Conformational control of electron-rich calix[6]arene skeleton by paraquat recognition

Article abstract of DOI:10.1016/j.tetlet.2012.10.105

Calix[6]arene derivatives having electron-donating groups were designed and synthesized for the recognition of electron-deficient organic guests. These compounds exhibited relatively well-resolved ¹H NMR spectra while most calix[6]arene derivatives reported previously showed broad spectra. The ¹H NMR spectra clearly indicated that the studied calix[6]arene derivatives adopted a 1,2,3-alternate conformation as the dominant conformation. The hydroxy derivative formed a host-guest complex with paraquat molecule, in which the calix[6]arene framework exclusively adopted a cone conformation. Thus, an efficient conformational conversion from the 1,2,3-alternate to the cone conformation took place upon the host-guest complexation.

Full text of DOI:10.1016/j.tetlet.2012.10.105

Tetrahedron Letters 54 (2013) 205–209
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conformational control of electron-rich calix[6]arene skeleton
by paraquat recognition
Shigehisa Akine a,b, , Daisuke Kusama a, Tatsuya Nabeshima a,b,
⇑
⇑
a Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
b Tsukuba Research Center for Interdisciplinary Materials Science (TIMS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Calix[6]arene derivatives having electron-donating groups were designed and synthesized for the recog-
nition of electron-deficient organic guests. These compounds exhibited relatively well-resolved 1H NMR
spectra while most calix[6]arene derivatives reported previously showed broad spectra. The 1H NMR
spectra clearly indicated that the studied calix[6]arene derivatives adopted a 1,2,3-alternate conforma-
tion as the dominant conformation. The hydroxy derivative formed a host–guest complex with paraquat
molecule, in which the calix[6]arene framework exclusively adopted a cone conformation. Thus, an effi-
cient conformational conversion from the 1,2,3-alternate to the cone conformation took place upon the
host–guest complexation.
Received 4 August 2012
Revised 10 October 2012
Accepted 12 October 2012
Available online 30 October 2012
Keywords:
Calixarene
Molecular recognition
Host–guest complex
Conformational isomers
Structural conversion
Ó 2012 Elsevier Ltd. All rights reserved.
The calixarenes are a class of cyclic phenol oligomers that are
used as a fragment of various kinds of host molecules and supra-
molecules.1 Calix[4]arenes, which have a small cavity, are widely
used as a platform for various kinds of functional molecules, such
as ionophores and metal ion sensors.2 In contrast, a calix[6]arene
has a larger cavity that is capable of incorporating organic mole-
cules.3 Therefore, its derivatives would be useful as a framework
for receptors or sensors for organic molecules. Another notable fea-
ture of the calix[6]arene derivatives is their conformational flexi-
bility. Such a structural flexibility would be useful in designing a
switching functional molecule whose function changes according
to the organic guest recognition, because the molecule has a large
cavity for binding organic guests as well as a flexible framework for
structural changes upon guest binding.
Nevertheless, there are relatively fewer reports on molecular
recognition by the calix[6]arene derivatives.4 The conformational
change of calix[6]arene derivatives upon guest recognition has
been rarely investigated to date.5,6 The difficulty mainly arises in
the conformational analysis of the calix[6]arene derivatives.7,8
Most calix[6]arene derivatives without bridging substituents show
severely broad NMR spectra due to interconversion among two or
more conformational isomers. This makes it difficult to definitely
determine the conformations before and after the conformational
conversions. Consequently, a calix[6]arene derivative whose con-
formations in solution can be clearly determined would be a key
molecular scaffold for the development of conformational conver-
sion systems.
We have now designed calix[6]arene derivatives 1 and 2
(Scheme 1a) that have electron-donating groups on their aromatic
rings for inclusion of an electron-deficient organic guest 3. We
found that these calix[6]arene derivatives 1 and 2 show relatively
well-resolved 1H NMR spectra, which facilitate the conformational
analysis of the calix[6]arene framework. In addition, the calix[6]ar-
ene 2 underwent an efficient conformational conversion from the
1,2,3-alternate to the cone isomer upon recognition of the guest
molecule (Scheme 1b).
To strengthen the interaction with an electron-deficient aro-
matic guest molecule, electron-donating substituents, such as hy-
droxy and alkoxy groups,9,10 were introduced into both the upper
and lower rims of the calix[6]arene framework.11,12 The hexa-p-
acetoxycalix[6]arene derivative 113 was synthesized by the low-
er-rim alkylation14 of the unsubstituted calix[6]arene (4)15 fol-
lowed by the Friedel–Crafts acetylation16 and the subsequent
Baeyer–Villiger oxidation.11a The hydrolysis of 1 under basic condi-
tions afforded the hexahydroxy derivative 2 (Scheme 2). Prior to
the host–guest binding study, we investigated the conformation
of compounds 1 and 2 in solution.
While the synthetic intermediates 5 and 6 showed broad or
averaged NMR spectra as observed for most unbridged calix[6]ar-
ene derivatives, the acetoxy derivative 1 showed relatively well-re-
solved signals in the 1H NMR spectrum in CDCl3 at room
temperature (see Supplementary data). The 1H NMR spectrum at
⇑
Corresponding authors. Tel./fax: +81 29 853 4507.
E-mail addresses: akine@chem.tsukuba.ac.jp (S. Akine), nabesima@chem.tsuku-
ba.ac.jp (T. Nabeshima).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.105

