Kinetics of formation of the host-guest complex of a viologen with cucurbit[7]uril

Article abstract of DOI:10.1021/ol300911a

Host-guest complexation between the dicationic viologen 1-tri(ethylene glycol)-1′-methyl-m-xylyl-4,4′-bipyridinium and cucurbit[7]uril (CB7) was studied at pH = 4.5 in water. The stability constants of the mono- and bis-CB7 adducts were determined at 25 °C by UV-vis spectroscopy. Stopped-flow kinetic experiments were performed to measure the formation and dissociation rate constants of the monoadduct: k₁ = (6.01 ± 0.03) × 10⁶ M^-1s^-1 and k_-1 = 52.7 ± 0.4 s^-1, respectively. Possible mechanisms of complexation are discussed in view of the kinetic results.

Full text of DOI:10.1021/ol300911a

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3248–3251
Kinetics of Formation of the HostꢀGuest
Complex of a Viologen with Cucurbit[7]uril
Jozsef Kalmar,†,‡ Shawna B. Ellis,† Michael T. Ashby,† and Ronald L. Halterman*,†
ꢀ
ꢀ
Department of Chemistry and Biochemistry, University of Oklahoma, Norman,
Oklahoma 73019, United States, and Department of Inorganic and Analytical
Chemistry, University of Debrecen, Hungary
RHalterman@ou.edu
Received April 9, 2012
ABSTRACT
Hostꢀguest complexation between the dicationic viologen 1-tri(ethylene glycol)-10-methyl-m-xylyl-4,40-bipyridinium and cucurbit[7]uril (CB7) was
studied at pH = 4.5 in water. The stability constants of the mono- and bis-CB7 adducts were determined at 25 °C by UVꢀvis spectroscopy. Stopped-
flow kinetic experiments were performed to measure the formation and dissociation rate constants of the monoadduct: k1 = (6.01 ( 0.03) ꢁ
106 Mꢀ1
s
ꢀ1 and kꢀ1 = 52.7 ( 0.4 sꢀ1, respectively. Possible mechanisms of complexation are discussed in view of the kinetic results.
In recent years, considerable efforts have been made to
design and characterize novel supramolecular systems of
organic dyes in order to develop technologies such as
molecular scale biological probes and sensors.1,2 Recently,
the effect of encapsulation by cucurbit[n]urils (n = 6, 7, 8)
on the photophysical and chemical characteristics of some
common fluorescent dyes were investigated in detail.3ꢀ5
The stability and structure of the inclusion complexes of
cucurbit[n]uril and organic cations6 including bispyridi-
nium (viologen) derivates3,7,8 havebeenextensivelystudied
by experimental (mainly NMR and UVꢀvis spectro-
scopic) and theoretical methods.9
The molecular mechanism of the association and dis-
sociation of the supramolecular complexes were usually
found to comprise several consecutive steps that include
structural rearrangemets.10,11 These steps have been ex-
perimentally studied and discussed in the cases of slow
reactions, when the system could be conveniently moni-
tored by NMR spectroscopy,10,11 and recently in the case
of fast reactions12 using stopped-flow spectroflourimetric
experiments. Herein we report the fast kinetic study of
the formation of the complex of the cucurbit[7]uril (ab-
breviated as CB7; see Figure 1) host with a viologen guest:
1-(methoxy-tri(ethylene glycol))-10-((3,5-dimethylphenyl)-
methyl)-4,40-bipyridinium dication13 (abbreviated as V,
see Figure 1), in a buffered aqueous solution at pH = 4.5.
† University of Oklahoma.
‡ University of Debrecen.
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2008, 73, 3266. (b) Halterman, R. L.; Moore, J. L.; Yakshe, K. A.;
Halterman, J. A. I.; Woodson, K. A. J. Incl. Phenom. Macrocycl. Chem.
2010, 66, 231.
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(8) Xiao, X.; Hu, Q.; Tao, Z.; Zhang, Y. Q.; Xue, S. F.; Zhu, Q. J.;
Wei, G. Chem. Phys. Lett. 2011, 514, 317.
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Theory Comput. 2010, 6, 984.
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2004, 126, 5806.
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Bohne, C. J. Am. Chem. Soc. 2011, 133, 20623.
(13) Preparation and characterization of synthesized compounds are
described in the Supporting Information.
r
10.1021/ol300911a
Published on Web 06/12/2012
2012 American Chemical Society

