Inclusion of carboxyl function inside of cucurbiturils and its use in molecular switches

Article abstract of DOI:10.1002/asia.201000388

We have prepared organic guest molecules in which two pyridinium rings are connected through an aromatic/aliphatic bridge bearing a carboxyl group. The supramolecular interactions between these guests and macrocyclic hosts cucurbit[7]uril (CB7) and cucurb

Full text of DOI:10.1002/asia.201000388

FULL PAPERS
DOI: 10.1002/asia.201000388
Inclusion of Carboxyl Function Inside of Cucurbiturils and its Use in
Molecular Switches
Viktor Kolman,[a] Petr Kulhanek,[b] and Vladimir Sindelar*[a]
Abstract: We have prepared organic
guest molecules in which two pyridini-
um rings are connected through an aro-
matic/aliphatic bridge bearing a car-
boxyl group. The supramolecular inter-
actions between these guests and mac-
rocyclic hosts cucurbit[7]uril (CB7) and
cucurbit[8]uril (CB8) has been studied.
We have demonstrated that the binding
modes of the complexes depend on the
type of central bridge present in the
guest molecules and the size of the
macrocycle. We have also showed that
the binding mode between cucurbitur-
ils and guests with aromatic bridges is
pH independent. On the other hand, a
guest containing an aliphatic bridge
and CB7 formed a pseudorotaxane,
which behaved as a pH-driven molecu-
lar switch.
Keywords: host–guest systems
inclusion compounds · molecular
devices self-assembly supra-
molecular chemistry
·
·
·
Introduction
where the macrocycle functions as a molecular wheel. Exter-
nal,[5] photochemical,[6] or pH[7,8] stimuli move the wheel
along an axle. The axle is usually represented by cationic
guests with two possible binding sides, each of which is pre-
ferred under different conditions by the wheel. We are par-
ticularly interested in pH-driven molecular switches. These
switches can be divided into two groups based on the type
of axle. In the first type,[7] CB binds around the diammoni-
um unit and, at high pH values, moves to the other side
after deprotonation of the ammonium groups to amine
groups. This type of molecular switches have recently been
used for the preparation of pH sensitive nanovalves for drug
delivery.[9] In the second type of switch,[8] which is closely re-
lated to our work, the axle component consists of a viologen
subunit with aliphatic sidearms that contain terminal carbox-
ylic acid groups. At low pH values, the wheel is bound
around an alkyl chain in close proximity to the carboxyl
group. The movement of CB towards the viologen central
unit is forced under basic condition by strong electrostatic
repulsion between the carboxylate group that has a negative
charge and the carbonyl portal of CB.
Cucurbit[n]urils (CBs) are rigid macrocycles suitable for
complexation with a wide range of organic and inorganic
guest molecules. CB6, the first member of the CB family,
was synthesized in 1905 from glycoluril and formaldehyde
in acidic media[1] and fully characterized in 1981.[2] In 2000,
the groups of Kim and Day independently discovered a
pathway for the synthesis of higher homologues of CB
(CB5, CB7, CB8, and CB10), and thus a way was opened
for further exploration of the supramolecular properties of
CB.[3] CBs are known to bind cationic organic guest mole-
cules in aqueous solution because of the partially negatively
charged carbonyl portal and the hydrophobic cavity.[4] In a
typical complex, the hydrophobic part of the guest is bound
inside the CB cavity and the complex is stabilized by ion–
dipole interactions between the cationic part of the guest
molecule and the negatively charged portal of the host. CBs
are also used for the preparation of molecular switches
[a] V. Kolman, Dr. V. Sindelar
To the best of our knowledge, there has been no attempt
to enhance such a type of molecular switch by relocating the
carboxyl moiety from the edges of the axle, where it hinders
further modification of the system, to the middle part where
it could also be included in the cavity of CB whilst retaining
its switching function after deprotonation. In such a case, a
way would open for further substitution of the axle or even
for potential polymerization. With such an intention, we
have prepared dicationic guests G1, G2, G3, and G4 in
Department of Chemistry
Masaryk University, Kotlarska 2, 61137 Brno (Czech Republic)
Fax : (+420)549-49-2443
E-mail: sindelar@chemi.muni.cz
[b] Dr. P. Kulhanek
National Centre for Biomolecular Research
Masaryk University
Kotlarska 2, 61137 Brno (Czech Republic)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000388.
