Paraquat guest-induced conformational templation of dicarboxylatocalixarenes

Article abstract of DOI:10.1080/10610278.2010.500731

Proximal dicarboxylatocalix[4]arene 4 and distal dicarboxylatocalix[6]arene 5 have been synthesised in good yields and their complexation abilities towards dicationic paraquat guest 3 have been studied by NMR spectroscopy. Both hosts are able to complex 3

Full text of DOI:10.1080/10610278.2010.500731

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Supramolecular Chemistry
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Paraquat guest-induced conformational templation of
dicarboxylatocalixarenes
Teresa Pierro a , Carmine Gaeta a & Placido Neri a
a Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, I-84084, Fisciano
(Salerno), Italy
Published online: 05 Aug 2010.
To cite this article: Teresa Pierro , Carmine Gaeta & Placido Neri (2010) Paraquat guest-induced conformational templation of
dicarboxylatocalixarenes, Supramolecular Chemistry, 22:11-12, 726-736, DOI: 10.1080/10610278.2010.500731
To link to this article: http://dx.doi.org/10.1080/10610278.2010.500731
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Supramolecular Chemistry
Vol. 22, Nos. 11–12, November–December 2010, 726–736
Paraquat guest-induced conformational templation of dicarboxylatocalixarenes†
Teresa Pierro, Carmine Gaeta and Placido Neri*
`
Dipartimento di Chimica, Universita di Salerno, Via Ponte don Melillo, I-84084 Fisciano (Salerno), Italy
(Received 7 May 2010; final version received 1 June 2010)
Proximal dicarboxylatocalix[4]arene 4 and distal dicarboxylatocalix[6]arene 5 have been synthesised in good yields and
their complexation abilities towards dicationic paraquat guest 3 have been studied by NMR spectroscopy. Both hosts are able
to complex 3 through an induced-fit mechanism, which originates from the conformational flexibility of calixarene
macrocycle. A pH-dependent switching system was realised in which guest inclusion can be controlled through an acid/base
external stimulus.
Keywords: calixarenes; carboxylatocalixarenes; paraquat recognition; induced-fit; switching system; association constant
1. Introduction
solid-state self-assembly of nanotubes based on a
p-carboxylatocalix[4]arene was reported by Dalgarno
et al. (10), while we have very recently shown that
p-carboxylatocalix[4]arene derivatives 1 and 2 are able to
‘grab’ a dicationic guest such as paraquat dichloride 3
(Chart 1) through an induced-fit mechanism (11). In
particular, tetramethoxy-p-carboxylatocalix[4]arene 1,
which mainly exists in solution as a mixture of partial-
cone (with two distal carboxy-groups in anti orientation)
and cone conformations, adopts a single new cone
conformation after addition of paraquat dichloride 3 (11).
These results prompted us to extend the study to the
behaviour of other carboxylatocalixarene hosts in the
presence of dicationic paraquat guest 3. In particular, we
wish to report here the synthesis and the conformational
templation of proximal dicarboxylatocalix[4]arene 4 and
distal dicarboxylatocalix[6]arene 5 upon complexation
with 3.
Calix[n]arene macrocycles (1) have gained a pivotal role
in several fields of supramolecular chemistry such as self-
assembly (2), molecular recognition and sensing (3),
catalysis (4), nanoscience (5) and biomimetism (6). In this
regard, an aspect of particular relevance is their
conformational mobility, which has allowed the synthesis
of specific calixarene hosts able to recognise appropriate
guests by means of adaptive structural changes (6a, 7–9).
An early example concerns an alkali metal cation
conformational templation observed for a tetramethoxy-
calix[4]arene derivative, for which four different con-
formers are present in solution (cone, partial-cone, 1,2-
alternate and 1,3-alternate), yet it adopts only a cone
conformation after addition of Liþ or Naþ, due to their
interaction with the oxygen atoms at the lower rim (8a). In
a similar way, our group has shown that alkali metal
cations are able to template the conformation of larger
calix[7-8]arene macrocycles (9). In another example
concerning conformationally flexible larger calixarenes,
mutually induced conformational changes were
observed during the binding of cationic cholinergic
guests by the water-soluble host p-sulphonatocalix[8]arene
(7a). In several reports, it has been shown that the
high conformational flexibility of the calix[6]arene
macrocycle allows beautiful examples of induced-fit
processes (6, 7b).