CB7, a detailed mathematical analysis of the titration data
was carried out with SpecFit/3214 (see details in the SI).15ꢀ17
In the V þ CB7 system, four absorbing components were
found, which means two new species besides V and CB7.
The new species were assigned as the 1:1 and 1:2 V/CB7
complexes (V•CB7 and V•(CB7)2, respectively), and the
spectroscopic data set was fitted to the 1:0 f 1:1 f 1:2
consecutive complexation model in 100 different wave-
lengths (from 240 to 340 nm), simultaneously. As seen at a
selected wavelength in Figure 2 (top panel), the fitted curve
is in good agreement with the experimental points. Con-
sequently, the equilibrium constants were determined to be
K1 = (1.1 ( 0.1) ꢁ 105 Mꢀ1 and K2 = (1.9 ( 0.2) ꢁ 103
Mꢀ1 (for the consecutive formation of V•CB7 and
V•(CB7)2, respectively). The distribution diagram is found
in the SI (Figure S5). Furtheremore, the matrix algebraic
fitting approach provided the molar absorbances of both
V•CB7 and V•(CB7)2 at each wavelength of data input,
enabling the reconstruction of the UV spectra of the
adducts as presented in Figure 2 (bottom panel). The
formation of the V•(CB7)2 type complex is unprecedented.
However, the UVꢀvis titration experiments cannot be de-
scribed by taking only three absorbing species (V, CB7,
and V•CB7) and their equlibria into account, as evident
from the deviation of the corresponding simulation
(Figure 2, top panel: dashed line) and the measured data.
Figure 2 (inset) also demonstrates that the absorbance
increases at high [CB7]0 even if its contribution to the
overall signal is subtracted. To describe V•(CB7)2, we
presume that the first CB7 docks near the more hydro-
phobic xylyl substituted end of the viologen and the
second, more weakly binding CB7 associates near the
ethylene glycol end of the viologen. The gas phase calcu-
lated structures shown in Figure 1 can aid in visualizing the
steric fit of one or two CB7 on the viologen, but the actual
detailed solution structures will be determined by the
additional hydrophobic interactions in these hostꢀguest
complexes. The 1:1 complex V•CB7 was also studied by 1H
NMR spectroscopy, utilizing a competitive binding ap-
proach described earlier,18,19 which allowed the indirect
measurement of the stability constant (see details in the SI:
K1 = (6.9 ( 1.6) ꢁ 105 Mꢀ1). The value of K1 measured by
NMR is reasonably close to that determined by the direct
UVꢀvis titration, considering that the calculations were
based on the 1H NMR spectrum of only one equilibrium
mixture, which introduced a 1 order of magnitude higher
numerical uncertainty compared to the case of the UVꢀvis
Figure 1. (a) Structure of 1-tri(ethylene glycol)-10-methyl-m-
xylyl-4,40-bipyridinium dication (V) and cucurbit[7]uril (CB7).
The counterions of V are Brꢀ (not indicated). (b) Potential
surface plots of mono-CB7-V and bis-CB7-V complexes as
calculated by Spartan 08 (AM-1 gas-phase).
Stopped-flow spectroscopy was used for the kinetic mea-
surements, and ensemble spectroscopic studies, including
1H NMR and UVꢀvis titration experiments, were em-
ployed to further characterize the stability of the hostꢀ
guest system. This guest was chosen in order to probe
the rate of association and dissociation of CB7 as it is
forced to pass along the pseudorotaxane tri(ethylene
glycol) arm to reach the presumed binding site, the
dicationic viologen moiety. The determination of the rate
of passage of CB7 over an extended arm will help inform
the design of shuttle rotaxanes or related nanomolecular
devices.
Viologen V was titrated with CB7 at pH = 4.5 in
aqueous acetate buffer, and the UVꢀvis spectra were
monitored as a function of titrant concentration (Figure 2
and Figure S4 in the Supporting Information (SI)). Two
well separated consecutive steps were identified in the
spectral observations at [V]0 = 12.5 μM and [CB7]0 =
2.5 ꢀ 2000 μM (V/CB7 from 1:0.2 to 1:160). At larger
concentrations of CB7 (>50 μM), its contribution to the
UV absorption was substantial. Therefore, its molar
absorption coefficients were determined in the region of
240ꢀ340 nm and taken into account during data evalua-
tion. In order to determine the binding model of V with
1
titration. The H NMR spectrum of a 1.0 mM CB7 and
(14) SpecFit/32 (from Spectrum Software Associates) is a compre-
hensive software package designed to evaluate spectroscopic titrations
and multiwavelength kinetic data based on user defined chemical
models. The mathematics of the software is based on singular value
decomposition (matrix algebra).
(15) Frans, S. D.; Harris, J. M. Anal. Chem. 1985, 57, 1718.
ꢀ
ꢀ
(16) Peintler, G.; Nagypal, I.; Jancso, A.; Epstein, I. R.; Kustin, K.
J. Phys. Chem. A 1997, 101, 8013.
ꢀ
(17) Peintler, G.; Nagypal, I.; Epstein, I. R.; Kustin, K. J. Phys.
Chem. A 2002, 106, 3899.
(18) Mock, W. L.; Shih, N. Y. J. Org. Chem. 1986, 51, 4440.
(19) Liu, S; Ruspic, C; Mukhopadhyay, P; Chakrabarti, S; Zavalij, P;
Isaacs, L. J. Am. Chem. Soc. 2005, 127, 15959.
Org. Lett., Vol. 14, No. 13, 2012
3249