206
S. Akine et al. / Tetrahedron Letters 54 (2013) 205–209
Scheme 1. (a) Calix[6]arene derivatives 1 and 2. (b) Conformational change in a calix[6]arene derivative upon guest recognition.
Scheme 2. Synthesis of calix[6]arene derivatives 1 and 2. Reagents and conditions: (a) n-C6H13I, Cs2CO3, DMF, 92%; (b) CH3COCl, AlCl3, CH2Cl2, 75%; (c) mCPBA, CH2Cl2, 75%;
(d) NaOH, MeOH then dil. HCl, 95%.
263 K more clearly showed that 1 almost exclusively adopted a
1,2,3-alternate conformation17,18 (Fig. 1). This conformation was
evident from the characteristic 1H NMR spectral pattern showing
two singlets (2.23 and 2.35 ppm) for the acetoxy groups in a 2:1 ra-
tio, one singlet (3.81 ppm) as well as a pair of doublets (3.34 and
4.45 ppm) for the calix methylene protons, two sets of signals (A
and B, hereafter) for the hexyl groups in a 2:1 ratio, etc. It is note-
worthy that protons of the 1,2-positions (B1 and B2) of the hexyl
group B were observed at a significantly high field (Table 1). In
the ROESY spectrum, correlations were observed between the pro-
tons of these hexyl groups (B1, B2, etc.) and the calix[6]arene skel-
eton. These observations strongly suggest that part of the hexyloxy
group B was located in the cavity surrounded by six aromatic rings.
Such spectral features of 1 indicative of the 1,2,3-alternate confor-
mation were also evident in the 1H NMR spectra in other solvents
(DMSO-d6, DMF-d7, acetonitrile-d3, methanol-d4, and acetone-d6;
see Supplementary data). This suggests that the 1,2,3-alternate
conformation is intrinsically the most stable among the possible
conformations in solution.
An X-ray crystallographic analysis of 1 (Fig. 2)19,20 further con-
firmed the structure suggested by the 1H NMR analysis. The mac-
rocyclic framework of the calix[6]arene moiety adopted a 1,2,3-
alternate conformation and the 1,2-positions of the hexyloxy group
B occupied the cavity. This structural feature suggests that several
C–HÁ Á Á and C–HÁ Á ÁO interactions are occurring between the hexyl
p
group B and the calix[6]arene framework. The electron-donating
substituents of the calix[6]arene framework probably make the
aromatic rings and ether oxygen atoms more negatively charged
that resulted in stronger C–HÁ Á Á and C–HÁ Á ÁO interactions. These
p
interactions probably stabilize the 1,2,3-alternate conformation.
This stabilization may also retard the conformational interconver-
sion to give the relatively well-resolved NMR spectra.
On the other hand, the hydroxy derivative 2 exists as a mixture
of the cone and 1,2,3-alternate isomers (2cone and 2alt, respectively)
in a 29:71 ratio in DMF-d7 at 263 K.21 The spectral pattern of the
1,2,3-alternate isomer 2alt with upfield shifted hexyl protons is
similar to that of the acetoxy derivative 1, but no such upfield shift
was observed for the cone isomer 2cone. The spectrum at higher