2. Results and discussion
2.1 Proximal dicarboxylatocalix[4]arene 4
The sodium salt of 5,11-dicarboxylato-25,26,27,28-tetra-
methoxycalix[4]arene (4) was synthesised exploiting the
reaction sequence shown in Scheme 1. In particular,
bromination of the known proximal dimethoxy-p-H-
calix[4]arene 6 (12) with Br2 in CHCl3 gave the
corresponding proximal p-dibromo-diol derivative 7 in
64% yield, which was alkylated with MeI in the presence
of Cs2CO3 as the base, to give 5,11-dibromo-25,26,27,28-
Recently, we have outlined that the supramolecular
properties of calixarenes bearing anionic carboxylato
groups have been only scarcely studied. In particular, the
*Corresponding author. Email: neri@unisa.it
†In memory of our dear friend Prof Dmitry Rudkevich.
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2010 Taylor & Francis
DOI: 10.1080/10610278.2010.500731
http://www.informaworld.com

Supramolecular Chemistry
727
Cl–
NaOOC
COONa
COONa
NaOOC
N+
O
O
O
O
O
O
O
O
N+
R
R
R
R
Cl–
1 R = Me
2 R = n-Pr
3
4
But
A
But
32
2
But
F
E
OR'
B
C
CH3
Na+
CH2
R =
OR
OR
RO
26
8
RO
OR'
O
CH2
R' =
O
But
But
20
14
D
But
5
Chart 1. Structure of compounds 1–5.
tetramethoxycalix[4]arene derivative (8) in 90% yield.
Tetramethoxy derivative 8 was 5,11-dilithiated by reaction
with n-BuLi in THF at 2308C (13) and quenched, after
30 min, with dry CO2 to give, after acidic work-up, the
5,11-dicarboxylic acid 9 in 51% yield. Then, the
corresponding 5,11-dicarboxylato sodium salt 4 was easily
obtained by treatment of 9 with an aqueous solution of
NaOH in MeOH heated at reflux for 1 h.
Br
Br
Br2
CHCl3
25°C, 4 h
O
HO
OH
O
O
O
OH HO
7
6
Acetone
reflux, 24 h
MeI, Cs2CO3
The 1H NMR spectrum (400 MHz, CDCl3/CD3OD,
1/8, v/v) of 4 at 298 K (Figure 1, bottom) shows broad
signals indicating a slow conformational interconversion.
This is due to the small dimension of the methoxy groups
at the lower rim, which allows their through-the-annulus
passage (14). Therefore, at room temperature, compound 4
is conformationally mobile and exists as an equilibrium
mixture of all possible conformational isomers. At lower
HOOC
Br
Br
COOH
1. n-BuLi
THF, –78°C
2. dry CO2 g,
–78°C
O
O
O
O
O
O
O
O
3. H3O+
9
8
CH3OH,
reflux, 1 h
1
NaOH
temperatures, the H NMR spectrum (400 MHz, CDCl3/
CD3OD, 1/8, v/v, 263 K) of 4 indicated the prevalence of
an asymmetrical conformer. In fact, it shows the presence
of two ArCH2Ar AX systems at 4.04/2.92 and
3.77/2.86 ppm (Figure 1, top), which correlates in the 2D
heteronuclear single quantum coherence (HSQC) spec-
trum (Figure 2) (400 MHz, CDCl3/CD3OD, 1/8, v/v,
263 K) with two signals at 31.55 and 31.49 ppm,
respectively, both attributable to ArCH2Ar carbons
between syn-oriented aromatic rings.
NaOOC
COONa
O
O
O
O
4
Scheme 1. Synthesis of proximal dicarboxylatocalix[4]arene 4.

728
T. Pierro et al.
Figure 1. 1H NMR spectrum [400 MHz, CDCl3/CD3OD, (1/8, v/v)] of 4 at relevant temperatures.
In addition, the 2D HSQC spectrum (Figure 2) shows
intense cross-peaks between broad 1H signals in the region
of 3.3–3.6 ppm and two pertinent carbon resonances at
37.1 and 37.2 ppm, which can be assigned to ArCH2Ar
groups between anti-oriented aromatic rings.
indicated the anti-partial-cone conformation 4a to be
the most stable. In fact, the anti-orientation between the
carboxylato-groups permits the minimisation of repulsive
electrostatic interactions between the negative charges.
A careful analysis of the methoxyl region of the 2D
HSQC spectrum at 263 K clearly evidenced that in
addition to 4a, other equilibrium conformers exist at lower
concentration. Their relative stability can be estimated, in
accordance with the molecular mechanics calculations, as
follows: anti-partial-cone . syn-partial-cone . cone .
1,3-alternate . anti-1,2-alternate . syn-1,2-alternate
(Figure 4).