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Chem. Asian J. 2010, 5, 2386 – 2392

which two pyridinium rings are connected through an aro-
matic/aliphatic bridge bearing carboxyl groups. We have in-
vestigated the modes of binding between these guest mole-
cules and the macrocycles CB7 and CB8. The ability of the
formed pseudorotaxanes to behave as pH-driven molecular
switches has been also studied.
Results and Discussion
Synthesis
CB7 and CB8 were prepared according to the procedure de-
scribed in the literature.[3] For the preparation of guests G1
and G2, compound 1[10] was first converted into the methyl
ester 2[11] (Scheme 1). The conversion appeared to be neces-
sary because the unprotected carboxylic acid reacts with the
neighboring methylbromide through an intramolecular reac-
tion to afford a lactone.[12] The obtained ester reacted with
pyridine to give the desired bispyridinium salt G1, which
was then deprotected to obtain the targeted benzoic acid de-
Figure 1. The 1H NMR spectra (300 MHz, D2O, acetate buffer; pH 4.74)
of guest G2 a) in the absence, and in the presence of b) 0.5 equiv, and
c) 1 equiv of CB7.
group. These signals were fully distinguishable using
2D NMR experiments (see the Supporting Information) and
assigned to individual parts of the molecule. Compound 3
was prepared according to the published procedure[13] and
used as the starting material for the preparation of guests
G3 and G4. The carboxyl group was protected from undesir-
able lactone formation by
1
rivatives G2. The H NMR spectrum of the free acid guest
G2 (Figure 1a) showed three sets of signals for the three dif-
ferent aromatic rings and two signals which could be as-
signed to the two methylene bridges on the middle ring in
ortho and meta position with respect to the carboxylic acid
esterification before its reaction
with pyridine.
Supramolecular Interaction
between G2 and CB7
The binding mode between
CB7 and G2 was then studied
using 1H NMR spectroscopy.
The 1H NMR spectrum of the
G2 guest molecule was pH de-
pendent because the carboxyl
group was directly attached to
the central aromatic unit.
Therefore, we carried out all
measurements in buffered D2O
solution. First, a solution of the
guest G2 in acetate buffer at
pH 4.74 was used. At this pH
value, the carboxyl group of the
guest became protonated. Upon
addition of one equivalent of
CB7 to the G2 solution
(Figure 1), all the pyridinium
ring A protons shifted upfield
by
approximately
0.3 ppm
(0.34 ppm for A2, and A3, and
0.28 ppm for A4) and the signal
of the methylene bridge X con-
necting ring A with the central
part B shifted upfield by
Scheme 1. The preparation of guests G1, G2, G3, and G4.
Chem. Asian J. 2010, 5, 2386 – 2392
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V. Sindelar et al.
FULL PAPERS
0.19 ppm. The signal corresponding to the B4 proton also
showed an upfield shift of 0.28 ppm whilst the other two
peaks of the middle ring B3 and B6 underwent a downfield
shift of 0.01 and 0.13 ppm. The chemical shifts of the re-
maining protons of the guest molecule, including proton Y
and aromatic protons C, remain unchanged. The location of
the carboxyl group of the guest G2 is uncertain because we
cannot follow the chemical shift of the acidic proton because
of deuterium exchange. Therefore, we carried out titration
experiments using guest G1, which contains a methyl ester
group on the central aromatic section. Upon the addition of
CB7 into solution, the protons of G1 experienced shifts
identical to those observed in the case of G2. Moreover, the
signal of the methyl ester protons did not undergo any
change in chemical shift, which confirmed that the ester
group was not included inside the cavity upon the complexa-
tion of G1 with CB7 (see the Supporting Information). The
above NMR experiments indicated that both guests G1 and
G2 formed identical inclusion complexes with CB7 in which
the pyridinium ring A was included in the cavity of CB7
whilst ring C remained outside the macrocycle (Figure 2a).
under basic conditions, complex formation would not take
place because of the electrostatic repulsion of the negatively
charged portals of CB7 and the carboxylate group of the
guest molecule. However, the type of binding recorded be-
tween CB7 and G1 by NMR was similar to the one ob-
served under acidic conditions, even in a highly basic buffer
solution (see the Supporting Information). The reason why
the deprotonation of the carboxyl group of G2 does not
affect the interactions with CB7 is probably because of its
sufficient distance from ring A where CB7 binds the guest
G2 molecule.