S. Akine et al. / Tetrahedron Letters 54 (2013) 205–209
207
Figure 1. 1H NMR spectrum of 1 (263 K, CDCl3, 600 MHz). The assignments are based on 2D COSY and ROESY spectra.
Table 1
temperatures showed broad signals, indicating the fast intercon-
version between the two conformational isomers.
1H NMR chemical shiftsa of selected protons of calix[6]arene 1
As described above, compounds 1 and 2 showed relatively well-
resolved 1H NMR spectra, from which we can clearly determine
their conformations in solution. Using these derivatives, the con-
formational change upon binding with guest species was investi-
gated by 1H NMR spectroscopy.
Hexyl group A
Hexyl group B
A1
A2
A3
A4
A5
A6
3.83
1.86
1.56
1.34
1.34
0.90
B1
B2
B3
B4
B5
B6
1.73
–0.04
0.76
0.92
1.16
0.87
Paraquat 3 as an electron-deficient guest was added to a solu-
tion of calix[6]arenes 1 and 2. While the acetoxy derivative 1
showed almost no interaction with 3, the hydroxy derivative 2,
which exists as a mixture of the cone and 1,2,3-alternate isomers,
interacted with 3. As the amount of guest 3 increased, the chemical
shifts of the cone isomer 2cone changed with the increase in its
intensity (Fig. 3, signals marked with ‘c’). On the other hand, the
mole fraction of the 1,2,3-alternate isomer 2alt decreased (Fig. 3,
signals marked with ‘a’). The overall isomeric ratio of the cone/
1,2,3-alternate isomer was reversed from 29:71 to 89:11 when 3
equiv of guest 3 were added. The spectral changes were almost
complete when more than 1 equiv of guest 3 was added. The up-
field shifted signals for the bound guest 3 (Fig. 3, signals marked
with ‘b’), which were observed separately from those of the
uncomplexed 3, indicated that the guest 3 is surrounded by the
aromatic rings of the calix[6]arene cavity. The 1:1 host–guest
(2cone/3) stoichiometry was clearly supported by the signal
integrals.
a
Chemical shifts in CDCl3 at 600 MHz at 263 K.
The guest recognition by a mixture of isomers 2cone and 2alt can
be described using the four equilibria shown in Scheme 3. The
three equilibrium constants, Kcone, Kalt, and Ki, were calculated by
a least-squares regression of the mole fraction changes, where
Kcone and Kalt are the guest binding constants for the two isomers
2cone and 2alt, respectively, and Ki for the isomerization constant
of 2. In the absence of guest 3, the two isomers 2cone and 2alt are
in an isomerization equilibrium with the equilibrium constant Ki
of 2.45, while the equilibrium constant between the complexed
forms 2coneÁ3 and 2altÁ3 was Kic = 0.077 (=KiÁKalt/Kcone). This differ-
ence indicates the reversal of the cone/1,2,3-alternate stability
Figure 2. X-ray crystal structure of
1 with thermal ellipsoids drawn at 30%
probability level. Hydrogen atoms and the less occupied disordered atoms are
omitted for clarity. Only one of the crystallographically independent molecules is
shown.