These data are compatible with a partial-cone con-
formation for 4, which lacks symmetry elements due to its
proximal disubstitution. In particular, two partial-cone
conformations are possible (Figure 3): one with the two
proximal carboxylato-groups in an anti orientation (anti-
partial-cone 4a) and another with those groups in a syn
orientation (syn-partial-cone 4b).
Molecular mechanics calculations (15) (optimised
potentials for liquid simulations (OPLS), CHCl3 solvent)
When paraquat dichloride 3 was added to a solution of
conformationally, mobile proximal calix[4]arene dicar-
ppm
24
26
28
30
32
34
36
38
40
42
31.55 and 31.49 ppm: attributables to
ArCH2Ar carbons between syn-oriented
calixarene aromatic rings
37.1 and 37.2 ppm: attributables to
ArCH2Ar carbons between
anti-oriented calixarene aromatic rings
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
ppm
Figure 2. 2D HSQC spectrum of 4 [400 MHz, CDCl3/CD3OD, (1/8, v/v), 263 K].

Supramolecular Chemistry
729
adaptative conformational changes in order to host the
guest (Scheme 2). The entire guest-induced conformation-
al templation can be visualised with the corresponding
lowest OPLS-energy structures as shown in Scheme 2.
The association constant of 3·4 complex was
determined by standard 1H NMR titrations [298 K,
400 MHz, CDCl3/CD3OD (1/8, v/v)] (16), in which the
guest concentration was kept constant while the host
concentration was varied (Figure 7). The addition of
increasing amounts of a 46.0 mM solution of 4 in
CDCl3/CD3OD (1/8, v/v) to a 2.98 mM solution of para-
quat in the same solvent caused upfield shifts of its signals
indicating a fast complexation equilibrium (16). The
titration data were analysed by nonlinear regression
analysis using the WinEQNMR program (16c) to give a
Kass of 11000 ^ 2000 M21, while a 1:1 stoichiometry for
3·4 complex was estimated by means of a molar ratio
plot (17).
–OOC
COO–
–OOC
O
O
O
O
O
O
O
O
COO–
4a
4b
Figure 3. The two possible partial-cone conformations for
derivative 4.
1
boxylate 4 in CDCl3/CD3OD (1/8, v/v), new H NMR
signals appeared that were assignable to the 3·4 complex
(Figure 5). In particular, three ArCH2Ar AX systems at
4.50/3.38 (4H), 4.53/3.39 (2H) and 4.48/3.39 ppm (2H)
emerged, which were indicative of a Cs-symmetrical cone
conformation. The presence of a symmetry plane bisecting
the opposite methylene bridges was also confirmed by
inspection of the aromatic region of the 1H NMR spectrum
of 3·4 complex. In fact, two meta-coupled doublets at 7.55
(2H, J ¼ 1.5 Hz) and 7.43 (2H, J ¼ 1.0 Hz) ppm, due to
the protons ortho to the carboxylato groups, were present.
In addition, two ortho-coupled doublets and one ortho-
coupled pseudo-triplet relative to the protons of the
unsubstituted aromatic rings, were present at 7.00 (2H,
J ¼ 7.7 Hz), 6.87 (2H, J ¼ 7.0 Hz) and 6.44 ppm (2H,
J ¼ 7.5 Hz), respectively.
The inclusion of paraquat 3 into the calixarene cavity
of 4 is mainly driven by electrostatic interactions between
the anionic carboxylato groups and the cationic paraquat
nitrogens. Therefore, considering that p-carboxylatocalix-
arene hosts are pH sensitive, their recognition abilities
versus organic quaternary ammonium ions should depend
on the pH of the solution. Thus, we decided to study the 1H
NMR spectrum of 3·4 complex at different pH values.
When 2 equiv. of DCl (35% w/w solution in D2O) were
added to a solution of 3·4 complex in CDCl3/CD3OD (1/8,
v/v) (Figure 8(b)), drastic changes in the 1H NMR
spectrum were observed (Figure 8(c)). In particular, the
aromatic signals of 3 were shifted downfield indicating the
presence of free paraquat in solution (Figure 8(c)). In
addition, the lack of conformational templation on the
calix[4]arene skeleton was evidenced by the extensive line
broadening (Figure 8(c)), typical of several slowly
exchanging conformations on the NMR time scale.