Supramolecular Interaction between G2 and CB8
As the cavity of CB7 is not large enough to engulf the cen-
tral aromatic unit containing the carboxyl group, we decided
to investigate the interactions between G2 and CB8. The in-
teractions of G2 with CB8 in acidic media (phosphate
buffer, pH 2.18)[15] differed dramatically to those with CB7.
Peaks A and X do not undergo any shift upon addition of
CB8. On the other hand, peaks B, C, and Y moved upfield
by amounts in range 0.15–0.48 ppm upon addition of
1 equivalent of CB8 (Figure 3). The observed chemical shifts
Figure 2. The binding modes between G2 and a) CB7, and b) CB8.
The central aromatic unit was partially included inside the
CB7 cavity, which left the carboxyl group out of the macro-
cycle. The reason why CB7 prefered to bind guest G1
around the aromatic ring A ahead of aromatic ring C can be
explained by sterically advantageous access of the macrocy-
cle to ring A. Ring A is located in the meta position with
regard to the carboxyl group, which provides enough room
for its encapsulation into the CB7 cavity. On the other hand,
ring C is attached in close proximity to a carboxyl group
(ortho position), which sterically prevents complex forma-
tion. It is important to note that CB7 is known to strongly
bind other compounds similar to G1 but which lack the car-
boxyl group on the central aromatic moiety.[14] Our experi-
ments show that the attachment of the carboxyl group on
the central aromatic unit makes this unit too big to be in-
cluded in CB7 and forces the macrocycle to remain bound
around the pyridinium ring.
Figure 3. The 1H NMR spectra (300 MHz, D2O, phosphate buffer;
pH 2.18) of guest G2 a) in the absence, and in the presence of
b) 0.5 equiv, and c) 1 equiv of CB8.
indicate that CB8 engulfs both rings B and C of the guest
molecule G2 in the cavity whilst pyridinium ring A re-
mained outside the macrocycle. Like before, we supported
our observation by further investigation of the complexation
between the ester G1 and CB8 (see the Supporting Informa-
tion). The chemical shift pattern is identical to the one
which was observed for G2. The methyl ester signal was
shifted upfield by 0.46 ppm upon addition of 1 equivalent of
CB8. This fact indicates that regardless of its sterical re-
quirements, the ester group is also included inside the cavity
of CB8 (Figure 2b).
We also carried out a titration of G2 with CB7 in basic
conditions using phosphate buffer (pH 12.32), in which the
carboxyl function is fully deprotonated. We expected that,
The inclusion of the two aromatic rings inside CB8 is not
surprising as this host had previously been known to bind
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Molecular Switches
two aromatic molecules inside its cavity.[16] However, that
CB8 engulfs ring C instead of ring A together with ring B is
perhaps unexpected. The structure of the guest molecule
was thought to play an important role in this issue. We ex-
pected that the positively charged nitrogen on the pyridini-
um ring C could interact with the oxygen of the carboxyl
group through ion–dipole interactions because of its close
proximity. Such an interaction is not possible in the case of
the second pyridinium ring A. Therefore, CB8 prefers to
bind G2 around the compact part where rings C and B are
packed together and not around the part formed by rings A
and B, which is too spacious to be advantageously included
inside the cavity.
a modified sander program from the AMBER package.[18]
The studied molecules were described by GAFF force
field[19] and the surrounding environment was modeled using
implicit an water model (for further information, see the
Supporting Information).[20] The results from 100 ns long
simulations for each protonation state are shown in Figure 4
and 5.