208
S. Akine et al. / Tetrahedron Letters 54 (2013) 205–209
Figure 3. 1H NMR spectral changes of 2 by the addition of guest 3 (600 MHz, DMF-d7, 263 K). The assignments (‘a’, 1,2,3-alternate isomers; ‘c’, cone isomers; ‘b’, guest 3 in
bound form; ‘g’, guest 3) were indicated in the spectra.
making the guest binding less favorable. On the other hand, the
guest binding of the cone isomer does not require such a significant
structural change. Thus, the partial self-inclusion structure of the
1,2,3-alternate isomer well accounts for the smaller Kalt resulting
in the efficient conformation conversion upon guest binding.
In summary, we have synthesized calix[6]arene derivatives 1
and 2 with electron-donating substituents. These compounds
exhibited relatively well-resolved 1H NMR spectra, which clearly
indicated that the 1,2,3-alternate conformation was dominant in
solution. We have also found that the 1,2,3-alternate conformation
Scheme 3. Equilibria of guest recognition and isomerization.
of the hydroxy derivative 2 was efficiently converted into the cone
conformation upon binding with the paraquat derivative 3 as a
upon guest binding. The binding constants for the two isomers
guest and that the
p–p stacking interaction may contribute to
2cone and 2alt (Kcone and Kalt) were calculated to be 5.6 Â 103 MÀ1
and 1.7 Â 102 MÀ1, respectively. It is noteworthy that Kcone is ca
30 times greater than Kalt, that is, the minor isomer 2cone can bind
to 3 much stronger than the major isomer 2alt. The difference in the
association constants for both isomers well explains the reversal in
the overall isomeric ratio, which is described as ([2cone] + [2coneÁ3])/
([2alt] + [2altÁ3]).
the host–guest interaction between 2 and 3. We are now investi-
gating the development of a new molecular switching system by
using the guest-induced conformational conversion, which would
change the structures of the supramolecular assembly and their
functions.
Acknowledgments
The complexation of calixarene 2 with guest 3 was also investi-
gated by UV–vis spectroscopy. When guest 3 was added to a solu-
tion of calixarene 2 in DMSO, a new absorption band appeared at
422 nm. This new band is assignable to the charge-transfer band
from the electron-rich aromatic rings of calixarene 2 to the elec-
This work was supported by the Sumitomo Foundation (S.A.)
and Grants-in-Aid for Scientific Research from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
tron-deficient guest 3, indicating efficient
In the host–guest binding of 2 to 3, the
p
–
p
stacking interaction.
Supplementary data
p–p stacking interaction
between the electron-rich aromatic rings of 2 and the electron-
deficient aromatic rings of 3 should play an important role. The ca-
lix[6]arene skeletons of both cone and 1,2,3-alternate isomers
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.10.105.
could efficiently interact with paraquat 3 via the
p–p stacking
interaction. However, the 1,2,3-alternate isomer adopted a confor-
mation in which part of the hexyl groups fills the calix[6]arene cav-
ity, as described above. This partial self-inclusion of the hexyl
groups should stabilize the unbound form of the 1,2,3-alternate
isomer, while the stabilization should be lost upon guest binding,
References and notes
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16. For acetylation at the upper rim, see Refs 11 and 15a.
17. 1H NMR (600 MHz, CDCl3, 263 K) d À0.04 (br, 4H), 0.76 (quint, J = 7.6 Hz, 4H),
0.87 (t, J = 7.3 Hz, 6H), 0.90 (t, J = 6.5 Hz, 12H), 0.92 (br, 4H), 1.16 (sext,
J = 7.3 Hz, 4H), 1.30–1.38 (m, 16H), 1.49–1.64 (m, 8H), 1.73 (br t, 4H), 1.81–1.91
(m, 8H), 2.23 (s, 12H), 2.35 (s, 6H), 3.34 (d, J = 15.7 Hz, 4H), 3.75 (s, 4H), 3.79–
3.87 (m, 8H), 4.45 (d, J = 15.7 Hz, 4H), 6.28 (d, J = 1.8 Hz, 4H), 6.96 (s, 4H), 7.07
(d, J = 1.8 Hz, 4H). For the spectra of 1 in acetone-d6, acetonitrile-d3, methanol-
d4, DMSO-d6, and DMF-d7, see the Supplementary data.
18. For early example of the 1,2,3-alternate conformation found in crystal
structure, see: McKervey, M. A.; Seward, E. M.; Ferguson, G.; Ruhl, B.; Harris,
S. J. J. Chem. Soc., Chem. Commun. 1985, 388–390.
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6537; (e) Harada, T.; Shinkai, S. J. Chem. Soc., Perkin Trans. 2 1995, 2231–2242.
19. Crystallographic data for 1Á3.5CHCl3ÁH2O: C93.5H125.5Cl10.5O19 (1925.66): triclinic,
ꢀ
P1, a = 13.994(3), b = 17.702(3), c = 22.176(4) Å,
a = 80.102(2), b = 74.409(2),
c
= 84.722(2) deg, V = 5206.4(16) Å3, Z = 2, T = 120 K, R1 = 0.0922 (I > 2
r(I)),
wR2 = 0.2362 (all data). CCDC-894347 contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
9. Formation of
a calix[6]arene-based pseudorotaxane by using a paraquat
derivative was reported, see: Arduini, A.; Ferdani, R.; Pochini, A.; Secchi, A.;
Ugozzoli, F. Angew. Chem., Int. Ed. 2000, 39, 3453–3456.
20. SHELXL 97, program for crystal structure refinement, Sheldrick, G. M. Acta
Crystallogr., Sect. A 2008, 64, 112–122.
10. Dialkoxybenzene derivatives and paraquat derivatives are widely used for
host–guest chemistry and molecular machinery systems, see: Balzani, V.;
21. Compound 2 was soluble in DMF-d7 and DMSO-d6 but was only slightly soluble
in acetone-d6 and methanol-d4 (almost insoluble in CDCl3 and acetonitrile-d3).
The 1H NMR spectra are shown in Supplementary data.