The original 1H NMR spectrum of 3·4 complex shown
in Figure 8(b) was regenerated in every detail upon addition
of 2.5 equiv of NaOD (2.0 ml of a 6.5 M solution in CD3OD)
(see Figure 8(d)) to the NMR sample previously treated
with DCl. Thus, the paraquat guest goes back completely
into the calixarene cavity, being driven by electrostatic
interactions with the anionic carboxylato groups regener-
ated by reaction with NaOD. The DCl/NaOD addition cycle
The chemical shift of guest protons shifted to higher
fields in the presence of the host. These shifts are very
likely determined by the shielding effects of the calixarene
aromatic nuclei consequent to the penetration of the guest
into the cavity of the host. This binding mode was
confirmed by the lowest OPLS-energy structure of 3·4
complex, obtained with the program MacroModel-9.0 and
is shown in Figure 6, where it is possible to observe the
close disposition of the anionic carboxylato groups and
the cationic nitrogen atom(s) to give electrostatic
interactions.
Therefore, the presence of 3 induces the oxygen-
through-the-annulus rotation of the inverted ArCOO2 ring
(spanned angle ,1608 (11)) of the prevalent anti-partial-
cone conformer 4a to ‘wrap’ the guest (Scheme 2).
Concomitantly, the less-concentrated conformers undergo
Figure 4. Energy-minimised structures of all possible conformations of derivative 4. The size of each conformer is approximately
proportional to its relative stability.

730
T. Pierro et al.
(b)
(a)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0 ppm
Figure 5. 1H NMR spectra [CDCl3/CD3OD (1/8, v/v), 400 MHz, 298 K] of (a) 4; (b) equimolar solution of 4 and paraquat dichloride 3.
was repeated once again, demonstrating that the process is
reversible. Thus, to the best of our knowledge, this is the
first example of a carboxylato-based calixarene host which
shows recognition abilities heavily dependent on the pH of
the medium (18). Interestingly, p-carboxylatocalixarene
host 4 offers the possibility to switch the inclusion of the
dicationic paraquat guest in or out of the calixarene cavity
through an acid/base external stimulus as a type of
‘molecular switch’ (19).
298 K indicates the presence of a mixture of different
conformations, which are frozen on the NMR timescale due
to the presence of bulky substituents at the lower rim. The
most abundant species present in CD3OD shows a singlet at
0.99 ppm integrating for four t-Bu groups, and an unusually
shielded signal at 20.28 ppm relative to the two t-Bu
groups of the equivalent calixarene rings bearing an acetate
group. A sharp singlet was present at 2.33 ppm (12H)
relative to the methyl protons of the equivalent p-methyl-
benzyl substituents at the lower rim. Regarding the
ArCH2Ar protons, a singlet (4H) due to H8 (and H26)
(Chart 1, Scheme 3) was present at 3.96 ppm, which
correlated in the 2D HSQC spectrum (298 K, 400 MHz,
CD3OD) with a 13C signal at 38.8 ppm. In accordance with
Gutsche’s ‘1H NMR Dd rule’ (20, 21) and de Mendoza’s
‘13C NMR single rule’ (22), these data clearly indicated
(23) the anti orientation of benzylated rings B and C (E and
F) (Chart 1, Scheme 3). In addition, an AB system was
present at 3.88/3.95 ppm (J ¼ 13.9 Hz, 8H), which is
related to ArCH2Ar groups linking differently alkylated
rings (H2, H14, H20 and H32) (Chart 1, Scheme 3). This
AB system correlates in the 2D HSQC spectrum (298 K,
400 MHz, CD3OD) with a 13C signal at 31.4 ppm. These
data are compatible with a syn disposition of the pertinent
aromatic rings coupled to an inward orientation of
carboxylato-bearing ring A (and D), which explains the
shielding of its t-Bu group resonating at 20.28 ppm. This
conclusion was confirmed by the presence of relevant cross-
peaks in the 2D NOESY spectrum between the shielded
t-Bu signal at 20.28 ppm and those of the remaining four
equivalent t-Bu groups at 0.99 ppm (36H) (Figure 9(a)) and
of proximal calixarene aromatic protons at 7.05 and
7.06 ppm (AB system, J ¼ 1.9 Hz, 8H) (Figure 9(b)).
Therefore, the most abundant conformation of 5
present in CD3OD can be described as 1,2,3-alternate with
an inward inclination of the central ring of each 3/4-cone
subunit (Figure 10), which gives rise to a self-filling of the
cavity.
2.2 Distal dicarboxylatocalix[6]arene 5
Prompted by these results we decided to study the
recognition properties of larger calixarene carboxylate
derivatives versus dicationic paraquat guest. Thus, we
synthesised distally substituted calix[6]arene derivative 5
by using the reaction sequence shown in Scheme 3.