The titration of G2 in neutral and basic buffer solutions
was problematic because of the extremely low solubility of
CB8. Nevertheless, from the spectra obtained before the
precipitation occurred (which is in the ratio G2/CB8=1:0.5
in phosphate buffer at pH 6.86), it is obvious that the bind-
ing mode of the complex is the same as at low pH, regard-
less of the deprotonation of the carboxylic acid group (see
the Supporting Information).
The complexation between CB8 and G2 at higher pH
values was probably allowed because of the interaction of
pyridinium ring C with the carboxylate group, which partial-
ly weakens the negative charge on the carboxylate group.
As a result, the repulsion between carboxylate and partial
negative charge of the CB8 portal could be overcome and
the formation of the complex takes place.
Computational Study of Guest G2
We have shown above that G2 binds to CB8 through the B
and C rings and this binding was not influenced by the
change of pH. The explanation for this would be that the
carboxyl group stabilizes the ring C in its close vicinity. This
tightly packed formation of two rings (B and C) would then
preferentially bind into the CB8 cavity. Because we did not
observe any decomplexation under basic conditions, this
packed form should be stable in a wide range of pH. To sup-
port our explanations, we decided to use computational
chemistry tools. Because of the complexity of calculations,
we did not try to examine the thermodynamics of complexa-
tion but rather focused only on the above-mentioned confor-
mational behavior of the guest molecule in water environ-
ment as a function of pH. Two phenomena were analyzed in
detail: a) The flexibility of rotation around methylene
bridges and b) its dependence on the protonation state (e.g.
pH) of the carboxyl group. For this purpose, the free energy
surfaces were calculated as a function of two dihedral
angles, c and f, for both protonation states. The dihedral
angles c and f determine the relative turning of rings A
and C towards ring B along the methylene bridges. The di-
hedral angle c is defined by the B1, B2, Y, and C1 atoms
and the dihedral angle f is defined by the B6, B5, X, and
Figure 4. The conformational space of guest G2 expressed as the depend-
ence of the free energy (in kcalmol-1) on two dihedral c and f: a) pro-
tonated state - low pH; b) deprotonated state - high pH. Contour lines
are plotted from 0 to 5 kcalmolÀ1 with 0.5 spacing.
No significant differences were found for guest molecule
G2 regardless of its protonation state (Figure 4). There are
four identical global minima (black spots) located at Æ788
and Æ888 for dihedral angles c and f, respectively (small
drifts for minima with c=+788 shown in Figure 4 are caused
by numerical errors). All these minima correspond to the
most stable conformers in which the ring C is in close prox-
imity to the carboxyl group as shown in Figure 5. There are
also two additional minima located at 1808 and Æ888 for di-
À
À
A1 atoms. In all calculations, the bonds A1 X and C1 Y
were considered as freely rotatable. The free energy surfaces
were calculated by Adaptive Biasing Force method[17] using
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Figure 5. The most stable conformers of protonated G2 from region
where c=78Æ58: front (left) and side (right) views.
hedral angles c and f. They are about 2 kcalmolÀ1 above
the global minima and thus they are less populated. All
global minima are separated by transition states with very
small barrier of about 2.5 kcalmolÀ1 except the region where
c approaches zero. In this area, the energy rises to 15 kcal
molÀ1 because of sterical clash between the carboxyl group
and ring C.
1
Figure 6. The H NMR spectra (300 MHz, D2O) of the guest G4 a) in the
absence, and b) in the presence of 1 equiv of CB7 (pH 3.5), c) after addi-
tion of base (pH 12), d) after addition of acid (pH 2).
The calculated free energy surfaces revealed that the
most likely conformers are those in which the torsion angle
c has a value of Æ788 (Figure 5). For this value, the pyridini-
um ring C is in a favorable orientation towards the carboxyl
group, which allows the most efficient electrostatic interac-
tion between them. It was demonstrated further that the
protonation state of the carboxyl group in compounds G2
does not have any significant impact on the structure and
population of the most probable conformers. Therefore, the
expected strong electrostatic interaction between the nega-
tively charged carboxyl group and the positively charged
pyridinium ring C was likely screened out by water environ-
ment and thus the packing of B and C rings was not influ-
enced by pH.