Figure 3. Kinetics of the formation of the 1:1 hostꢀguest adduct
of V with CB7. (Top panel) Single exponential kinetic curves
recorded at 260 nm (black lines: result of the global fit with the
simple one-step kinetic model). (Bottom panel) The pseudo-
first-order rate constants as the function of the CB7 concentra-
tions. Dots: values for the experimental kinetic curves. Solid
line: results of the global fit with the simple one-step kinetic
model. Dashed line: results of the global fit with the two-step
kinetic model (see details in the SI). [V]0 = 12.5 μM, [CB7]0 =
from 2.5 to 100 μM, pH = 4.5 (acetate buffer), T = 25.0 °C.
Figure 2. UVꢀvis titration of V with CB7. (Top panel) The
titration curve measured at 260 nm (dots: parallel experimental
points; triangles: experiments at high [CB7]0). Continuous line:
fitted curve with the consecutive complexation model (from
SpecFit/32). Dotted line: simulation of the absorbance reading
taking into account the presence of only V, CB7, and their 1:1
adduct in an equilibrium system. (Inset) Triangles: the measured
absorbance reading is corrected with the contribution of CB7 at
high [CB7]0. Continuous line: fitted curve with the consecutive
complexation model (from SpecFit/32). (Bottom panel) UVꢀvis
spectrum of V and the derived (reconstructed from SpecFit/32
fit) UVꢀvis spectra of the 1:1 (V•CB7) and the 1:2 complexes
(V•CB7)2). [V]0 = 12.5 μM, [CB7]0 = from 2.5 to 2000 μM,
pH = 4.5 (acetate buffer), T = 25.0 °C.
(see Figure S5). All the recorded kinetic curves were single
exponential and could be fitted to obtain pseudo-first-
order rate constants (Figure 3). The simplest one-step
kinetic model that describes the stopped-flow data is the
following:
1.0 mM V in unbuffered D2O (Figure S4a in the SI)
exhibited broadened xylyl signals and much less perturbed
ethylene glycol signals as would be consistent with the first
CB7 binding near the xylyl capping group. Addition of a
second equivalent of CB7 broadened all hydrogen signals
in the capping groups, which would be consistent with a
possible second weaker CB7 binding (Figure S4b). Further-
more, weak signals which indicate the presence of V•(CB7)2
were found in the ESI-MS spectrum of the solution of
1 mM V and 2 mM CB7 (Figure S4d and Table S1).
The kinetics and mechanism of the formation of V•CB7
in water were investigated in detail. The rate of formation
of V•CB7 from V and CB7 is on the millisecond time scale.
Therefore, stopped-flow spectrophotometry is required to
study the kinetics. V (25 μM) was mixed with CB7 solutions
of varying concentrations (from 5.0 to 200 μM). For this
concentration range of V and CB7 at pH = 4.5 and 25 °C,
formation of the 1:2 complex V•(CB7)2 is insignificant
The differential rate law and the expression of the equilib-
rium constant for the one-step model are as follows:
d[V]
¼ ꢀk1[V][CB7] þ kꢀ1[V CB7]
ð1Þ
3
dt
[V CB7]Eq
3
[V]Eq[CB7]Eq
k1
K1 ¼
¼
ð2Þ
k
ꢀ1
where square brackets indicate time dependent actual con-
centrations, and [X]Eq is the corresponding equilibrium
(20) Espenson, J. H. Chemical Kinetics and Reaction Mechanisms,
2nd ed.; McGraw-Hill Series in Advanced Chemistry; McGraw-Hill Inc.:
1995; pp 53ꢀ54.
3250
Org. Lett., Vol. 14, No. 13, 2012