Alkylation of the known 1,2,4,5-tetrakis-( p-methylbenzyl-
oxy)-calix[6]arene 10 (20) with ethyl bromoacetate in
refluxing acetone for 5 days, using K2CO3 as the base,
gave diester derivative 11 in 15% yield. Then, 5 was easily
obtained by hydrolysis of 11 with an aqueous solution of
NaOH in refluxing EtOH for 12 h.
Characterisation of dicarboxylatocalix[6]arene 5 was
performed by spectral analysis, in particular the presence of
a pseudo-molecular ion peak (MHþ) at m/z 1506 in the
ESI(þ) mass spectrum confirmed the molecular formula.
The 1H NMR spectrum (400 MHz, 298 K, CD3OD) of 5 at
A VT 1H NMR study indicated the absence of
conformational interconversions upon lowering the
temperature of a sample of 5 from 298 to 258 K. Instead,
upon heating, a coalescence at 333 K was ascertained for
Figure 6. Side (left) and top (right) views of the lowest OPLS-
energy structure of the 3·4 complex.

Supramolecular Chemistry
731
Scheme 2. The conformational templation of p-carboxylatocalix[4]arene derivative 4 induced by dicationic paraquat guest 3.
the ArCH2Ar AB system, which led to an energy barrier of
16.5 kcal/mol, which could be determined for the rotation
of carboxylato-bearing rings.
correlates in the 2D HSQC spectrum (298 K, 400 MHz,
CD3OD) with 13C signals at 30.3 and 30.0 ppm,
1
respectively. The observed H Dd (1.45 and 1.05) and
The complexation ability of derivative 5 towards
1
dicationic paraquat guest 3 was investigated by H NMR
13C d values for each ArCH2Ar group clearly indicated a
syn orientation between all the adjacent aromatic rings.
Therefore, the addition of paraquat dichloride 3 induces
the change of the prevalent 1,2,3-alternate conformation
of calix[6]arene host 5 to a cone one, which is blocked in
the NMR time scale. In accordance with this confor-
mational change, the shielded t-Bu group of carboxylato-
bearing ring A (and D) now resonates at the normal value
of 1.18 ppm (Figure 11). An association constant value of
2.7 £ 104 M21 and a 1:1 stoichiometry were determined
experiments (400 MHz) in CD3OD at 298 K (Figure 11).
Upon addition of a solution of paraquat dichloride 3
(1.0 M in CD3OD) to a CD3OD solution of host 5
(0.013 M), a new set of signals emerged due to the
formation of a 3·12 complex (Figure 11) slowly
exchanging in the NMR time scale. In particular, two
ArCH2Ar AX systems appeared at 3.38/4.83 ppm (8H,
J ¼ 16.0 Hz) and 3.12/4.17 ppm (4H, J ¼ 16.0 Hz), which
9.4
3.0
9.2
9.0
8.8
8.6
8.4
8.2
8.0
7.8
7.6
2.5
2.0
1.5
1.0
0.5
0.0
7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 9.2 9.4
δ (ppm)
0
1
2
3
4
5
6
7
8
[4] / 10–3
M
Figure 7. Plot of chemical shift d of ArH protons of 3 as a function of the concentration of p-carboxylatocalix[4]arene 4 [CDCl3/CD3OD
(1/8, v/v), 258C, 400 MHz]. Inset: corresponding molar ratio plot.

732
T. Pierro et al.
calix[6]arene cavity, because very large shifts are usually
observed in such cases (18b, 18c, 24). Therefore, the guest
most likely has to be located in the lower rim region to give
a better electrostatic interaction with the appended syn
carboxylate groups. This binding mode was confirmed by
the lowest OPLS-energy calculated structure of 3·5
complex (Figure 12), in which paraquat dicationic guest
templates the calix[6]arene cone conformation by means
of electrostatic interactions with anionic carboxylato
groups at the lower rim.
(e)
(d)
(c)
3. Conclusion
In summary, we have shown that calixarene carboxylate
derivatives 4 and 5 are able to complex dicationic
paraquat guest 3 through an induced-fit mechanism, which
originates from the conformational flexibility of calixar-
ene macrocycle. In particular, in the case of proximal
p-carboxylatocalix[4]arene 4, an oxygen-through-the-
annulus rotation of the inverted ArCOO2 ring of the
prevalent anti-partial-cone conformer occurs to ‘wrap’ the
guest. Larger adaptive structural changes are observed for
distal calix[6]arene carboxylate 5, in which a half of the
molecule rotates from the most abundant 1,2,3-alternate
conformation to give a cone structure upon guest
templation at the lower rim.