Supramolecular Interaction between G4 and CB7
The pseudorotaxanes formed by an inclusion of guest G1 or
G2 into macrocycle CB7 or CB8 failed to behave as pH-de-
pendent molecular switches. Therefore, we prepared guest
molecules G3 and G4 in which an aliphatic part connects
the two pyridinium ends instead of an aromatic ring as used
in guests G1 and G2. First, we investigated the interaction
of protonated G4 with CB7 using 1H NMR spectroscopy.
Figure 7. Representation of pH-driven switch between G4 and CB7.
nificant upfield shift (ca. 1.0 ppm) of the methyl ester signal.
This indeed supports the proposed location of CB7 in the
centre of the G3/G4 in which the ester/carboxyl group is in-
cluded inside the cavity.
1
We found that the H NMR spectra of G4 in the absence of
CB7 were identical over a wide range of pH values (2–12;
see the Supporting Information); thus, it was not necessary
to use buffered solution. In acidic media, it was observed
that upon addition of 1 equivalent of CB7 into G4, aliphatic
protons of the guest and aromatic proton A2 exhibited up-
field shifts whilst signals of A3 and A4 did not show any
change in chemical shifts (Figure 6).
The obtained NMR spectra were in agreement with the
formation of an inclusion complex where CB7 sits around
the aliphatic chain in the middle of the guest molecule
(Figure 7). The inclusion of the carboxyl group inside the
macrocycle was further confirmed by the titration of methyl
ester G3 with CB7 (see the Supporting Information). The
addition of CB7 into a solution of G3 was followed by a sig-
We also investigated the influence of pH on the binding
mode of the complex between G4 and CB7. The change of
pH from acidic to basic leads to a pronounced downfield
shift of all aliphatic protons and an upfield shift of aromatic
protons. As NMR spectra of the guest molecules are pH in-
dependent, the pH-induced shifts were caused only by a
sliding of the macrocycle from the central aliphatic chain
over to the pyridinium terminal unit (Figure 7). The switch
of CB7 was most likely driven by electrostatic repulsion be-
tween the anionic carboxylate group and the carbonyl portal
of CB7 with partial negative charge. The switching was re-
versible, as shown by NMR spectroscopy (Figure 6). There-
fore, pseudorotaxane, formed by G4 and CB7, behaves as a
pH-driven molecular switch.
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Molecular Switches
5.72, 4H), 8.66 (t, J=7.84, 2H), 8.18 (t, J=7.07, 4H), 4.76 (t, J=7.52,
4H), 3.76 (s, 3H), 2.85 (m, 1H), 2.54 (m, 2H), 2.42 ppm (m, 2H);
13C NMR (75 MHz, D2O): d=169.3, 140.1, 138.4, 122.4, 53.4, 46.9, 33.4,
26.5 ppm; HRMS-ESI m/z (%) calcd for C17H22Br2N2O2: 143.0835
[MÀ2BrÀ]2+; found: 143.0813.
1,1’-(3-carboxypentane-1,5-diyl)dipyridinium dichloride (G4). A solution
of G3 (200 mg, 0.43 mmol) in hydrochloric acid (35%, 5 mL) was heated
to reflux for 12 h. The mixture was concentrated under reduced pressure
to give a brown residue. The residue was washed with diethyl ether to
obtain a brown oil (140 mg, 95%).1H NMR (300 MHz, D2O): d=8.94 (d,
J=6.16, 4H), 8.64 (t, J=7.73, 2H), 8.15 (t, J=6.89, 4H), 4.76 (t, J=7.52,
4H), 2.75 (m, 1H), 2.51 (m, 2H), 2.41 ppm (m, 2H); 13C NMR (75 MHz,
D2O): d=170.5, 139.9, 138.2, 122.2, 53.2, 33.3, 26.4 ppm; HRMS-ESI: m/z
(%) calcd for C16H20Br2N2O2: 271.1441 [MÀH+À2BrÀ]+; found:
271.1455.
