, J 7.2 Hz, CH3CH), 5.54 (8H, s, ArCH2N), 5.76
(4H, d, J 7.2 Hz, outer of OCH2O), 6.91 (8H, d, J 8.3 Hz, Ar), 7.28e7.42
(24H, m, Ar), 7.69 (8H, d, J 8.3 Hz, Ar), 7.75 (4H, s, C]CH), dc
(100.6 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 54.1 (ArCH2N),
60.6 (ArCH2O), 100.2 (OCH2O), 114.9, 119.3, 120.6, 122.7, 123.7, 127.2,
128.0, 128.6, 129.1, 134.9, 138.9, 147.9, 154.0, 158.6. MS: 1668.36
[Mþ23]þ.
€
3. Calixarenes. A Versatile Class of Macrocyclic Compounds; Vicens, J., Bohmer, V.,
Eds.; Kluwer Academic: Dordrecht, the Netherlands, 1991.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
4. Csok, Z.; Kegl, T.; Parkanyi, L.; Varga, A.; Kunsagi-Mate, S.; Kollar, L. Supramol.
Chem. 2011, 23, 710e719.
ꢀ
ꢀ
ꢀ
5. Csok, Z.; Takatsy, A.; Kollar, L. Tetrahedron 2012, 68, 2657e2661.
6. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596e2599.
7. Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302e1315.
8. Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952e3015.
9. Mehran, N.; Bare, G. A. L.; Sherman, J. C. Tetrahedron Lett. 2011, 52, 1791e1793.
10. Hui, B. W.-Q.; Sherman, J. C. Chem. Commun. 2012, 109e111.
11. Li, Y.; Giles, M. D.; Liu, S.; Laurent, B. A.; Hoskins, J. N.; Cortez, M. A.; Sreerama,
S. G.; Gibb, B. C.; Grayson, S. M. Chem. Commun. 2011, 9036e9038.
Cavitand 7, reprecipitation from CH2Cl2/n-pentane yields brown
oil that solidifies upon standing (943 mg, 82%). nmax (KBr): 965,
1112, 1247, 1466, 2879 cmꢁ1
; dH (400.13 MHz, CDCl3): 1.82 (12H, br
d, J 7.2 Hz, CH3CH), 3.36 (12H, s, PEGeOCH3), 3.55e3.75 (450H, br
m, PEG-chain), 3.91 (8H, br s, PEGeCH2N), 4.57 (8H, br s,
PEGeCH2CH2), 4.69 (4H, br s, inner of OCH2O), 4.95 (8H, s, ArCH2O),
5.10 (4H, br q, J 7.2 Hz, CH3CH), 5.79 (4H, br s, outer of OCH2O),
6.96 (8H, br s, Ar), 7.40 (4H, br s, Ar), 7.74 (8H, br s, Ar), 7.97 (4H, br s,
C]CH), dc (100.6 MHz, CDCl3): 16.1 (CH3CH), 31.2 (CH3CH),
50.4 (PEGeCH2N), 58.9 (PEGeOCH3), 60.6 (ArCH2O), 69.4
(PEGeCH2CH2), 70.5 (PEG-chain), 71.9 (CH2OCH3), 100.1 (OCH2O),
114.9, 120.5, 122.6, 123.5, 127.2, 138.8, 147.3, 154.0, 158.6. GPC:
Mn¼5800.
ꢀ
12. Lledo, A.; Kamioka, S.; Sather, A. C.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2011, 50,
1299e1301.
13. Morales-Sanfrutos, J.; Ortega-Munoz, M.; Lopez-Jaramillo, J.; Hernandez-Mateo,
F.; Santoyo-Gonzalez, F. J. Org. Chem. 2008, 73, 7768e7771.
14. Lau, Y. H.; Rutledge, P. J.; Watkinson, M.; Todd, M. H. Chem. Soc. Rev. 2011, 40,
2848e2866.
15. Chang, K.-C.; Su, I.-H.; Senthilvelan, A.; Chung, W.-S. Org. Lett. 2007, 9,
3363e3366.