(b)
(a)
9
8
7
6
5
4
3
Figure 8. 1H NMR spectra [400 MHz, in CDCl3/CD3OD (1/8,
v/v), 298 K] recorded on proximal dicarboxylatocalix[4]arene 4
(9.6 mM) before (a) and after the successive addition of (b) 1.5
equiv. of paraquat dichloride 3, (c) 2.0 equiv. of DCl, (d) 2.5
equiv. of NaOD and (e) 2.5 equiv. of DCl.
In addition, we have also shown that the complexing
abilities of calixarene carboxylate hosts are strongly
dependent on the pH of the medium. Therefore, a
switching system was realised in which the inclusion of
dicationic paraquat guest in/out of the cavity of
p-carboxylatocalixarene host 4 can be controlled through
an acid/base external stimulus. This process is reversible
and consequently the acid/base addition cycle can be
iterated several times.
for the slowly exchanging 3·5 complex by integration of
1
pertinent H NMR signals.
The two aromatic protons of paraquat guest in the 3·5
complex were accidentally isochronous and resonate at
8.87 ppm reflecting only minor shifts upon complexation.
This indicates that guest 3 is not included inside the
But
But
A
But
2
But
But
32
But
But
But
But
F
E
K2CO3
BrCH2COOEt
B
C
OH
RO
OR'
RO
OR'
OR
OR
OR
OR
OR
OR
RO
NaOH
8
26
Acetone
reflux
RO
EtOH
reflux
RO
RO
OR'
OH
OR'
D
But
But
But
But
But
But
20
14
But
CH2
But
But
CH2
CH3
10 R =
5 R =
11 R =
CH3
CH3
CH2
O–Na+
O
OEt
CH2
CH2
R' =
R' =
O
Scheme 3. Synthesis of distal dicarboxylatocalix[6]arene 5.

Supramolecular Chemistry
733
(a)
(b)
ppm
ppm
–0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
0.94
0.96
–0.25
–0.30
–0.35
–0.40
–0.45
ppm
8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 ppm
Figure 9. Expansion of 2D NOESY spectrum of dicarboxylatocalix[6]arene 5 (250 MHz, CD3OD, 298 K).
4. Experimental section
62.8 MHz (13C) on a Bruker Avance-250 spectrometer;
chemical shifts are reported relative to the residual solvent
peak (CHCl3: d 7.26; C DCl3: d 77.23; CH3OD: d 4.87;
C D3OD: d 49.15). Standard pulse programs, provided by
the manufacturer, were used for DEPT, HSQC and NOESY
multipulse sequences.
4.1 General comments
ESI-MS measurements were performed on a Micromass
Bio-Q triple quadrupole mass spectrometer equipped with
electrospray ion source. Flash chromatography was
performed on silica gel (60, 40–63 mm). All chemicals
were reagent grade and were used without further
purification. Anhydrous DMF and THF were purchased
and used without further purification. Reaction tempera-
tures were measured externally; reactions were monitored
by TLC on silica gel plates (0.25 mm) and visualised by UV
light and spraying with H2SO4–Ce(SO4)2. Compounds 6
(12) and 10 (18) were prepared following literature
procedures. All 1D and 2D NMR spectra were recorded at
400 (1H) and 100 MHz (13C) on Bruker Avance-400
spectrometer, or at 300 (1H) and 75.5 MHz (13C) on a
Bruker Avance-300 spectrometer, or at 250 (1H) and
4.2 Synthesis of sodium 5,11-dicarboxylato-
25,26,27,28-tetramethoxycalix[4]arene (4)
4.2.1 5,11-Dibromo-25,26-dimethoxy-27,28-
dihydroxycalix[4]arene (7)
Br2 (1.0 g, 8.0 mmol) was added dropwise to a solution of
derivative 6 (0.7 g, 1.5 mmol) (12) in CHCl3. The reaction
mixture was stirred for 2 h at room temperature, and the
solid product was filtered and triturated with aqueous 1 M
solution of sodium bisulphite. The precipitate was
dissolved in CH2Cl2, dried on Na2SO4, filtered and the
solvent was removed under reduced pressure to obtain 7
1
(0.58 g, 64% yield). ESI(þ) MS: m/z ¼ 633 (MNaþ); H
NMR (CDCl3, 298 K, 400 MHz, mixture of cone
conformer and a minor one in a 10:4 ratio): d 8.31 (s,
*
2H, OH cone conformer), 7.73 (s, 0.4 £ 2H , OH minor
*
conformer), 7.20–6.87 (overlapped, 10H, ArH cone
conformer and 0.4 £ 10H , ArH minor conformer),
*
4.40–3.23 (overlapped, 8H, ArCH2Ar cone conformer;
0.4 £ 8H , ArCH Ar minor conformer), 4.05 (s, 6H,
*
2
OCH cone conformer), 3.44 (s, 0.4 £ 6H, OCH minor
*
3
3
conformer); 13C NMR (CDCl3, 390 K, 400 MHz): d 115.2,
154.6, 150.9, 150.6, 134.5, 133.6, 133.5, 131.6, 131.3,
131.1, 131.0, 130.6, 129.6, 125.7, 112.7, 62.9, 59.9, 37.9,
34.4, 31.8, 31.6, 31.0, 30.7. Anal. calcd for C30H26Br2O4:
C 59.04; H 4.29. Found: C, 59.14; H, 5.50.