Conclusions
In conclusion, we have prepared guests G1–G4 that consist
of two pyridinium terminal units, which are connected by an
aromatic or aliphatic central bridge. In all cases, the central
unit of the guests contains one carboxyl group or its methyl
ester. We have shown that CB7 forms inclusion complexes
with guests G1 and G2 by the inclusion of pyridinium
ring A inside its cavity. On the other hand, CB8 is able to
engulf pyridinium unit C of the guests G1 and G2 together
with the central ring B and the carboxyl moiety. Surprisingly,
identical modes of binding with CB7 and CB8 were ob-
served regardless of the protonation/deprotonation of the
carboxyl group of the guest G2. Different binding behaviors
were observed between guest G4 and CB7. CB7 bound in
the middle of the guest G4 including the aliphatic part to-
gether with carboxyl group at low pH. In basic conditions,
electrostatic repulsion between carboxylate group and CB7
portal forces the macrocycle to preferentially bind the ter-
minal pyridinium ring instead of the central aliphatic chain.
Therefore, this pseudorotaxane behaves as a molecular
switch where the position of the wheel is controlled by the
pH of the solution.
Acknowledgements
This work was supported by the Grant Agency of the Czech Republic
(P207/10/0695 to VS), the Ministry of Education of the Czech Republic
(LC06030 to PK), and the European Communityꢁs Seventh Framework
Programme (grant agreement no. 205872 to P.K.). Access to the META-
Centrum supercomputing facilities provided under the research intent
MSM6383917201 is highly appreciated.
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Synthesis
1,1’-[2-methyloxycarbonyl-1,4-phenylene-bis(methylene)]dipyridinium di-
bromide (G1). To a solution of 1 (400 mg, 1.2 mmol) in acetonitrile
(50 mL) pyridine (300 mg, 3.7 mmol) was added dropwise. The reaction
mixture was refluxed overnight. The precipitated solid was filtered off
and washed with acetonitrile to obtain a white solid (438 mg, 76%).
1H NMR (300 MHz, D2O): d=9.01 (d, J=6.17, 2H), 8.86 (d, J=6.07,
2H), 8.66 (m, 2H), 8.30 (s, 1H), 8.19 (t, J=7.09, 2H), 8.12 (t, J=7.10,
2H), 7.88 (d, J=7.92, 1H), 7.70 (d, J=6.97, 1H), 6.21 (s, 2H), 6.02 (s,
2H), 3.91 ppm (s, 3H); 13C NMR (75 MHz, D2O): d=167.7, 147.0, 146.6,
145.0, 144.8, 135.8, 134.5, 134.4, 134.2, 133.0, 131.0, 129.2, 128.6, 64.0,
62.8, 53.5 ppm; HRMS-ESI: m/z (%) calcd for C20H20Br2N2O2: 160.0757
[MÀ2BrÀ]2+; found: 160.0771.
1,1’-[2-carboxy-1,4-phenylene-bis(methylene)]dipyridinium
dibromide
(G2). A solution of G1 (0.5 g, 1,04 mmol) in hydrochloric acid (24%,
30 mL) was heated to reflux for 5 h. The mixture was concentrated under
reduced pressure to obtain a slight yellow residue. The residue was
1
washed with diethyl ether to obtain a white solid (0.45 g, 97%). H NMR
(300 MHz, D2O): d=9.02 (d, J=5.88, 2H), 8.86 (d, J=5.90, 2H), 8.65
(m, 2H), 8.14 (m, 5H), 7.83 (d, J=7.79, 1H), 7.69 ppm (d, J=7.94, 1H);
13C NMR (75 MHz, D2O): d=169.3, 146.9, 146.5, 145.0, 144.9, 135.7,
134.3, 134.2, 132.8, 132.0, 129.2, 128.5, 63.9, 62.8 ppm; HRMS-ESI: m/z
(%) calcd for: C19H18Br2N2O2 305.1285 [MÀH+À2BrÀ]+; found:
305.1287.
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(500 mg) was added. The reaction mixture was refluxed for 14 h. The pre-
cipitated oil was decanted and washed with diethyl ether to obtain a pale
brown solid (680 mg, 90%). 1H NMR (300 MHz, D2O): d=8.94 (d, H=
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