16. Chang, K.-C.; Su, I.-H.; Lee, G.-H.; Chung, W.-S. Tetrahedron Lett. 2007, 48,
7274e7278.
17. Park, S. Y.; Yoon, J. H.; Hong, C. S.; Souane, R.; Kim, J. S.; Matthews, S. E.; Vicens,
J. J. Org. Chem. 2008, 73, 8212e8218.
Cavitand 8 (isolated as a 1:1 mixture of two rotamers due to
C(O)eN hindered rotation), trituration with MeOH affords light
yellow solid (309 mg, 68%), mp 205e210 ꢂC. Anal. Calcd for
18. Tian, D.; Yan, H.; Li, H. Supramol. Chem. 2010, 22, 249e255.
19. Souchon, V.; Maisonneuve, S.; David, O.; Leray, I.; Xie, J.; Valeur, B. Photochem.
Photobiol. Sci. 2008, 7, 1323e1331.
20. Jomova, K.; Valko, M. Toxicology 2011, 283, 65e87.
21. Starnes, S. D.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 2001, 123,
4659e4669.
C
112H128N16O20: C, 66.65; H, 6.39; N, 11.10. Found: C, 66.51; H, 6.60,
N, 11.01. nmax (KBr): 975, 1247, 1499, 1616, 1693 cmꢁ1
;
dH
(400.13 MHz, CDCl3): 1.49 (36H, s, (C(CH3)3)), 1.65e2.00 (28H, m,
CH3CH overlapping with 2ꢀ pyr(CH2)), 3.10e3.45 (12H, br m,
pyr(CHeN) overlapping with pyr(CH2eN)), 4.15 (4H, br s, ax. of
triazoleeCH2-pyr), 4.50e4.75 (8H, br s, eq. of triazoleeCH2-pyr
overlapping with inner of OCH2O), 4.96 (8H, s, ArCH2O), 5.10 (4H,
q, J 7.2 Hz, CH3CH), 5.80 (4H, d, J 7.2 Hz, outer of OCH2O), 6.97 (8H, d,
J 8.0 Hz, Ar), 7.41 (4H, s, Ar), 7.70e7.80 (12H, Ar overlapping with
C]CH), dc (100.6 MHz, CDCl3): 16.1 (CH3CH), 22.6 and 23.3 (pyr-
CH2), 28.4 (C(CH3)3), 28.90 (pyr-CH2), 31.2 (CH3CH), 46.6 and 47.0
(pyr(CH2eN)), 51.5 and 52.7 (pyr(CHeN)), 57.1 (triazoleeCH2-pyr),
60.6 (ArCH2O), 79.8 and 80.2 (C(CH3)3), 100.0 (OCH2O), 114.9, 119.9,
22. Tucci, F. C.; Renslo, A. R.; Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed.
2000, 39, 1076e1079.
23. Barrett, E. S.; Irwin, J. L.; Edwards, A. J.; Sherburn, M. S. J. Am. Chem. Soc. 2004,
126, 16747e16749.
24. Rissanen, K. Angew. Chem., Int. Ed. 2005, 44, 3652e3654.
25. MacGillivray, L. R.; Atwood, J. L. Nature 1997, 389, 469e472.
€
26. Schroder, T.; Sahu, S. N.; Anselmetti, D.; Mattay, J. Isr. J. Chem. 2011, 51, 725e742.
27. Ballester, P. Chem. Soc. Rev. 2010, 39, 3810e3830.
28. Tiefenbacher, K.; Rebek, J. J. Am. Chem. Soc. 2012, 134, 2914e2917.
29. Rebek, J. Acc. Chem. Res. 2009, 42, 1660e1668.
€
€
30. Schrodinger Suite 2012 Semiempirical NDDO Module; Schrodinger LLC: New
York, NY, 2012.
31. Gans, P.; Sabatini, A.; Vacca, A. Hyperquad 2006, Version 3.1.60; Protonic
Software: Leeds, U.K., 2006.