Figure 10. Different views of the lowest OPLS-energy (CHCl3
solvent, GB/SA implicit model solvent) inward-1,2,3-alternate
conformation of free 5. Hydrogen atoms are omitted for clarity.

734
T. Pierro et al.
ppm
4
4.5 4.0 3.5
ppm
1.2
ppm
9
8
7
6
5
4
3
2
1
0
ppm
Figure 11. 1H NMR spectra (400 MHz, 298 K, CD3OD) of (bottom) free 5 and after the addition of (middle) 0.5 or (top) 1 equiv. of guest
3. Inset: Expansion of the methylene region of COSY-45 spectrum of 3·5 complex in CD3OD (400 MHz, 298 K).
4.2.2 5,11-Dibromo-25,26,27,28-
ether/chloroform, 8/3, v/v) to give 8 (15 mg, 24%).
ESI(þ) MS: m/z ¼ 661.2 (MNaþ). 1H NMR (1,1,2,2-
tetrachloroethane-d2 (TCDE), 390 K, 300 MHz): d 7.15–
6.67 (broad, 10H, ArH), 3.66 (overlapped, 20H, ArCH2Ar
and OCH3). 13C NMR (TCDE, 390 K, 75 MHz): d 160.9,
160.1, 134.8, 134.3, 132.1, 131.6, 125.4, 117.9, 63.4, 34.8.
Anal. calcd for C32H30Br2O4: C 60.21; H 4.74. Found: C,
59.30; H, 4.64.
tetramethoxycalix[4]arene (8)
To a solution of derivative 7 (0.6 g, 0.1 mmol) in dry DMF
(10 ml) was added NaH (mineral oil 60%, 0.48 g,
19.9 mmol), and the mixture was kept under stirring at
708C for 15 min. CH3I (2.8 g, 19.9 mmol) was added and
the mixture was kept under stirring at 708C for 12 h, under
nitrogen. The reaction was quenched with aqueous 1 M
HCl (50 ml) and the product was extracted with CH2Cl2
(2 £ 50 ml). The organic layer was washed with aqueous
1 M HCl (3 £ 50 ml) and brine (50 ml). The organic layer
was dried over Na2SO4, and the solvent was removed
under reduced pressure. The crude product was subjected
to flash chromatography on silica gel (petroleum
4.2.3 5,11-Dicarboxy-25,26,27,28-
tetramethoxycalix[4]arene (9)
Derivative 8 (0.10 g, 0.16 mmol) was dissolved in dry THF
(6 ml) under nitrogen atmosphere. The reaction mixture
was stirred at 2788C for 15 min, then n-BuLi was added
Figure 12. Different views of the lowest OPLS-energy (CHCl3 solvent, GB/SA implicit model solvent) structure of 3·5 complex.
Hydrogen atoms of the calix[6]arene host (blue) are omitted for clarity. Dicationic paraquat guest, in close contact with anionic
carboxylato groups (red), is represented as yellow CPK model.

Supramolecular Chemistry
735
(0.6 ml, 2.5 M in hexane solution). The mixture was stirred
for 30 min at 2788C and then dry CO2 was bubbled for
30 min. The reaction was quenched with ice cold water
(20 ml) and the product was extracted with CH2Cl2 and
washed with aqueous 1 M HCl (2 £ 20 ml) obtaining pure
derivative 9 (0.046 g, 51%). ESI(2) MS: m/z ¼ 567.42
J ¼ 7.6 Hz, 8H), 7.08 (bd, ArH, J ¼ 7.6 Hz, 8H). 13C
NMR (TCDE, 62.5 MHz, 373 K): d 12.2, 19.1, 29.6, 32.1,
58.5, 68.5, 73.2, 124.2, 124.5, 126.5, 127.0, 131.1, 131.3,
131.4, 133.6, 135.1, 143.9, 144.2, 151.2, 167.2. Anal.
calcd for C106H128O10: C, 81.50; H, 8.26. Found: C,
81.43; H, 8.34.