concentration under the applied conditions. The integrated
rate law is a single exponential expression when the system is
close to equilibrium20 (see details in the SI):
shown in Figure 3 bottom panel (dashed line). A critical
comparison of the two different kinetic models rules out a
multistep process which occurs on the stopped-flow time
scale (see SI). In other words, the existence of slowly
exchanging multiple isomers of V•CB7 is not supported
by the kinetic results.22 Isomers which exchange in a fast
pre-equilibrium are also excluded.12 The presented meth-
odology cannot rule out the presence of isomers with
similar UVꢀvis spectral properties.
ξ[V CB7]Eq
3
[V] ¼ [V]Eq
þ
exp(ꢀξt)
ð3Þ
ξ þ k1[V CB7]Eq
3
where:
ξ ¼ k1([V]Eq þ [CB7]Eq) þ k
ꢀ1
In summary, the formation of a 1:1 complex of viologen
V with CB7 is assumed to take place in one step; no
evidence was found for a more complicated mechanism
of association and dissociation as has been described in the
case of analogous hostꢀguest systems.10,11 This method of
kinetic analysis not only provided the association equilib-
rium constant with high precision but also gave the first
direct measurement of the rate of association and dissocia-
tion of CB7 from viologen guests. The rate of CB7 passage
over the extended arm is slower than seen for the inclusion
of a compact guest into CB7.12 Analysis of the absorbance
spectral data provides evidence for the consecutive for-
mation of 1:1 (K1 = (1.1 ( 0.1) ꢁ 105 Mꢀ1) and 1:2 (K2 =
(1.9 ( 0.2) ꢁ 103 Mꢀ1) complexes of V•CB7 and V•(CB7)2.
The kinetic curves in Figure 3 were simultaneously
(globally) fitted to eq 3 with the nonlinear Levenbergꢀ
Marquard least-squares method: to give the rate con-
stants k1 = (6.01 ( 0.03) ꢁ 106 Mꢀ1 sꢀ1 and kꢀ1 = 52.7 (
0.4 sꢀ1. The kinetically deduced value of the stability
constant (K1 = k1/k = 1.15 ꢁ 105 Mꢀ1) is in good
ꢀ1
agreement with the results of the UVꢀvis titration.
It is possible to assume that the 1:1 adduct of V and CB7
does not exist as only one stable structure but represents a
mixture of isomers, in which case the different forms
should be in equilibrium with each other. However, as
we mentioned before, the mathematical analysis of the
spectral data obtained during the UVꢀvis titration did not
require the introduction of another absorbing species be-
sides V, V•CB7, and V•(CB7)2. Thus, this does not indicate
the existence of different isomers of V•CB7.15,17 The
kinetic data set was also reinvestigated for evidence to sup-
port the occurrence of additional equilibrium processes.
The re-evaluation of the kinetic data set according to a
kinetic model which incorporates two isomers in equi-
librium for V•CB7 was carried out with the ZiTa software
package.21 The detailed procedures are given in the SI; the
calculated rate constants with the two-step model are
Acknowledgment. Support through the NSF (DMR-
0805233 to R.L.H.; CHE-0911328 to M.T.A.) and from
the University of Oklahoma and Oklahoma State Regents
for Higher Education is appreciated. J.K. is grateful to
Bernadett Biri (University of Debrecen) for the inspiring
discussions.
Supporting Information Available. Detailed experimen-
tal and mathematical procedures, characterization of
viologen V and its complexes. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Peintler, G. ZiTa 5.0. The first use of this comprehensive
chemical kinetics program package was described in: Peintler, G.;
Nagypal, I.; Epstein, I. R. J. Phys. Chem. 1990, 94, 2954.
ꢀ
ꢀ
ꢀ
(22) Kormanyos, B.; Horvath, A. K.; Peintler, G.; Nagypal, I.
J. Phys. Chem. A 2007, 111, 8104.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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