1
(M 2 H2); H NMR (TCDE, 390 K, 300 MHz): d 7.46–
6.40 (10H, ArH), 3.48 (overlapped ArCH2Ar and OCH3,
20H); 13C NMR (TCDE, 390 K, 75 MHz): d 166.8, 160.8,
129.7, 129.2, 127.4, 126.9, 121.3, 120.5, 58.5, 30.4. Anal.
calcd for C34H32O8: C 71.82; H 5.67. Found: C, 71.72;
H, 5.77.
4.3.2 Sodium 5,11,17,23,29,35-hexa-tert-butyl-39,42-
bis(carboxylato-methoxy)-37,38,40,41-tetrakis[(4-
methylbenzyl)oxy]calix[6]arene (5)
To a solution of derivative 11 (0.27 g, 0.17 mmol) in EtOH
(10 ml) was added an aqueous 1 M solution of NaOH
(3.5 ml). The reaction mixture was kept under stirring at
the refluxing temperature overnight, and the solvent was
removed under reduced pressure. H2O (20 ml) was added
and, after 1 h, the solid was filtered and washed with
MeOH (2 £ 20 ml) to obtain derivative 5 as a colourless
solid, 0.24 g, quantitative yield. 1H NMR (DMSO-d6,
373 K, 300 MHz), d 1.27 (br s, t-Bu, 54H), 2.30 (br s,
OCH2C6H4CH3, 12H), 4.04 (broad, ArCH2Ar, 12H), 4.08
(br s, OCH2COO2, 4H), 4.79 (br s, OCH2C6H4CH3, 8H),
7.09–7.32 (overlapped ArH, 28H); 13C NMR (toluene,
75.0 MHz, 320 K): d 30.3, 30.5, 30.9, 31.7, 31.9, 34.4,
74.9, 76.37, 133.6, 133.7, 134.1, 135.3, 145.8, 152.2,
155.0, 175.1.
4.2.4 Sodium 5,11-dicarboxylato-25,26,27,28-
tetramethoxycalix[4]arene (4)
Derivative 9 (0.10 g, 0.18 mmol) was dissolved in EtOH
(5 ml), a 1.0 M solution of NaOH in EtOH was added
(1.8 ml) and the mixture was heated at reflux for 1 h. The
solvent was removed under reduced pressure and the
product was washed with water and filtered to give
1
derivative 4 as a colourless solid in quantitative yield. H
NMR (TCDE, 390 K, 300 MHz): d 7.40–6.38 (10H, ArH),
3.53 (overlapped ArCH2Ar and OCH3, 20H); 13C NMR
(TCDE, 390 K, 75 MHz): d 165.0, 160.0, 130.3, 129.2,
127.0, 126.9, 120.9, 120.2, 57.2, 30.4.
4.4 Complexation studies
4.3 Synthesis of sodium 5,11,17,23,29,35-hexa-tert-
butyl-39,42-bis(carboxylato-methoxy)-37,38,40,41-
tetrakis[(4-methylbenzyl)oxy]calix[6]arene (5)
1H NMR titrations were performed at 298 K (400 MHz) in
CDCl3/CD3OD (1/8, v/v). Chemical shifts were externally
referenced to the residual solvent peak (CHCl3: d 7.26;
CH3OD: d 4.87). The Paraquat dichloride 3 concentration
(2.98 mM) was kept constant while the host concentration
was varied (0–8 mM). The signals of guest 3 were
followed and the data were analysed by nonlinear
regression analysis using the WinEQNMR program.
4.3.1 5,11,17,23,29,35-Hexa-tert-butyl-39,42-
bis(ethoxycarbonylmethoxy)-37,38,40,41-tetrakis[(4-
methylbenzyl)oxy]calix[6]arene (11)
To a solution of 10 (1.0 g, 0.7 mmol) (20) in acetone
(75 ml) was added K2CO3 (6.0 g, 43.2 mmol), and the
mixture was kept under stirring at the refluxing
temperature for 1 h. BrCH2COOEt was added (7.2 g,
43.2 mmol) and the reaction mixture was kept under
stirring at the refluxing temperature for 96 h. The solvent
was removed under reduced pressure and the product was
dissolved in CH2Cl2 (50 ml) and washed with aqueous
1 M solution of HCl (50 ml) and H2O (50 ml). The organic
phase was dried on Na2SO4, filtered and the solvent was
removed under reduced pressure. The crude product was
subjected to flash chromatography on silica gel (pet-
roleum ether/CH2Cl2 6/4, v/v) to give derivative 11 as a
white solid, 0.17 g, 15% yield. ESI(þ) MS: m/z ¼ 1563
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